Sample records for polimorfismo pro12ala del

  1. PPARγ2Pro12Ala Polymorphism and Human Health

    PubMed Central

    He, Weimin

    2009-01-01

    The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARγ) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPARγ have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPARγ, Pro12Ala of PPARγ2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPARγ2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPARγ2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPARγ2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies. PMID:19390629

  2. Pro12Ala PPAR γ2 gene polymorphism in PCOS women: the role of compounds regulating satiety.

    PubMed

    Bidzińska-Speichert, Bożena; Lenarcik, Agnieszka; Tworowska-Bardzińska, Urszula; Slęzak, Ryszard; Bednarek-Tupikowska, Grażyna; Milewicz, Andrzej

    2012-03-01

    Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

  3. Evidence for greater oxidative substrate flexibility in male carriers of the Pro 12 Ala polymorphism in PPARgamma2.

    PubMed

    Thamer, C; Haap, M; Volk, A; Maerker, E; Becker, R; Bachmann, O; Machicao, F; Häring, H U; Stumvoll, M

    2002-03-01

    The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene is associated with reduced type 2 diabetes risk and increased insulin sensitivity. It is possible that the oxidative shift from lipid to glucose as a fuel is more efficient in Ala allele carriers. To test this hypothesis, we examined carbohydrate and lipid oxidation by indirect calorimetry in lean, glucose tolerant subjects with (X/Ala, n = 25) and without the Pro12Ala polymorphism (Pro/Pro, n = 73) basally and after insulin stimulation during a 2-hour eugylcaemic hyperinsulinaemic clamp. Insulin sensitivity was non-significantly greater in X/Ala (0.13 +/- 0.01 micromol/kg/min/pM) than in Pro/Pro (0.12 +/- 0.01 micromol/kg/min/pM, p = 0.27). Basally, there were no lipid nor carbohydrate oxidation differences between the groups. Interestingly, the decrease in lipid oxidation during insulin stimulation was significantly greater in male X/Ala (- 0.51 +/- 0.06 mg/kg/min) than in male Pro/Pro (- 0.35 +/- 0.04 mg/kg/min, p = 0.03). No difference was observed in females. Analogously, the change in carbohydrate oxidation in male X/Ala (1.34 +/- 0.2 mg/kg/min) was significantly greater than in male Pro/Pro (1.03 +/- 0.12 mg/kg/min, p = 0.05). The respiratory quotient increased more, but not significantly more, in male X/Ala (0.11 +/- 0.01) than in male Pro/Pro subjects (0.08 +/- 0.01, p = 0.08) but similarly in females. These results indicate that the mechanism by which the Ala allele improves insulin sensitivity might involve enhanced suppression of lipid oxidation permitting more efficient (predominantly non-oxidative) glucose disposal. It is unclear why this could be demonstrated only in males, although gender differences in substrate oxidation are well documented.

  4. Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

    PubMed Central

    Al-Jarallah, Khaled F.; Shehab, Diaa K.; Haider, Mohammad Z.

    2011-01-01

    BACKGROUND AND OBJECTIVES: Peroxisome proliferator–activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association. DESIGN AND SETTING: A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period. PATIENTS AND METHODS: The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading. RESULTS The Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne’s functional index, and radiological grading using Kellgren-Lawrence (K-L) grading. CONCLUSIONS This study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA. PMID:21245597

  5. Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

    PubMed Central

    Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

    2016-01-01

    The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia. PMID:27075119

  6. Breast-Feeding Modulates the Influence of the Peroxisome Proliferator–Activated Receptor-γ (PPARG2) Pro12Ala Polymorphism on Adiposity in Adolescents

    PubMed Central

    Verier, Caroline; Meirhaeghe, Aline; Bokor, Szilvia; Breidenassel, Christina; Manios, Yannis; Molnár, Dénes; Artero, Enrique G.; Nova, Esther; De Henauw, Stefaan; Moreno, Luis A.; Amouyel, Philippe; Labayen, Idoia; Bevilacqua, Noemi; Turck, Dominique; Béghin, Laurent; Dallongeville, Jean; Gottrand, Frédéric

    2010-01-01

    OBJECTIVE The peroxisome proliferator–activated receptor-γ2 (PPARG2) Pro12Ala polymorphism has been associated with a higher BMI and a lower risk of type 2 diabetes in adulthood. The association between adiposity and PPARG variants can be influenced by environmental factors such as early growth, dietary fat, and (as recently shown) breast-feeding. The objectives of this study were to assess 1) the influence of the PPARG2 Pro12Ala polymorphism on adiposity markers in adolescents and 2) a possible modulating effect of breast-feeding on these associations. RESEARCH DESIGN AND METHODS Data on breast-feeding duration, BMI, and genotypes for the Pro12Ala polymorphism were available for 945 adolescents (mean age 14.7 years). The breast-feeding duration was obtained from parental records. We measured weight, height, waist circumference, and six skinfold thicknesses. RESULTS No significant associations between the Pro12Ala polymorphism and any of the above-mentioned anthropometric parameters were found. There were significant interactions between the PPARG2 Pro12Ala polymorphism and breast-feeding with regard to adiposity measurements (all adjusted P < 0.05). Indeed, in children who had not been breast-fed, Ala12 allele carriers had higher adiposity parameters (e.g., Δ BMI +1.88 kg/m2, adjusted for age, sex, and center, P = 0.007) than Pro12Pro adolescents. In contrast, in breast-fed subjects, there was no significant difference between Ala12 allele carriers and Pro12Pro children in terms of adiposity measurements, whatever the duration of breast-feeding. CONCLUSIONS Breast-feeding appears to counter the deleterious effect of the PPARG2 Pro12Ala polymorphism on anthropometric parameters in adolescents. PMID:19846795

  7. Association between the Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 and inflammatory bowel disease: a meta-analysis.

    PubMed

    Zhang, Zhi-Feng; Yang, Ning; Zhao, Gang; Zhu, Lei; Wang, Li-Xia

    2012-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD. Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951-1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852-1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110-5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064-5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899-1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103-5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799-1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population. AlaAla genotype may be a protective factor in the European Caucasian population against the development of CD in a recessive way.

  8. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk.

    PubMed

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I(2) = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I(2) = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I(2) = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I(2) = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I(2) = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I(2) = 51%). In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk.

  9. PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet

    PubMed Central

    Garaulet, Marta; Smith, Caren E; Hernández-González, Teresa; Lee, Yu-Chi; Ordovás, Jose M.

    2014-01-01

    Scope The goal of this study was to examine whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ (PPARγ) is associated with insulin resistance, obesity and weight loss and to analyze potential interactions between fat intake and PPARγ polymorphism in a Spanish overweight/obese population. Materials and methods We recruited 1465 subjects enrolled in a behavioural treatment program for obesity based on a Mediterranean diet, which included the following: dietary treatment, physical activity, nutritional education and behavioral techniques. A significant association was found between PPARγ2 Pro12Ala genotype and plasma insulin concentration and homeostasis model assessment insulin resistance. Subjects with the Ala12 genotype had lower insulin levels than those with the Pro12Pro genotype. We detected a gene–diet interaction between the PPARγ Pro12Ala polymorphism and MUFA for BMI and body fat. Furthermore, we detected an interaction between the PPARγ Pro12Ala polymorphism and fat intake for total weight loss (p<0.001). When total fat intake was high, Ala12-carriers exhibited a significantly lower percentage of total weight loss than major-allele-carriers (p=0.037). Conclusion Data are consistent with previous results showing a protective role for the Ala12 allele against insulin resistance, and replicate an earlier study that detected an interaction between dietary MUFA and PPARγ2 for BMI. Our detection of a gene–diet interaction between PPARγ Pro12Ala and fat intake for weight loss may explain previous discrepancies among different studies. PMID:22102511

  10. Association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma gene and strength athlete status.

    PubMed

    Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Cieszczyk, Pawel; Zarebska, Aleksandra; Sawczyn, Stanislaw

    2013-01-01

    The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ(2) test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni's correction for multiple testing was applied. A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio.

  11. Impact of the Pro12Ala polymorphism of the PPARγ2 gene on diabetes and obesity in a highly consanguineous population

    PubMed Central

    Bener, Abdulbari; Zirie, M; Al-Hamaq, AOAA; Nawaz, Z; Samson, N; Mohammad, R

    2015-01-01

    Background: The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of transcription factors. It has been reported that they play important roles in obesity and the development of type 2 diabetes mellitus (T2DM). Materials and Methods: This case-control study was carried out among 764 Qatari patients with diabetes and 764 healthy subjects above 20 years of age at Primary Healthcare Clinics (PHCs) from January 2011 to December 2012. Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI) and other clinical parameters. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler using two specific probes. Univariate and multivariate statistical analysis were performed. Results: The study revealed that in the diabetes group, Pro/(10.2% vs 9.4%; P = 0.606) and Ala/Ala (1.4% vs 0.9%; P = 0.343) were higher than in controls, whereas Pro/Pro (88.4% vs 89.7%;P = 0.413) was lower in diabetes patients, but no significant difference was observed among the genotype groups. In obese patients with diabetes, Pro/Pro (89% vs 89.9%;P = 0.792) and Pro/Ala (8.9% vs 10.1%;P = 0.671) were lower than in obese healthy subjects. No homozygous Ala/Ala was found in obese healthy subjects, whereas 6 Ala/Ala homozygotes were in obese diabetes group. But in diabetes group, obese patients had higher homozygous of Pro/Pro (89.3% vs 87.8%;P = 0.523) and Ala/Ala (1.8% vs 1.2%;P = 0.771) compared to non-obese patients. Conclusion: The current study did not reveal an association between the Pro12Ala polymorphism of the PPAR γ2 gene and type 2 diabetes (T2D) in Qatari's population. PMID:25593831

  12. Association between the Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor Gamma 2 and Inflammatory Bowel Disease: A Meta-Analysis

    PubMed Central

    Zhao, Gang; Zhu, Lei; Wang, Li-Xia

    2012-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD. Methods and Findings Electronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951–1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852–1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110–5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064–5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899–1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103–5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799–1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population. Conclusion AlaAla genotype may be a protective factor in the European Caucasian population against the

  13. Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala genotype.

    PubMed

    Tok, E C; Aktas, A; Ertunc, D; Erdal, E M; Dilek, S

    2005-06-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism has been suggested as a protective factor for polycystic ovary syndrome (PCOS). In this study, we aimed to investigate metabolic features and reproductive hormones in women with PCOS and compare these features with control women on the basis of Pro12Ala genotype. This study involved 60 randomly selected women with PCOS and 60 controls. Main outcome measures were anthropometric measures, variables of glucose metabolism and reproductive hormones. All the patients were genotyped for Pro12Ala variant of PPAR-gamma2 gene. Patients with Pro12Ala polymorphism were more obese in both groups. Furthermore, they had lower fasting insulin levels, were less insulin-resistant and were less glucose-intolerant as demonstrated by 2 h glucose concentrations. However, there was no difference in reproductive hormone levels on the basis of Pro12Ala genotype. Both control women and women with PCOS had significant differences in glucose metabolism on the basis of PPAR-gamma2 Pro12Ala polymorphism. Pro12Ala variant may break the process that leads to PCOS in susceptible women, instead of being a direct causal relationship between Pro12Ala polymorphism and PCOS.

  14. Impact of the PPAR-γ2 Pro12Ala Polymorphism and ACE Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: Evidence From BENEDICT

    PubMed Central

    De Cosmo, Salvatore; Motterlini, Nicola; Prudente, Sabrina; Pellegrini, Fabio; Trevisan, Roberto; Bossi, Antonio; Remuzzi, Giuseppe; Trischitta, Vincenzo; Ruggenenti, Piero

    2009-01-01

    OBJECTIVE Cross-sectional studies found less microalbuminuria in type 2 diabetic patients with the Ala12 allele of the peroxisome proliferator–activated receptor-γ2 (PPAR-γ2) Pro12Ala polymorphism. We prospectively evaluated the association between Pro12Ala polymorphism (rs1801282) and new-onset microalbuminuria. RESEARCH DESIGN AND METHODS Pro12Ala polymorphism was genotyped by TaqMan-based assay in genomic DNA of 1,119 consenting patients from BErgamo NEphrologic DIabetic Complications Trial (BENEDICT)—a prospective, randomized trial evaluating ACE inhibition effect on new-onset microalbuminuria (albuminuria 20–200 μg/min in at least two of three consecutive overnight urine collections in two consecutive visits) in hypertensive type 2 diabetes with albuminuria <20 μg/min at inclusion. RESULTS Baseline characteristics of Ala (Ala/Ala or Ala/Pro) carriers and Pro/Pro homozygotes were similar, with a nonsignificant trend to lower albuminuria (P = 0.1107) in the 177 Ala carriers. Over a median (interquartile range) of 44.0 (17.1–51.9) months, 7 (4%) Ala carriers and 86 (9.1%) Pro/Pro homozygotes developed microalbuminuria (hazard ratio [HR] 0.45 [95% CI 0.21–0.97]; P = 0.042). Final albuminuria was significantly lower in Ala carriers than Pro/Pro homozygotes (7.3 ± 9.1 vs. 10.5 ± 24.9 μg/min, respectively), even after adjustment for baseline albuminuria (P = 0.048). Baseline and follow-up blood pressure and metabolic control were similar in both groups. Incidence of microalbuminuria was significantly decreased by ACE versus non-ACE inhibitor therapy in Pro/Pro homozygotes (6.3 vs. 11.9%, respectively, HR 0.46 [0.29–0.72]; P < 0.001). CONCLUSIONS In type 2 diabetes, the Ala allele protects from worsening albuminuria and new-onset microalbuminuria, and ACE inhibition blunts the excess risk of microalbuminuria associated with the Pro/Pro genotype. Evaluating Pro12Ala polymorphism may help identifying patients at risk who may benefit the most from

  15. Effects of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ2 gene on metabolic syndrome risk: a meta-analysis.

    PubMed

    Zhang, Ruyi; Wang, Jiao; Yang, Rui; Sun, Jia; Chen, Rongping; Luo, Haizhao; Liu, Duan; Cai, Dehong

    2014-02-01

    Associations between peroxisome proliferator-activated receptor γ2 (PPARγ2) gene polymorphism and metabolic syndrome risk remained controversial and ambiguous. Thus, we performed a meta-analysis to assess the association between Pro12Ala polymorphism in PPARγ2 gene and metabolic syndrome susceptibility. An electronic literature search was conducted on Medline, OVID, Cochrane Library database, and the China National Knowledge Internet up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the fixed or random effects model. Ten studies involving a total of 4456 cases and 10343 controls were included in this meta-analysis. No statistical evidence of association was found between Pro12Ala polymorphism and metabolic syndrome risk in all genetic models (homozygote model: OR=0.83, 95% CI=0.62-1.12; heterozygote model: OR=1.04, 95% CI=0.94-1.14; dominant model: OR=1.02, 95% CI=0.93-1.12; recessive model: OR=0.83, 95% CI=0.62-1.11). No statistical evidence of significant association was observed when stratified by ethnicity, definition of metabolic syndrome, source of control groups and quality score of the selected articles. All in all, the results did not support a major role of the Pro12Ala variant of the PPARγ2 gene in metabolic syndrome risk. This meta-analysis suggested that the effect of Pro12Ala polymorphism in PPARγ2 gene may not be related to metabolic syndrome as an entity. However, Pro12Ala may affect the single component of metabolic syndrome. A large, well designed study is required to more adequately assess the role for Pro12Ala polymorphism on metabolic syndrome. © 2013 Elsevier B.V. All rights reserved.

  16. Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous

    PubMed Central

    Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla OAA; Mohammad, Ramzi M; Yousafzai, Mohammad T

    2013-01-01

    Aim The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. Design A cross-sectional survey conducted from January 2011–December 2012. Setting Primary health care clinics. Subjects A random sample of 1,528 Qatari male and female population older than 20 years of age. Materials and methods Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5′-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5′ LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Result Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12–2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). Conclusion The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar’s population. On the other

  17. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    PubMed Central

    Tariq, Khadija; Malik, Saira Bano; Ali, Syeda Hafiza Benish; Maqsood, Sundas Ejaz; Azam, Aisha; Muslim, Irfan; Khan, Muhammad Shakil; Azam, Maleeha; Waheed, Nadia Khalida

    2013-01-01

    Purpose The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. Methods A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Results We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33–0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2–0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37–1.19). Conclusions We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan. PMID:23559865

  18. Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study.

    PubMed

    Ruchat, S-M; Rankinen, T; Weisnagel, S J; Rice, T; Rao, D C; Bergman, R N; Bouchard, C; Pérusse, L

    2010-04-01

    Exercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme. We analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes. The only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Deltaglucose disappearance index Ala/Ala 0.22 +/- 0.22, Pro/Ala 0.14 +/- 0.06, Pro/Pro 0.004 +/- 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 +/- 0.41, Pro/Ala 0.44 +/- 0.14, Pro/Pro 0.09 +/- 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 +/- 37.73, Pro/Ala -11.92 +/- 40.30, Pro/Pro -46.30 +/- 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 +/- 448.5, Pro/Ala 534.6 +/- 218.3, Pro/Pro -7.44 +/- 88.18; p = 0.003). Compared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.

  19. Meta-analysis of association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 gene and diabetic retinopathy in Caucasians and Asians.

    PubMed

    Ma, Jinlan; Li, Yan; Zhou, Fang; Xu, Xiaoyi; Guo, Gang; Qu, Yi

    2012-01-01

    The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) gene is reported to be associated with diabetes. However, the gene's association with diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) has been investigated in numerous epidemiologic studies with controversial results. This meta-analysis aimed to collectively assess the association of the Pro12Ala polymorphism with DR in T2DM. An electronic literature search was conducted on PubMed, ISI Web of Knowledge, EMBASE, and the China National Knowledge Internet. A dominant model [(Pro/Ala +Ala/Ala) versus Pro/Pro] was used to ensure adequate statistical power. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effect model. Potential sources of heterogeneity and bias were explored. This meta-analysis included genotype data from 2,720 cases with DR and 2,450 controls free of DR from eight eligible publications. The results showed the Ala allele had a protective effect on DR in T2DM (OR=0.81; 95% CI: 0.68-0.98, p=0.03). There was no significant evidence against homogeneity (I(2)=46%, P(heterogeneity)=0.07). The sensitivity analysis showed a robust association of the Pro12Ala polymorphism with DR in T2DM after a study involving Caucasians that presented a big effect on heterogeneity (OR=0.75; 95% CI: 0.62-0.91, p=0.003) was excluded. Possible ethnic differences in the association of the Pro12Ala single nucleotide polymorphism and DR were demonstrated; a significant association was illustrated in the Caucasian subgroup (OR=0.74; 95% CI: 0.59-0.94, p=0.01) but was not found in the Asian subgroup (OR=0.77; 95% CI: 0.55-1.07, p=0.12). No publication bias was observed. This meta-analysis suggested a significant association exists between the Pro12Ala polymorphism and DR in T2DM with ethnic differences. The Ala allele had a significant protective effect against DR in T2DM.

  20. Meta-analysis of association between the Pro12Ala polymorphism of the peroxisome proliferator–activated receptor-γ2 gene and diabetic retinopathy in Caucasians and Asians

    PubMed Central

    Ma, Jinlan; Li, Yan; Zhou, Fang; Xu, Xiaoyi; Guo, Gang

    2012-01-01

    Purpose The Pro12Ala polymorphism of the peroxisome proliferator–activated receptor-γ2 (PPARγ2) gene is reported to be associated with diabetes. However, the gene’s association with diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) has been investigated in numerous epidemiologic studies with controversial results. This meta-analysis aimed to collectively assess the association of the Pro12Ala polymorphism with DR in T2DM. Methods An electronic literature search was conducted on PubMed, ISI Web of Knowledge, EMBASE, and the China National Knowledge Internet. A dominant model [(Pro/Ala +Ala/Ala) versus Pro/Pro] was used to ensure adequate statistical power. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed effect model. Potential sources of heterogeneity and bias were explored. Results This meta-analysis included genotype data from 2,720 cases with DR and 2,450 controls free of DR from eight eligible publications. The results showed the Ala allele had a protective effect on DR in T2DM (OR=0.81; 95% CI: 0.68–0.98, p=0.03). There was no significant evidence against homogeneity (I2=46%, Pheterogeneity=0.07). The sensitivity analysis showed a robust association of the Pro12Ala polymorphism with DR in T2DM after a study involving Caucasians that presented a big effect on heterogeneity (OR=0.75; 95% CI: 0.62–0.91, p=0.003) was excluded. Possible ethnic differences in the association of the Pro12Ala single nucleotide polymorphism and DR were demonstrated; a significant association was illustrated in the Caucasian subgroup (OR=0.74; 95% CI: 0.59–0.94, p=0.01) but was not found in the Asian subgroup (OR=0.77; 95% CI: 0.55–1.07, p=0.12). No publication bias was observed. Conclusions This meta-analysis suggested a significant association exists between the Pro12Ala polymorphism and DR in T2DM with ethnic differences. The Ala allele had a significant protective effect against DR in T2DM. PMID:22993484

  1. Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome.

    PubMed

    Baldani, Dinka Pavicic; Skrgatic, Lana; Cerne, Jasmina Z; Ferk, Polonca; Simunic, Velimir; Gersak, Ksenija

    2014-03-01

    Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity.

  2. Association between the Peroxisome proliferator-activated receptor-gamma Pro12Ala Variant and Haplotype and Pancreatic Cancer in a High-Risk Cohort of Smokers: A Pilot Study

    PubMed Central

    Fesinmeyer, Megan Dann; Stanford, Janet L.; Brentnall, Teresa A.; Mandelson, Margaret T.; Farin, Federico M.; Srinouanprachanh, Sengkeo; Afsharinejad, Zahra; Goodman, Gary E.; Barnett, Matt J.; Austin, Melissa A.

    2010-01-01

    Objectives The Pro12Ala variant in the proliferator-activated receptor-gamma (PPARG) gene has been associated with diabetes and several cancers. This pilot study tested for the association between Pro12Ala and pancreatic cancer risk in a high-risk sample of smokers. Methods A nested case-control study was conducted in 83 incident cases of pancreatic cancer and 166 matched controls originally recruited into a cohort chemoprevention study of lung cancer. Associations between Pro12Ala and pancreatic cancer risk were measured using conditional logistic regression. Results Carriers of the G allele (Ala) of the Pro12Ala variant had a borderline increased relative risk of pancreatic cancer compared to homozygous carriers of the C allele (Pro), with an odds ratio (OR) of 1.79 (95% confidence interval (CI): 0.96–3.33, p-value: 0.06). Among subjects randomized to high-dose vitamin A, the OR was 2.80 (95: CI: 1.16–6.74, p-value 0.02) versus 1.20 (95% CI: 0.45–3.23, p-value 0.71) in the placebo group. A haplotype including Pro12Ala was also significantly associated with pancreatic cancer risk in all subjects and in subjects randomized to vitamin A. Conclusions This analysis presents the first evidence that PPARG may be associated with pancreatic cancer risk, and this candidate gene should be investigated in future, larger studies. PMID:19436234

  3. Association of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 with decreased basic metabolic rate in women with polycystic ovary syndrome.

    PubMed

    Koika, Vasiliki; Marioli, Dimitra J; Saltamavros, Alexandros D; Vervita, Vasiliki; Koufogiannis, Kleanthis D; Adonakis, George; Decavalas, George; Georgopoulos, Neoklis A

    2009-08-01

    The peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor involved in glucose homeostasis and energy metabolism. A missense mutation at codon 12 in the PPARgamma2 has been associated with increased body mass index (BMI) and attenuated insulin resistance (IR) in polycystic ovary syndrome (PCOS). We have recently shown a decreased basic metabolic rate (BMR) in PCOS. The aim of the present study is to determine the prevalence of the Pro12Ala polymorphism of the PPARgamma2 gene and its associations with indices of IR and BMR in lean and slightly overweight PCOS women. Case-control association study involving 156 PCOS women with biochemical hyperandrogenism, chronic anovulation and polycystic ovarian morphology in ultrasound and 56 unrelated healthy controls. Hormonal determinations were performed by electrochemiluminescence quantitation or RIA. BMR was measured by indirect calorimetry. All subjects were genotyped by a PCR-restriction fragment length polymorphism assay. Genotype frequencies of the Pro12Ala polymorphism in PPARgamma2 did not differ among PCOS women and control subjects. The presence of Pro12Ala polymorphism of PPARgamma2 was associated with lower BMR (P=0.04). This finding was valid in our subgroup of lean PCOS (BMI<25 kg/m(2)), in which the Ala variant was also associated with higher total testosterone values. The Pro12Ala polymorphism in the PPARgamma2 gene is associated with decreased BMR in women with PCOS and biochemical hyperandrogenemia. These young women are therefore at risk to increase their body weight and should restrict their energy intake by diet and enhance their energy expenditure by exercise.

  4. Towards Understanding the Tandem Mass Spectra of Protonated Oligopeptides. 2: The Proline Effect in Collision-Induced Dissociation of Protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp)

    NASA Astrophysics Data System (ADS)

    Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G.; Paizs, Béla

    2011-06-01

    The product ion spectra of proline-containing peptides are commonly dominated by y n ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y 2 ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y 2 / b 3 abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y 2 / b 3 abundance ratio decreases.

  5. Towards understanding the tandem mass spectra of protonated oligopeptides. 2: The proline effect in collision-induced dissociation of protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp).

    PubMed

    Bleiholder, Christian; Suhai, Sándor; Harrison, Alex G; Paizs, Béla

    2011-06-01

    The product ion spectra of proline-containing peptides are commonly dominated by y(n) ions generated by cleavage at the N-terminal side of proline residues. This proline effect is investigated in the current work by collision-induced dissociation (CID) of protonated Ala-Ala-Xxx-Pro-Ala (Xxx includes Ala, Ser, Leu, Val, Phe, and Trp) in an electrospray/quadrupole/time-of-flight (QqTOF) mass spectrometer and by quantum chemical calculations on protonated Ala-Ala-Ala-Pro-Ala. The CID spectra of all investigated peptides show a dominant y(2) ion (Pro-Ala sequence). Our computational results show that the proline effect mainly arises from the particularly low threshold energy for the amide bond cleavage N-terminal to the proline residue, and from the high proton affinity of the proline-containing C-terminal fragment produced by this cleavage. These theoretical results are qualitatively supported by the experimentally observed y(2)/b(3) abundance ratios for protonated Ala-Ala-Xxx-Pro-Ala (Xxx = Ala, Ser, Leu, Val, Phe, and Trp). In the post-cleavage phase of fragmentation the N-terminal oxazolone fragment with the Ala-Ala-Xxx sequence and Pro-Ala compete for the ionizing proton for these peptides. As the proton affinity of the oxazolone fragment increases, the y(2)/b(3) abundance ratio decreases.

  6. Lack of association between the Pro12Ala polymorphism of the PPAR-gamma 2 gene and type 2 diabetes mellitus in the Qatari consanguineous population.

    PubMed

    Badii, Ramin; Bener, Abdulbari; Zirie, Mahmoud; Al-Rikabi, Ammar; Simsek, Mehmet; Al-Hamaq, Abdulla O A A; Ghoussaini, Maya; Froguel, Philippe; Wareham, Nick J

    2008-03-01

    Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma 2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma 2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro12Ala polymorphism in PPAR gamma 2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro12Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro12Ala polymorphism in PPAR gamma 2 gene and the type 2 diabetes in Qatar.

  7. The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucose/insulin metabolism interact with prenatal exposure to famine.

    PubMed

    de Rooij, Susanne R; Painter, Rebecca C; Phillips, David I W; Osmond, Clive; Tanck, Michael W T; Defesche, Joep C; Bossuyt, Patrick M M; Michels, Robert P J; Bleker, Otto P; Roseboom, Tessa J

    2006-05-01

    An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

  8. Association of Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor gamma 2 (PPARγ2) Gene with Type 2 Diabetes Mellitus in Ethnic Kashmiri Population.

    PubMed

    Majid, Misbah; Masood, Akbar; Kadla, Showkat Ahmad; Hameed, Iqra; Ganai, Bashir A

    2017-02-01

    Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia associated with insulin resistance and relative insulin deficiency. T2DM is believed to be attributable to the combined effect of genetic and environmental factors. Peroxisome proliferator-activated receptor gamma 2 (PPARγ2) is one of the main candidate genes that are implicated in T2DM. A common proline 12 alanine (Pro12Ala) polymorphism in PPARγ2 has been shown to be associated with T2DM. The aim of this work was to investigate the possible role of PPARγ2 gene polymorphism, as a genetic risk factor for T2DM. The study comprised 200 ethnic unrelated subjects (100 T2DM patients and 100 controls). PCR-RFLP technique was used for genotyping analysis. The frequency of the Pro allele was 79 and 91.5 % for controls and cases, respectively (P < 0.05; OR 3.2; 95 % CI 1.64-6.3). The Pro12Ala polymorphism was in Hardy-Weinberg equilibrium in both patients and controls (χ 2  = 0.13, P > 0.05). We found a significant association of Pro12Ala polymorphism of PPARγ2 gene with T2DM, however the genotypes showed statistically significant association only with few clinical parameters including body mass index, total cholesterol, and low-density lipoprotein (P < 0.05). The study signifies that Pro allele in PPARγ2 may be a genotypic risk factor that confers susceptibility to T2DM in ethnic Kashmiri population.

  9. Controlled self-assembling structures of ferrocene-dipeptide conjugates composed of Ala-Pro-NHCH2CH2SH chain.

    PubMed

    Moriuchi, Toshiyuki; Nishiyama, Taiki; Tayano, Yoshiki; Hirao, Toshikazu

    2017-12-01

    Bioorganometallic ferrocene-dipeptide conjugates with the Ala-Pro-cysteamine chain, Fc-L-Ala-L-Pro-NHCH 2 CH 2 SH (2) and Fc-L-Ala-D-Pro-NHCH 2 CH 2 SH (4) (Fc=ferrocenoyl), were prepared by the reduction of the ferrocene-dipeptide conjugates, Fc-L-Ala-L-Pro-cystamine-L-Pro-L-Ala-Fc (1) or Fc-L-Ala-D-Pro-cystamine-D-Pro-L-Ala-Fc (3), respectively. Control of the self-assembling structures of the ferrocene-dipeptide conjugates was demonstrated by changing the chirality of the amino acid. The molecular structure of 2 composed of the L-Ala-L-Pro-NHCH 2 CH 2 SH chain confirmed the formation of intramolecular hydrogen bond of N-H⋯N pattern between the NH of cysteamine moiety and the nitrogen of Pro moiety. Furthermore, intermolecular hydrogen bonds between NH (Ala) and CO (Pro of another molecule) and between NH (cysteamine) and CO (the ferrocenoyl moiety of another molecule) were formed, wherein each molecule is connected to four neighboring molecules by continuous intermolecular hydrogen bonds to form the hydrogen-bonded molecular assembling structure. On the contrary, the left-handed helical assembly through an intermolecular hydrogen-bonding network of 15-membered intermolecularly hydrogen-bonded ring between NH (Ala) and CO (the ferrocenoyl moiety of another molecule) and between NH (the cysteamine moiety of another molecule) and CO (Ala) was observed in the crystal packing of 4 composed of the L-Ala-D-Pro-NHCH 2 CH 2 SH chain. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Effect of the PPARG2 Pro12Ala Polymorphism on Associations of Physical Activity and Sedentary Time with Markers of Insulin Sensitivity in Those with an Elevated Risk of Type 2 Diabetes.

    PubMed

    Yates, Thomas; Davies, Melanie J; Henson, Joseph; Edwardson, Charlotte; Webb, David; Bodicoat, Danielle H; Webb, M'Balu; Howard, Philip; Cooper, Jackie A; Humphries, Steve E; Khunti, Kamlesh; Talmud, Philippa

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is an important regulator of metabolic health and a common polymorphism in the PPAR-γ2 gene (PPARG2) may modify associations between lifestyle behaviour and health. To investigate whether the PPARG2 Pro12Ala genotype modifies the associations of sedentary behaviour and moderate-to-vigorous intensity physical activity (MVPA) with common measures of insulin sensitivity. Participants with a high risk of impaired glucose regulation were recruited, United Kingdom, 2010-2011. Sedentary and MVPA time were objectively measured using accelerometers. Fasting and 2-hour post-challenge insulin and glucose were assessed; insulin sensitivity was calculated using Matsuda-ISI and HOMA-IS. DNA was extracted from whole blood. Linear regression examined associations of sedentary time and MVPA with insulin sensitivity and examined interactions by PPARG2 Pro12Ala genotype. 541 subjects were included (average age = 65 years, female = 33%); 18% carried the Ala12 allele. Both sedentary time and MVPA were strongly associated with HOMA-IS and Matsuda-ISI after adjustment for age, sex, ethnicity, medication, smoking status and accelerometer wear time. After further adjustment for each other and BMI, only associations with Matsuda-ISI were maintained. Every 30 minute difference in sedentary time was inversely associated with a 4% (0, 8%; p = 0.043) difference in Matsuda-ISI, whereas every 30 minutes in MVPA was positively associated with a 13% (0, 26%; p = 0.048) difference. The association of MVPA with Matsuda-ISI was modified by genotype (p = 0.005) and only maintained in Ala12 allele carriers. Conversely, sedentary time was not modified by genotype and remained inversely associated with insulin sensitivity in Pro12 allele homozygotes. The association of MVPA with Matsuda-ISI was modified by PPARG2 Pro12Ala genotype with significant associations only observed in the 18% of the population who carried the Ala12 allele, whereas

  11. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population

    PubMed Central

    Rooki, Hassan; Haerian, Monir-Sadat; Azimzadeh, Pedram; Ebrahimi, Mahmoud; Mirhafez, Reza; Ferns, Gordon; Ghayour-Mobarhan, Majid; Zali, Mohammad-Reza

    2013-01-01

    BACKGROUND: Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. MATERIALS AND METHODS: Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. RESULTS: The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. CONCLUSIONS: Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences. PMID:24497707

  12. Impact of GNB3-C825T, ADRB3-Trp64Arg, UCP2-3′UTR 45 bp del/ins, and PPARγ-Pro12Ala Polymorphisms on Bofutsushosan Response in Obese Subjects: A Randomized, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Park, Junghyun; Bose, Shambhunath; Hong, Sun-Woo; Lee, Dong-Ki; Yoo, Jae-Wook; Lim, Chi-Yeon; Lee, Myeongjong

    2014-01-01

    Abstract Obesity is known to be influenced by a number of genes, including the β3 subunit of G protein (GNB3), β3-adrenergic receptor (ADRB3), uncoupling protein 2 (UCP2), and peroxisome proliferator activated receptor gamma (PPARγ). The single nucleotide polymorphisms (SNPs) of the above genes, such as GNB3-C825T, ADRB3-Trp64Arg, UCP2-3′UTR 45 bp del/ins, and PPARγ-Pro12Ala, are associated with obesity and body mass index. The present study evaluates the impact of Bofutsushosan, a traditional Eastern Asian herbal medicine with known anti-obesity properties, on obese subjects according to the presence of the above-mentioned SNPs. Upon randomization, the volunteers were allocated to receive Bofutsushosan (n=55) or placebo (n=56) treatments for 8 weeks. Following the treatment schedule, significant reductions in total cholesterol and significant improvement in the Korean version of obesity-related quality of life scale were seen in the Bofutsushosan-treated group, but not in placebo. Bofutsushosan exerted significant anti-obesity effects on a number of parameters in the carriers of the GNB3-825T allele, but only on waist circumference in the GNB3-C/C homozygote. Significant anti-obesity impact of Bofutsushosan was also seen on a number of obesity-indices in both ADRB3-Arg64 carriers and ADRB3-Trp64 homozygotes, as well as in UCP2-D/D carriers, but not in UCP2-D/I+I/I variants. The effect of Bofutsushosan was more pronounced in PPARγ-Pro/Pro genotype compared to PPARγ-Pro/Ala variants. Thus, the results revealed differential responses of the subjects to the anti-obesity effects of Bofutsushosan treatment according to the polymorphism of the vital obesity-related genes. Our study provides new insight into individualized clinical applications of Bofutsushosan for obesity. PMID:24827746

  13. The association between the Pro12Ala variant in the PPARγ2 gene and type 2 diabetes mellitus and obesity in a Chinese population.

    PubMed

    Wang, Xia; Liu, Jun; Ouyang, Yingying; Fang, Min; Gao, Hui; Liu, Liegang

    2013-01-01

    Conflicting results have been reported on the association of the Pro12Ala polymorphism of the PPARγ2 gene with the risk of type 2 diabetes or obesity. A total of 3146 subjects with 1145 cases of type 2 diabetes and 2001 healthy controls were included in the study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using an allelic discrimination assay-by-design TaqMan method. Overall, the Ala allele frequency was 5.6% in control subjects and 3.9% in diabetes subjects (P = 0.023). We found a statistically significant association of carriers of the Ala allele with greater homoeostasis model assessment of beta cell function index in all subjects (P = 0.046). After controlling for confounders, carriers of the Ala allele had a decreased risk of diabetes compared with noncarriers [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.49-0.83; P = 0.001]. A beneficial effect of the Ala allele was also observed for obesity (OR 0.64, 95% CI 0.42-0.96; P = 0.030). Our results suggested that the presence of the Ala allele may contribute to improved insulin secretory capacity and may confer protection from type 2 diabetes and obesity in the Chinese population.

  14. Characterization of the Ala62Pro polymorphic variant of human cytochrome P450 1A1 using recombinant protein expression

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

    Lee, Seung Heon; Kang, Sukmo; Dong, Mi Sook

    2015-06-15

    Cytochrome P450 (CYP) 1A1 is a heme-containing enzyme involved in detoxification of hydrophobic pollutants. Its Ala62Pro variant has been identified previously. Ala62 is located in α-helix A of CYP1A1. Residues such as Pro and Gly are α-helix breakers. In this study, the Ala62Pro variant was characterized using heterologous expression. E. coli expressing the Ala62Pro variant, and the purified variant protein, had lower CYP (i.e. holoenzyme) contents than their wild-type (WT) equivalents. The CYP variant from E. coli and mammalian cells exhibited lower 7-ethoxyresorufin O-dealkylation (EROD) and benzo[a]pyrene hydroxylation activities than the WT. Enhanced supplementation of a heme precursor during E.more » coli culture did not increase CYP content in E. coli expressing the variant, but did for the WT. As for Ala62Pro, E. coli expressing an Ala62Gly variant had a lower CYP content than the WT counterpart, but substitution of Ala62 with α-helix-compatible residues such as Ser and Val partially recovered the level of CYP produced. Microsomes from mammalian cells expressing Ala62Pro and Ala62Gly variants exhibited lower EROD activities than those expressing the WT or Ala62Val variant. A region harboring α-helix A has interactions with another region containing heme-interacting residues. Site-directed mutagenesis analyses suggest the importance of interactions between the two regions on holoenzyme expression. Together, these findings suggest that the Ala62Pro substitution leads to changes in protein characteristics and function of CYP1A1 via structural disturbance of the region where the residue is located. - Highlights: • Ala62 is located in α-helix A of the carcinogen-metabolizing enzyme CYP1A1. • Pro acts as an α-helix breaker. • A variant protein of CYP1A1, Ala62Pro, had lower heme content than the wild-type. • The variant of CYP1A1 had lower enzyme activities than the wild-type.« less

  15. The 482Ser of PPARGC1A and 12Pro of PPARG2 Alleles Are Associated with Reduction of Metabolic Risk Factors Even Obesity in a Mexican-Mestizo Population.

    PubMed

    Vázquez-Del Mercado, Mónica; Guzmán-Ornelas, Milton-Omar; Corona Meraz, Fernanda-Isadora; Ríos-Ibarra, Clara-Patricia; Reyes-Serratos, Eduardo-Alejandro; Castro-Albarran, Jorge; Ruíz-Quezada, Sandra-Luz; Navarro-Hernández, Rosa-Elena

    2015-01-01

    The aim of this study was to investigate the relationship between functional polymorphisms Gly482Ser in PPARGC1A and Pro12Ala in PPARG2 with the presence of obesity and metabolic risk factors. We included 375 individuals characterized as Mexican-Mestizos and classified by the body mass index (BMI). Body dimensions and distribution of body fat were measured. The HOMA-IR and adiposity indexes were calculated. Adipokines and metabolic profile quantification were performed by ELISA and routine methods. Genetic polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism analysis. A difference between obese and nonobese subjects in polymorphism PPARGC1A distribution was observed. Among obese individuals, carriers of genotype 482Gly/Gly were observed to have decreased body fat, BMI, and body fat ratio versus 482Ser/Ser carriers and increased resistin and leptin levels in carriers Gly+ phenotype versus Gly- phenotype. Subjects with PPARG2 Ala- phenotype (genotype 12Pro/Pro) showed a decreased HOMA-IR index versus individuals with Ala+ phenotype (genotypes 12Pro/Ala plus 12Ala/Ala). We propose that, in obese Mexican-Mestizos, the combination of alleles 482Ser in PPARGC1A and 12Pro in PPARG2 represents a reduced metabolic risk profile, even when the adiposity indexes are increased.

  16. The 482Ser of PPARGC1A and 12Pro of PPARG2 Alleles Are Associated with Reduction of Metabolic Risk Factors Even Obesity in a Mexican-Mestizo Population

    PubMed Central

    Vázquez-Del Mercado, Mónica; Guzmán-Ornelas, Milton-Omar; Corona Meraz, Fernanda-Isadora; Ríos-Ibarra, Clara-Patricia; Reyes-Serratos, Eduardo-Alejandro; Castro-Albarran, Jorge; Ruíz-Quezada, Sandra-Luz; Navarro-Hernández, Rosa-Elena

    2015-01-01

    The aim of this study was to investigate the relationship between functional polymorphisms Gly482Ser in PPARGC1A and Pro12Ala in PPARG2 with the presence of obesity and metabolic risk factors. We included 375 individuals characterized as Mexican-Mestizos and classified by the body mass index (BMI). Body dimensions and distribution of body fat were measured. The HOMA-IR and adiposity indexes were calculated. Adipokines and metabolic profile quantification were performed by ELISA and routine methods. Genetic polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism analysis. A difference between obese and nonobese subjects in polymorphism PPARGC1A distribution was observed. Among obese individuals, carriers of genotype 482Gly/Gly were observed to have decreased body fat, BMI, and body fat ratio versus 482Ser/Ser carriers and increased resistin and leptin levels in carriers Gly+ phenotype versus Gly− phenotype. Subjects with PPARG2 Ala− phenotype (genotype 12Pro/Pro) showed a decreased HOMA-IR index versus individuals with Ala+ phenotype (genotypes 12Pro/Ala plus 12Ala/Ala). We propose that, in obese Mexican-Mestizos, the combination of alleles 482Ser in PPARGC1A and 12Pro in PPARG2 represents a reduced metabolic risk profile, even when the adiposity indexes are increased. PMID:26185753

  17. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12

    PubMed Central

    Landouré, Guida; Zhu, Peng-Peng; Lourenço, Charles M.; Johnson, Janel O.; Toro, Camilo; Bricceno, Katherine V.; Rinaldi, Carlo; Meilleur, Katherine G.; Sangaré, Modibo; Diallo, Oumarou; Pierson, Tyler M.; Ishiura, Hiroyuki; Tsuji, Shoji; Hein, Nichole; Fink, John K.; Stoll, Marion; Nicholson, Garth; Gonzalez, Michael; Speziani, Fiorella; Dürr, Alexandra; Stevanin, Giovanni; Biesecker, Leslie G.; Accardi, John; Landis, Dennis M. D.; Gahl, William A.; Traynor, Bryan J.; Marques, Wilson; Züchner, Stephan; Blackstone, Craig; Fischbeck, Kenneth H.; Burnett, Barrington G.

    2013-01-01

    We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly-conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. PMID:23857908

  18. The novel endomorphin degradation blockers Tyr-Pro-DClPhe-Phe-NH (EMDB-1) and Tyr-Pro-Ala-NH (EMDB-2) prolong endomorphin-2 action in rat ileum in vitro.

    PubMed

    Fichna, Jakub; Perlikowska, Renata; Gach, Katarzyna; do-Rego, Jean-Claude; Cravezic, Aurore; Janecka, Anna; Storr, Martin A

    2010-07-01

    The endogenous opioid system is involved in the control of gastrointestinal (GI) motility. The potential use of endogenous MOR ligands, endomorphins (EMs), as therapeutics is limited because of their rapid enzymatic degradation and short duration of action. Targeting enzymatic degradation is an approach to prolong EM activity. In the present study, we characterized the effects of novel blockers of EM degradation in GI tissue preparation in vitro. The effects of actinonin, diprotin A (DIP) and the novel peptide EM degradation blockers Tyr-Pro-DClPhe-Phe-NH(2) (EMDB-1), Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3) on EM-2-mediated inhibition of electrically induced cholinergic twitch contractions were compared in rat ileum in vitro using an organ bath. EMDB-1 and EMDB-2 significantly prolonged the inhibitory effect of EM-2 on smooth muscle contractility in rat ileum. EMDB-2 extended the EM-2 action for up to 60 min compared to 10 min in controls and was more potent than the conventional peptidase inhibitor DIP. EMDB-1 and EMDB-2 are potent EM degradation blockers, which prolong the inhibitory effects of EM-2 on smooth muscle contractility in rat ileum. These novel compounds may be of future use when targeting the endogenous opioid system in the treatment of GI motility disorders such as diarrhea.

  19. Vibrational and chiroptical spectroscopic characterization of gamma-turn model cyclic tetrapeptides containing two beta-Ala residues.

    PubMed

    Vass, Elemér; Majer, Zsuzsa; Kohalmy, Krisztina; Hollósi, Miklós

    2010-08-01

    The optical spectroscopic characterization of gamma-turns in solution is uncertain and their distinction from beta-turns is often difficult. This work reports systematic ECD and vibrational circular dichroism (VCD) spectroscopic studies on gamma-turn model cyclic tetrapeptides cyclo(Ala-beta-Ala-Pro-beta-Ala) (1), cyclo(Pro-beta-Ala-Pro-beta-Ala) (2) and cyclo(Ala-beta-Ala-Ala-beta-Ala) (3). Conformational analysis performed at the 6-31G(d)/B3LYP level of theory using an adequate PCM solvent model predicted one predominant conformer for 1-3, featuring two inverse gamma-turns. The ECD spectra in ACN of 1 and 2 are characterized by a negative n-->pi* band near 230 nm and a positive pi-->pi* band below 200 nm with a long wavelength shoulder. The ECD spectra in TFE of 1-3 show similar spectra with blue-shifted bands. The VCD spectra in ACN-d(3) of 1 and 2 show a +/-/+/- amide I sign pattern resulting from four uncoupled vibrations in the case of 1 and a sequence of two positive couplets in the case of 2. A -/+/+/- amide I VCD pattern was measured for 3 in TFE-d(2). All three peptides give a positive couplet or couplet-like feature (+/-) in the amide II region. VCD spectroscopy, in agreement with theoretical calculations revealed that low frequency amide I vibrations (at approximately 1630 cm(-1) or below) are indicative of a C(7) H-bonded inverse gamma-turns with Pro in position 2, while gamma-turns encompassing Ala absorb at higher frequency (above 1645 cm(-1)). Copyright 2010 Wiley-Liss, Inc.

  20. The conformation of cyclo(-D-Pro-Ala4-) as a model for cyclic pentapeptides of the DL4 type.

    PubMed

    Heller, Markus; Sukopp, Martin; Tsomaia, Natia; John, Michael; Mierke, Dale F; Reif, Bernd; Kessler, Horst

    2006-10-25

    The conformation of the cyclic pentapeptide cyclo(-D-Pro-Ala(4)-) in solution and in the solid state was reinvestigated using modern NMR techniques. To allow unequivocal characterization of hydrogen bonds, relaxation behavior, and intramolecular distances, differently labeled isotopomers were synthesized. The NMR results, supported by extensive MD simulations, demonstrate unambiguously that the preferred conformation previously described by us, but recently questioned, is indeed correct. The validation of the conformational preferences of this cyclic peptide is important given that this system is a template for several bioactive compounds and for controlled "spatial screening" for the search of bioactive conformations.

  1. Interactions of the PPARγ2 polymorphism with fat intake affecting energy metabolism and nutritional outcomes in obese women.

    PubMed

    Rosado, Eliane L; Bressan, Josefina; Martínez, J Alfredo; Marques-Lopes, Iva

    2010-01-01

    To determine the influence of the Pro12Ala polymorphism of the PPARγ2 gene and the dietary lipid intake on energy metabolism and nutritional outcomes in obese women after an acute fat load or following a low-calorie diet for 10 weeks. Sixty obese women (aged 30-46 years) participated in the study and were assigned to 2 groups depending on the genotype: Pro12Pro and Pro12Ala/Ala12Ala carriers. At baseline and after 2 nutritional (short- or long-term) interventions, measurement of anthropometrical and body composition (bioelectrical impedance) variables, dietary assessments, energy metabolism (indirect calorimetry) measurements as well as biochemical and molecular (PPARγ2 genotype) analyses were performed. All women received a high-fat test meal to determine the postprandial metabolism (short term) and an energy-restricted diet for 10 weeks (long term). The frequencies of the Pro12Pro and Pro12Ala/Ala12Ala genotypes were 83.33 and 16.67%, respectively, and reached Hardy-Weinberg equilibrium. Interestingly, the postprandial energy expenditure after the fat load was higher in subjects carrying the Ala allele. At baseline, the habitual monounsaturated fatty acid (MUFA) intake inversely correlated with fat oxidation and body mass index in the obese Pro12Ala/Ala12Ala carriers, while a lower PUFA intake (%) in the long-term trial was associated with an increase in the respiratory quotient only in Ala carriers but not in the Pro12Pro genotyped group. The Pro12Ala polymorphism in the PPARγ2 gene influenced energy metabolism in the assayed short- and long-term situations since the response to both nutritional interventions differed according to the genotype. The results suggest that fat oxidation and energy expenditure may be lower in Pro12Pro carriers compared to Pro12Ala/Ala12Ala genotypes, while in obese women with Pro12Ala/Ala12Ala polymorphisms in the PPARγ2 gene fat oxidation was negatively correlated with the MUFA and PUFA (%) intake. Copyright © 2010 S. Karger AG

  2. [Ala12]MCD peptide: a lead peptide to inhibitors of immunoglobulin E binding to mast cell receptors.

    PubMed

    Buku, A; Condie, B A; Price, J A; Mezei, M

    2005-09-01

    An effort was made to discover mast cell degranulating (MCD) peptide analogs that bind with high affinity to mast cell receptors without triggering secretion of histamine or other mediators of the allergic reaction initiated by immunoglobulin E (IgE) after mast cell activation. Such compounds could serve as inhibitors of IgE binding to mast cell receptors. An alanine scan of MCD peptide reported previously showed that the analog [Ala12]MCD was 120-fold less potent in histamine-releasing activity and fivefold more potent in binding affinity to mast cell receptors than the parent MCD peptide. Because this analog showed marginal intrinsic activity and good binding affinity it was subsequently tested in the present study as an IgE inhibitor. In contrast to MCD peptide, [Ala12]MCD showed a 50% inhibition of IgE binding to the Fc epsilon RI alpha mast cell receptor by using rat basophilic leukemia (RBL-2H3) mast cells and fluorescence polarization. Furthermore, in a beta-hexosaminidase secretory assay, the peptide also showed a 50% inhibition of the secretion of this enzyme caused by IgE. An attempt was made to relate structural changes and biologic differences between the [Ala12]MCD analog and the parent MCD peptide. The present results show that [Ala12]MCD may provide a base for designing agents to prevent IgE/Fc epsilon RI alpha interactions and, consequently, allergic conditions.

  3. Glycyl-alanyl-histidine protects PC12 cells against hydrogen peroxide toxicity.

    PubMed

    Shimura, Hideki; Tanaka, Ryota; Shimada, Yoshiaki; Yamashiro, Kazuo; Hattori, Nobutaka; Urabe, Takao

    2017-11-22

    Peptides with cytoprotective functions, including antioxidants and anti-infectives, could be useful therapeutics. Carnosine, β-alanine-histidine, is a dipeptide with anti-oxidant properties. Tripeptides of Ala-His-Lys, Pro-His-His, or Tyr-His-Tyr are also of interest in this respect. We synthesized several histidine-containing peptides including glycine or alanine, and tested their cytoprotective effects on hydrogen peroxide toxicity for PC12 cells. Of all these peptides (Gly-His-His, Ala-His-His, Ala-His-Ala, Ala-Ala-His, Ala-Gly-His, Gly-Ala-His (GAH), Ala-His-Gly, His-Ala-Gly, His-His-His, Gly-His-Ala, and Gly-Gly-His), GAH was found to have the strongest cytoprotective activity. GAH decreased lactate dehydrogenase (LDH) leakage, apoptosis, morphological changes, and nuclear membrane permeability changes against hydrogen peroxide toxicity in PC12 cells. The cytoprotective activity of GAH was superior to that of carnosine against hydrogen peroxide toxicity in PC12 cells. GAH also protected PC12 cells against damage caused by actinomycin D and staurosporine. Additionally, it was found that GAH also protected SH-SY5Y and Jurkat cells from damage caused by hydrogen peroxide, as assessed by LDH leakage. Thus, a novel tripeptide, GAH, has been identified as having broad cytoprotective effects against hydrogen peroxide-induced cell damage.

  4. Capping Parallel β-Sheets of Acetyl(Ala)6NH2 with an Acetyl(Ala)5ProNH2 Can Arrest the Growth of the Sheet, Suggesting a Potential for Curtailing Amyloid Growth. An ONIOM and Density Functional Theory Study

    PubMed Central

    2015-01-01

    We present ONIOM calculations using B3LYP/d95(d,p) as the high level and AM1 as the medium level on parallel β-sheets containing four strands of Ac-AAAAAA-NH2 capped with either Ac-AAPAAA-NH2 or Ac-AAAPAA-NH2. Because Pro can form H-bonds from only one side of the peptide linkage (that containing the C=O H-bond acceptor), only one of the two Pro-containing strands can favorably add to the sheet on each side. Surprisingly, when the sheet is capped with AAPAAA-NH2 at one edge, the interaction between the cap and sheet is slightly more stabilizing than that of another all Ala strand. Breaking down the interaction enthalpies into H-bonding and distortion energies shows the favorable interaction to be due to lower distortion energies in both the strand and the four-stranded sheet. Because another strand would be inhibited for attachment to the other side of the capping (Pro-containing) strand, we suggest the possible use of Pro residues in peptides designed to arrest the growth of many amyloids. PMID:24422496

  5. Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor.

    PubMed

    Zou, Xuan; Dong, Fangtian; Zhang, Shuying; Tian, Rong; Sui, Ruifang

    2013-05-01

    The familial transthyretin (TTR) amyloidosis (FTA) demonstrates variable penetrance of clinical features associated with mutations in the plasma thyroid hormone-binding protein TTR gene. The purpose of this study was to assess the ocular features, to analyze vitreous and serum vascular endothelial growth factor (VEGF) levels, and to identify the genetic defect in a Chinese family with TTR FTA. The pedigree of interest was a three-generation family with eleven members. The primary ocular signs were vitreous opacities, beginning from the third or fourth decade, accompanied by retinal vasculitis, hemorrhages, and widespread pinpoint deposits in the peripheral retina. Two patients underwent vitrectomy with marked improvement of visual acuity postoperatively. Vitreous and serum samples for VEGF were analyzed with an enzyme-linked immunosorbent assay (ELISA). Forty-eight healthy adult volunteers were enrolled as a control group for the analysis of serum VEGF. Eight subjects who underwent vitrectomy for a macular epiretinal membrane or macular hole were enrolled as control for the analysis of vitreous VEGF. Both serum and vitreous VEGF levels of patients were raised compared to that of controls. Venous blood was collected from family members and the genomic DNA was extracted. All exons and exon-intron boundaries of the TTR gene were sequenced. A previously-described pathogenic transversion in exon 2 (c.G106C, p.Ala36Pro) was identified. Within this family eight individuals were confirmed as affected. In conclusion, a Chinese family with TTR Ala36Pro associated FTA is characterized by early ocular involvement. Widespread pinpoint lesions indicate RPE lesions caused by TTR deposition. FTA is associated with increased VEGF levels, both in serum and vitreous. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Moisture-Absorption and Water Dynamics in the Powder of Egg Albumen Peptide, Met-Pro-Asp-Ala-His-Leu.

    PubMed

    Yang, Shuailing; Liu, Xuye; Zhang, Mingdi; Lin, Songyi; Chen, Feng

    2017-01-01

    Moisture absorbed into the powder of Met-Pro-Asp-Ala-His-Leu (MPDAHL)-a novel egg albumen antioxidant peptide-profoundly affects its properties. In this study, we elucidated water dynamics in MPDAHL using DVS, DSC, and low-field 1 H NMR. Based on the DVS data, we found that MPDAHL sorption kinetics obey a parallel exponential model. DSC results indicated that both water and heating could change the microstructure of MPDAHL. The T 2 parameters of NMR reflected the different phases of moisture absorption revealed that there were 4 categories of water with different states or mobility in the MPDAHL during the moisture absorption process. The fastest fraction T 2b mainly dominated the hygroscopicity of MPDAHL and the absorbed water significantly changed the proton distribution and structure of MPDAHL. Thus, this study shows that DVS, DSC, and low-field 1 H NMR are effective methods for monitoring water mobility and distribution in synthetic peptides. It can be used to improve the quality assurance of functional peptides. © 2016 Institute of Food Technologists®.

  7. 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

  8. 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.

  9. Manduca sexta proprophenoloxidase activating proteinase-3 (PAP3) stimulates melanization by activating proPAP3, proSPHs, and proPOs

    PubMed Central

    Wang, Yang; Lu, Zhiqiang; Jiang, Haobo

    2014-01-01

    Melanization participates in various insect physiological processes including antimicrobial immune responses. Phenoloxidase (PO), a critical component of the enzyme system catalyzing melanin formation, is produced as an inactive precursor prophenoloxidase (proPO) and becomes active via specific proteolytic cleavage by proPO activating proteinase (PAP). In Manduca sexta, three PAPs can activate proPOs in the presence of two serine proteinase homologs (SPH1 and SPH2). While the hemolymph proteinases (HPs) that generate the active PAPs are known, it is unclear how the proSPHs (especially proSPH1) are activated. In this study, we isolated from plasma of bar-stage M. sexta larvae an Ile-Glu-Ala-Arg-p-nitroanilide hydrolyzing enzyme that cleaved the proSPHs. This proteinase, PAP3, generated active SPH1 and SPH2, which function as cofactors for PAP3 in proPO activation. Cleavage of the purified recombinant proSPHs by PAP3 yielded 38 kDa bands similar in mobility to the SPHs formed in vivo. Surprisingly, PAP3 also can activate proPAP3 to stimulate melanization in a direct positive feedback loop. The enhanced proPO activation concurred with the cleavage activation of proHP6, proHP8, proPAP1, proPAP3, proSPH1, proSPH2, proPOs, but not proHP14 or proHP21. These results indicate that PAP3, like PAP1, is a key factor of the self-reinforcing mechanism in the proPO activation system, which is linked to other immune responses in M. sexta. PMID:24768974

  10. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis

    PubMed Central

    Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

    2013-01-01

    Background Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. Objectives To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. Methods The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Results Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. Conclusions The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. PMID:23252768

  11. Loss of the Arabidopsis thaliana P4-ATPases ALA6 and ALA7 impairs pollen fitness and alters the pollen tube plasma membrane.

    PubMed

    McDowell, Stephen C; López-Marqués, Rosa L; Cohen, Taylor; Brown, Elizabeth; Rosenberg, Alexa; Palmgren, Michael G; Harper, Jeffrey F

    2015-01-01

    Members of the P4 subfamily of P-type ATPases are thought to create and maintain lipid asymmetry in biological membranes by flipping specific lipids between membrane leaflets. In Arabidopsis, 7 of the 12 Aminophospholipid ATPase (ALA) family members are expressed in pollen. Here we show that double knockout of ALA6 and ALA7 (ala6/7) results in siliques with a ~2-fold reduction in seed set with a high frequency of empty seed positions near the bottom. Seed set was reduced to near zero when plants were grown under a hot/cold temperature stress. Reciprocal crosses indicate that the ala6/7 reproductive deficiencies are due to a defect related to pollen transmission. In-vitro growth assays provide evidence that ala6/7 pollen tubes are short and slow, with ~2-fold reductions in both maximal growth rate and overall length relative to wild-type. Outcrosses show that when ala6/7 pollen are in competition with wild-type pollen, they have a near 0% success rate in fertilizing ovules near the bottom of the pistil, consistent with ala6/7 pollen having short and slow growth defects. The ala6/7 phenotypes were rescued by the expression of either an ALA6-YFP or GFP-ALA6 fusion protein, which showed localization to both the plasma membrane and highly-mobile endomembrane structures. A mass spectrometry analysis of mature pollen grains revealed significant differences between ala6/7 and wild-type, both in the relative abundance of lipid classes and in the average number of double bonds present in acyl side chains. A change in the properties of the ala6/7 plasma membrane was also indicated by a ~10-fold reduction of labeling by lipophilic FM-dyes relative to wild-type. Together, these results indicate that ALA6 and ALA7 provide redundant activities that function to directly or indirectly change the distribution and abundance of lipids in pollen, and support a model in which ALA6 and ALA7 are critical for pollen fitness under normal and temperature-stress conditions.

  12. Loss of the Arabidopsis thaliana P4-ATPases ALA6 and ALA7 impairs pollen fitness and alters the pollen tube plasma membrane

    PubMed Central

    McDowell, Stephen C.; López-Marqués, Rosa L.; Cohen, Taylor; Brown, Elizabeth; Rosenberg, Alexa; Palmgren, Michael G.; Harper, Jeffrey F.

    2015-01-01

    Members of the P4 subfamily of P-type ATPases are thought to create and maintain lipid asymmetry in biological membranes by flipping specific lipids between membrane leaflets. In Arabidopsis, 7 of the 12 Aminophospholipid ATPase (ALA) family members are expressed in pollen. Here we show that double knockout of ALA6 and ALA7 (ala6/7) results in siliques with a ~2-fold reduction in seed set with a high frequency of empty seed positions near the bottom. Seed set was reduced to near zero when plants were grown under a hot/cold temperature stress. Reciprocal crosses indicate that the ala6/7 reproductive deficiencies are due to a defect related to pollen transmission. In-vitro growth assays provide evidence that ala6/7 pollen tubes are short and slow, with ~2-fold reductions in both maximal growth rate and overall length relative to wild-type. Outcrosses show that when ala6/7 pollen are in competition with wild-type pollen, they have a near 0% success rate in fertilizing ovules near the bottom of the pistil, consistent with ala6/7 pollen having short and slow growth defects. The ala6/7 phenotypes were rescued by the expression of either an ALA6-YFP or GFP-ALA6 fusion protein, which showed localization to both the plasma membrane and highly-mobile endomembrane structures. A mass spectrometry analysis of mature pollen grains revealed significant differences between ala6/7 and wild-type, both in the relative abundance of lipid classes and in the average number of double bonds present in acyl side chains. A change in the properties of the ala6/7 plasma membrane was also indicated by a ~10-fold reduction of labeling by lipophilic FM-dyes relative to wild-type. Together, these results indicate that ALA6 and ALA7 provide redundant activities that function to directly or indirectly change the distribution and abundance of lipids in pollen, and support a model in which ALA6 and ALA7 are critical for pollen fitness under normal and temperature-stress conditions. PMID:25954280

  13. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

    PubMed

    Dirschka, T; Radny, P; Dominicus, R; Mensing, H; Brüning, H; Jenne, L; Karl, L; Sebastian, M; Oster-Schmidt, C; Klövekorn, W; Reinhold, U; Tanner, M; Gröne, D; Deichmann, M; Simon, M; Hübinger, F; Hofbauer, G; Krähn-Senftleben, G; Borrosch, F; Reich, K; Berking, C; Wolf, P; Lehmann, P; Moers-Carpi, M; Hönigsmann, H; Wernicke-Panten, K; Hahn, S; Pabst, G; Voss, D; Foguet, M; Schmitz, B; Lübbert, H; Szeimies, R-M

    2013-04-01

    Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy. © 2012 Biofrontera Bioscience GmbH BJD © 2012 British Association of Dermatologists.

  14. P12.105-ALA GUIDED REMOVAL AND COMBINED TREATMENT IN MALIGNANT GLIOMA

    PubMed Central

    Oppido, P.A.; Carapella, C.M.; Pompili, A.; Vidiri, A.; Pace, A.; Villani, V.

    2014-01-01

    INTRODUCTION: Malignant gliomas are the most unfavourable brain tumours. Recent evidence suggests that extensive tumour removal is associated with better survival. The current treatment is complete as possible resection of the contrast-enhancing tumour tissue, followed by adjuvant treatment with radiotherapy and chemotherapy. As it appears difficult to distinguish between infiltration tumour and normal tissue, specially in recurrent tumours, the radical removal becomes harmful. Techniques to visualize the borderline tumour intraoperatively are helpful. More recently, fluorescence guidance has taken advantage of intrinsic metabolic and structural changes that occur within malignant glioma by exploiting the eme biosynthetic pathway and a natural biochemical in that pathway, 5-aminolevulinic acid (5-ALA). METHODS: Since the end of 2009, in our Institute 54 patients were operated on using fluorescence guided tumour resection. Preoperatively, all enrolled patients had MRI showing contrast enhancing lesions. MRI within 72 hours after surgery and thereafter at 3-month interval was performed. 32 patients were newly diagnosed tumour, 22 were recurrent malignant glioma. An oral dose of 20 mg 5-ALA /kg body weight was administered to each patient. By a NC4 OPMI Pentero operating microscope (Zeiss), enabled switching from xenon light to violet-blue light for visualizing fluorescence, the surgical resection was performed. Histology was in 48 glioblastoma (1 gliosarcoma), in 4 anaplastic oligodendroglioma, in 1 oligodendroglioma I WHO and in 1 pleomorphic xanthoastrocytoma. All the patients, as first line treatment, were submitted to radiotherapy and chemotherapy; in recurrent tumours second and in some cases third line treatments were administered. The follow-up ranged from 2 years to 8 months. RESULTS: In all cases the yellow fluorescence due to 5-ALA in cortical vessels was seen. In 47 glioblastoma, 4 anaplastic oligodendroglioma and 1 xanthoastrocytoma the tumour tissue

  15. Engineering an ATP-dependent D-Ala:D-Ala ligase for synthesizing amino acid amides from amino acids.

    PubMed

    Miki, Yuta; Okazaki, Seiji; Asano, Yasuhisa

    2017-05-01

    We successfully engineered a new enzyme that catalyzes the formation of D-Ala amide (D-AlaNH 2 ) from D-Ala by modifying ATP-dependent D-Ala:D-Ala ligase (EC 6.3.2.4) from Thermus thermophilus, which catalyzes the formation of D-Ala-D-Ala from two molecules of D-Ala. The new enzyme was created by the replacement of the Ser293 residue with acidic amino acids, as it was speculated to bind to the second D-Ala of D-Ala-D-Ala. In addition, a replacement of the position with Glu performed better than that with Asp with regards to specificity for D-AlaNH 2 production. The S293E variant, which was selected as the best enzyme for D-AlaNH 2 production, exhibited an optimal activity at pH 9.0 and 40 °C for D-AlaNH 2 production. The apparent K m values of this variant for D-Ala and NH 3 were 7.35 mM and 1.58 M, respectively. The S293E variant could catalyze the synthesis of 9.3 and 35.7 mM of D-AlaNH 2 from 10 and 50 mM D-Ala and 3 M NH 4 Cl with conversion yields of 93 and 71.4 %, respectively. This is the first report showing the enzymatic formation of amino acid amides from amino acids.

  16. Harnessing cellular differentiation to improve ALA-based photodynamic therapy in an artificial skin model

    NASA Astrophysics Data System (ADS)

    Maytin, Edward; Anand, Sanjay; Sato, Nobuyuki; Mack, Judith; Ortel, Bernhard

    2005-04-01

    During ALA-based photodynamic therapy (PDT), a pro-drug (aminolevulinic acid; ALA) is taken up by tumor cells and metabolically converted to a photosensitizing intermediate (protoporphyrin IX; PpIX). ALA-based PDT, while an emerging treatment modality, remains suboptimal for most cancers (e.g. squamous cell carcinoma of the skin). Many treatment failures may be largely due to insufficient conversion of ALA to PpIX within cells. We discovered a novel way to increase the conversion of ALA to PpIX, by administering agents that can drive terminal differentiation (i.e., accelerate cellular maturation). Terminally-differentiated epithelial cells show higher levels of intracellular PpIX, apparently via increased levels of a rate-limiting enzyme, coproporphyrinogen oxidase (CPO). To study these mechanisms in a three-dimensional tissue, we developed an organotypic model that mimics true epidermal physiology in a majority of respects. A line of rat epidermal keratinocytes (REKs), when grown in raft cultures, displays all the features of a fully-differentiated epidermis. Addition of ALA to the culture medium results in ALA uptake and PpIX synthesis, with subsequent death of keratinocytes upon exposure to blue light. Using this model, we can manipulate cellular differentiation via three different approaches. (1) Vitamin D, a hormone that enhances keratinocyte differentiation; (2) Hoxb13, a nuclear transcription factor that affects the genetically-controlled differentiation program of stratifying cells (3) Hyaluronan, an abundant extracellular matrix molecule that regulates epidermal differentiation. Because the raft cultures contain only a single cell type (no blood, fibroblasts, etc.) the effects of terminal differentiation upon CPO, PpIX, and keratinocyte cell death can be specifically defined.

  17. Expression Levels of ALA Dehydratase as a Marker of ALA-PDT Efficacy

    NASA Astrophysics Data System (ADS)

    Avital, Schauder; Tamar, Feuerstein; Zvi, Malik

    2010-05-01

    Accelerated synthesis of protoporphyrinIX (PpIX) following ALA pre-treatment followed by light irradiation is the principle of ALA-PDT. Several limiting enzymes were suggested to control PpIX accumulation and PDT efficacy, among them porphobilinogen deaminase (PBGD) and ferrochelatase. Here we reveal the centrality of ALA dehydratase (ALAD) activity in predicting ALA-PDT efficacy. Silencing of ALAD expression and activity was carried out in leukemic cells using shRNA plasmid transfection or Pb2+ intoxication. ALAD activity, porphyrin synthesis and mitochondrial activity were determined versus PDT efficacy. In K562 ALAD-silenced cells, ALAD activity and expression were reduced and as a result, PpIX synthesis was almost abolished. Following ALA treatment and irradiation, ALAD-silenced cells depicted normal mitochondrial activity, in contrast to control and non-silencing transfected cells where accumulated PpIX and irradiation caused ROS formation and mitochondrial damage. Morphological analysis by scanning electron microscopy (SEM) of ALA-PDT treated cells showed no morphological changes in ALAD-silenced cells, while controls exhibited cell deformations and lysis. Annexin V-FITC/PI staining as well as LDH-L leakage testing showed that membrane integrity was undamaged following ALA-PDT in ALAD silenced cells. Pb2+ treatment in MEL cells impaired ALAD activity and reduced PpIX synthesis but to a lesser extent. In conclusion, we show that a dramatic reduction in PpIX accumulation following down regulation of ALAD expression prevents an efficient PDT. Thus, ALAD has a major role in regulating PpIX synthesis and ALA-PDT therapeutic outcome. Monitoring ALAD expression or activity in various tumors may be useful as prognostic tool to predict PDT efficacy.

  18. ALA-Butyrate prodrugs for Photo-Dynamic Therapy

    NASA Astrophysics Data System (ADS)

    Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

    2010-05-01

    The use of 5-aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy (PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo-irradiation conditions showed that butyryloxyethyl 5-amino-4-oxopentanoate (ALA-BAC) generated the most efficient photodynamic destruction compared to ALA. ALA-BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA-BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA-BAC over ALA stems from its ability to induce photo-damage at a significantly lower dose than ALA.

  19. α-Linolenic acid (ALA) is an anti-inflammatory agent in inflammatory bowel disease.

    PubMed

    Reifen, Ram; Karlinsky, Anna; Stark, Aliza H; Berkovich, Zipi; Nyska, Abraham

    2015-12-01

    Studies suggest that consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) plays a protective role in inflammatory bowel disease; however, the use of plant-derived oils rich in α-linolenic acid (ALA) has not been widely investigated. The aims of this study were to test the effects of two different sources of (n-3) PUFA, fish and plant-derived oils, in two animal models of experimental colitis and to determine whether the (n-3) PUFA-enriched diets could ameliorate the inflammatory status. Rats were fed diets rich in corn, fish or sage oil with or without vitamin A supplementation for 3weeks then colitis was induced by adding dextran sodium sulfate to the drinking water or by injecting 2,4,6-trinitrobenzene sulfonic acid. We show that colitic rats fed the sage oil diets had a lower inflammatory response, improved histological repair and had less necrotic damage in the mucosa when compared to the corn and fish oil groups. Colonic damage and myeloperoxidase activity were significantly lower. Colonic mRNA levels of pro-inflammatory genes including interleukin IL-6, cyclooxygenase 2 and tumor necrosis factor α were markedly down-regulated in rats fed fish and sage oils compared to control. These results were supported by experiments in the human colonic epithelial cell line Caco-2, where ALA supplementation was shown to be effective in inhibiting inflammation induced by IL-1β by down-regulating mRNA levels of pro-inflammatory genes including IL-8, COX2 and inducible nitric oxide synthase. Taken together, these results suggest that plant-derived oil rich in ALA could ameliorate the inflammatory damage in colitis. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Evaluation of the Urine Protein/Creatinine Ratio Measured with the Dipsticks Clinitek Atlas PRO 12.

    PubMed

    Hermida, Fernando J; Soto, Sonia; Benitez, Alfonso J

    2016-01-01

    Screening for urine proteins is recommended for the detection of albuminuria in high risk groups. The aim of this study was to compare the Clinitek Atlas PRO12 reagent urine strip with quantitative methods for the determination of protein/creatinine ratio and to evaluate the usefulness of the semi-quantitative Clinitek Atlas PRO12 reagent urine strip as a tool in the early detection of albuminuria among the general population. Six hundred first morning urine specimens were collected from outpatients with various clinical conditions. The results showed that the test data for the urine dipstick Clinitek Atlas PRO12 show good agreement with the quantitative measurement of protein, creatinine and protein/creatinine ratio. In addition, this study shows that 97.2% of the samples which gave "normal" protein/creatinine ratios by the semi-quantitative method, showed albumin/creatinine ratio < 30 mg/g by the quantitative methods. Our results show that Clinitek Atlas PRO12 reagent strips can be used for the purposes of albuminuria screening in the general population.

  1. Progesterone-associated proteins PP12 and PP14 in the human endometrium.

    PubMed

    Rutanen, E M; Koistinen, R; Seppälä, M; Julkunen, M; Suikkari, A M; Huhtala, M L

    1987-01-01

    Two proteins, designated as PP12 and PP14 were originally isolated from soluble extracts of the human placenta and its adjacent membranes. We have shown that they are synthesized by decidualized/secretory endometrium and not by placenta. Both proteins occur at high concentrations in human amniotic fluid, which is therefore an excellent source for purification. PP12 is a 34-kDa glycoprotein, which has an N-terminal amino acid sequence of Ala-Pro-Trp-Gln-Cys-Ala-Pro-Cys-Ser-Ala. This is identical with that of somatomedin-binding protein purified from the amniotic fluid. PP12 too binds somatomedin-C, or IGF-I (insulin-like growth factor-I). Human secretory endometrium synthesizes and secretes PP12, and progesterone stimulates its secretion. PP14 is a 28-kDa glycoprotein. Its N-terminal sequence shows homology to that of beta-lactoglobulins from various species. We have found PP14 in the human endometrium, serum and milk. Immunologically, PP14 is related to progestagen-associated endometrial protein (PEP), alpha-2 pregnancy-associated endometrial protein (alpha-2, PEG), endometrial protein 15 (EP15), alpha-uterine protein (AUP) and chorionic alpha-2 microglobulin (CAG-2). In ovulatory menstrual cycles, the concentration of PP14 increases in endometrial tissue as the secretory changes advance. In serum, the PP14 concentration begins to rise later than the progesterone levels, and high serum PP14 levels are maintained for the first days of the next cycle. By contrast, no elevation of serum PP14 level is seen in anovulatory cycles. Our results show that progesterone-associated proteins are synthesized by the human endometrium and appear in the peripheral circulation, where they can be quantitatively measured using immunochemical techniques.

  2. Alpha lipoic acid (ALA) modulates expression of apoptosis associated proteins in hippocampus of rats exposed during postnatal period to sodium arsenite (NaAsO2).

    PubMed

    Dixit, Shilpi; Dhar, Pushpa; Mehra, Raj D

    2015-01-01

    The present study focused on the role of exogenous alpha lipoic acid (ALA) in amelioration of inorganic arsenic ( iAs ) induced effects on apoptosis and apoptosis associated proteins in developing rat hippocampus. NaAsO 2 (1.5/2.0 mg/kg bw) alone or along with ALA (70 mg/kg bw) was administered to rat pups (experimental groups) by intraperitoneal (i.p.) route from postnatal day (PND) 4-15. Controls received no treatment/distilled water/ALA. On PND 16, the animals were perfusion fixed and the brains were processed for paraffin embedding (CV and TUNEL staining) and cryopreservation (immunohistochemistry). The fresh brain tissue was used for Western blotting. Significant increase was observed in TUNEL positive cells and Bax (pro-apoptotic protein) expression in hippocampal sub-regions of iAs alone treated groups, whereas Bcl-2 expression was intensified in animals receiving ALA with iAs . Densitometric analysis (Western blots) revealed optimal restoration of Bax and Bcl-2 ratio in animals receiving ALA with iAs , thereby suggesting the protective role of ALA in iAs induced developmental neurotoxicity.

  3. Evidence that PC2 is the endogenous pro-neurotensin convertase in rMTC 6-23 cells and that PC1- and PC2-transfected PC12 cells differentially process pro-neurotensin.

    PubMed

    Rovère, C; Barbero, P; Kitabgi, P

    1996-05-10

    The neuropeptide precursor proneurotensin/neuromedin N (pro-NT/NN) is mainly expressed and differentially processed in the brain and in the small intestine. We showed previously that rMTC 6-23 cells process pro-NT/NN with a pattern similar to brain tissue and increase pro-NT/NN expression in response to dexamethasone, and that PC12 cells also produce pro-NT/NN but are virtually unable to process it. In addition, PC12 cells were reported to be devoid of the prohormone convertases PC1 and PC2. The present study was designed to identify the proprotein convertase(s) (PC) involved in pro-NT/NN processing in rMTC 6-23 cells and to compare PC1- and PC2-transfected PC12 cells for their ability to process pro-NT/NN. rMTC 6-23 cells were devoid of PC1, PC4, and PC5 but expressed furin and PC2. Stable expression of antisense PC2 RNA in rMTC 6-23 cells led to a 90% decrease in PC2 protein levels that correlated with a > 80% reduction of pro-NT/NN processing. PC2 expression was stimulated by dexamethasone in a time- and concentration-dependent manner. Stable PC12/PC2 transfectants processed pro-NT/NN with a pattern similar to that observed in the brain and in rMTC 6-23 cells. In contrast, stable PC12/PC1 transfectants reproduced the pro-NT/NN processing pattern seen in the gut. We conclude that (i) PC2 is the major pro-NT/NN convertase in rMTC 6-23 cells; (ii) its expression is coregulated with that of pro-NT/NN in this cell line; and (iii) PC2 and PC1 differentially process pro-NT/NN with brain and intestinal phenotype, respectively.

  4. A study of parallelism of the occlusal plane and ala-tragus line.

    PubMed

    Sadr, Katayoun; Sadr, Makan

    2009-01-01

    Orientation of the occlusal plane is one of the most important clinical procedures in prostho-dontic rehabilitation of edentulous patients. The aim of this study was to define the best posterior reference point of ala-tragus line for orientation of occlusal plane for complete denture fabrication. Fifty-three dental students (27 females and 26 males) with complete natural dentition and Angel's Class I occlusal relationship were selected. The subjects were photographed in natural head position while clenching on a Fox plane. After tracing the photographs, the angles between the following lines were measured: the occlusal plane (Fox plane) and the superior border of ala-tragus, the occlusal plane (Fox plane) and the middle of ala-tragus as well as the occlusal plane (Fox plane) and the inferior border of ala-tragus. Descriptive statistics, one sample t-test and independent t-test were used. P value less than 0.05 was considered significant. There was no parallelism between the occlusal plane and ala-tragus line with three different posterior ends and one sample t-test showed that the angles between them were significantly different from zero (p<0.05). However, the supe-rior border of ala-tragus line had the lowest mean angle, 1.80° (3.12) and was almost parallel to the occlusal plane. The superior border of the tragus is suggested as the posterior reference for ala-tragus line.

  5. ALA Pretreatment Improves Waterlogging Tolerance of Fig Plants

    PubMed Central

    An, Yuyan; Qi, Lin; Wang, Liangju

    2016-01-01

    5-aminolevulinic acid (ALA), a natural and environmentally friendly plant growth regulator, can improve plant tolerance to various environmental stresses. However, whether ALA can improve plant waterlogging tolerance is unknown. Here, we investigated the effects of ALA pretreatment on the waterlogging-induced damage of fig (Ficus carica Linn.) plants, which often suffer from waterlogging stress. ALA pretreatment significantly alleviated stress-induced morphological damage, increased leaf relative water content (RWC), and reduced leaf superoxide anion (O2⋅¯) production rate and malonaldehyde (MDA) content in fig leaves, indicating ALA mitigates waterlogging stress of fig plants. We further demonstrated that ALA pretreatment largely promoted leaf chlorophyll content, photosynthetic electron transfer ability, and photosynthetic performance index, indicating ALA significantly improves plant photosynthetic efficiency under waterlogging stress. Moreover, ALA pretreatment significantly increased activities of leaf superoxide dismutase (SOD) and peroxidase (POD), root vigor, and activities of root alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH), indicating ALA also significantly improves antioxidant ability and root function of fig plants under waterlogging stress. Taken together, ALA pretreatment improves waterlogging tolerance of fig plants significantly, and the promoted root respiration, leaf photosynthesis, and antioxidant ability may contribute greatly to this improvement. Our data firstly shows that ALA can improve plant waterlogging tolerance. PMID:26789407

  6. A Study of Parallelism of the Occlusal Plane and Ala-Tragus Line

    PubMed Central

    Sadr, Katayoun; Sadr, Makan

    2009-01-01

    Background and aims Orientation of the occlusal plane is one of the most important clinical procedures in prostho-dontic rehabilitation of edentulous patients. The aim of this study was to define the best posterior reference point of ala-tragus line for orientation of occlusal plane for complete denture fabrication. Materials and methods Fifty-three dental students (27 females and 26 males) with complete natural dentition and Angel’s Class I occlusal relationship were selected. The subjects were photographed in natural head position while clenching on a Fox plane. After tracing the photographs, the angles between the following lines were measured: the occlusal plane (Fox plane) and the superior border of ala-tragus, the occlusal plane (Fox plane) and the middle of ala-tragus as well as the occlusal plane (Fox plane) and the inferior border of ala-tragus. Descriptive statistics, one sample t-test and independent t-test were used. P value less than 0.05 was considered significant. Results There was no parallelism between the occlusal plane and ala-tragus line with three different posterior ends and one sample t-test showed that the angles between them were significantly different from zero (p<0.05). However, the supe-rior border of ala-tragus line had the lowest mean angle, 1.80° (3.12) and was almost parallel to the occlusal plane. Conclusion The superior border of the tragus is suggested as the posterior reference for ala-tragus line. PMID:23230496

  7. Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans

    PubMed Central

    Black, Mary Helen; Fingerlin, Tasha E.; Allayee, Hooman; Zhang, Weiming; Xiang, Anny H.; Trigo, Enrique; Hartiala, Jaana; Lehtinen, Allison B.; Haffner, Steven M.; Bergman, Richard N.; McEachin, Richard C.; Kjos, Siri L.; Lawrence, Jean M.; Buchanan, Thomas A.; Watanabe, Richard M.

    2015-01-01

    OBJECTIVE We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes. PMID:18162503

  8. ALA-PDT mediated DC vaccine for skin squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Ji, Jie; Fan, Zhixia; Zhou, Feifan; Wang, Xiaojie; Shi, Lei; Zhang, Haiyan; Wang, Peiru; Yang, Degang; Zhang, Linglin; Wang, Xiuli; Chen, Wei R.

    2015-03-01

    Dendritic cell (DC) based vaccine has emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have only achieved limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secret INF-Υ and IL-12). ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumor in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing DC-based cancer vaccine, which could improve the clinical application of PDT- DC vaccines.

  9. The role of DAMPS in ALA-PDT for skin squamous cell carcinoma (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Xiuli; Wang, Xiaojie; Ji, Jie; Zhang, Haiyan; Shi, Lei

    2016-03-01

    5-Aminolevulinic acid mediated photodynamic therapy (ALA-PDT) is an established local approach for skin squamous cell carcinoma. It is believed that dangerous signals damage-associated molecular patterns (DAMPs) play an important role in ALA-PDT. In this study, we evaluated in vitro and in vivo expressions of major DAMPs, calreticulin (CRT), heat shock proteins 70 (HSP70), and high mobility group box 1 (HMGB1), induced by ALA-PDT using immunohistochemistry, western blot, and ELISA in a squamous cell carcinoma (SCC) mouse model. The role of DAMPs in the maturation of DCs potentiated by ALA-PDT-treated tumor cells was detected by FACS and ELISA. Our results showed that ALA-PDT enhanced the expression of CRT, HSP70, and HMGB1. These induced DAMPs played an important role in activating DCs by PDT-treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, CD80, and CD86) and functional maturation (enhanced capability to secrete IFN-γ and IL-12). Furthermore, injecting ALA-PDT-treated tumor cells into naïve mice resulted in complete protection against cancer cells of the same origin. Our findings indicate that ALA-PDT can upregulate DAMPs and enhance tumor immunogenicity, providing a promising strategy for inducing a systemic anticancer immune response.

  10. Expression of the alaE gene is positively regulated by the global regulator Lrp in response to intracellular accumulation of l-alanine in Escherichia coli.

    PubMed

    Ihara, Kohei; Sato, Kazuki; Hori, Hatsuhiro; Makino, Yumiko; Shigenobu, Shuji; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2017-04-01

    The alaE gene in Escherichia coli encodes an l-alanine exporter that catalyzes the active export of l-alanine using proton electrochemical potential. In our previous study, alaE expression was shown to increase in the presence of l-alanyl-l-alanine (Ala-Ala). In this study, the global regulator leucine-responsive regulatory protein (Lrp) was identified as an activator of the alaE gene. A promoter less β-galactosidase gene was fused to an alaE upstream region (240 nucleotides). Cells that were lacZ-deficient and harbored this reporter plasmid showed significant induction of β-galactosidase activity (approximately 17-fold) in the presence of 6 mM l-alanine, l-leucine, and Ala-Ala. However, a reporter plasmid possessing a smaller alaE upstream region (180 nucleotides) yielded transformants with strikingly low enzyme activity under the same conditions. In contrast, lrp-deficient cells showed almost no β-galactosidase induction, indicating that Lrp positively regulates alaE expression. We next performed an electrophoretic mobility shift assay (EMSA) and a DNase I footprinting assay using purified hexahistidine-tagged Lrp (Lrp-His). Consequently, we found that Lrp-His binds to the alaE upstream region spanning nucleotide -161 to -83 with a physiologically relevant affinity (apparent K D , 288.7 ± 83.8 nM). Furthermore, the binding affinity of Lrp-His toward its cis-element was increased by l-alanine and l-leucine, but not by Ala-Ala and d-alanine. Based on these results, we concluded that the gene expression of the alaE is regulated by Lrp in response to intracellular levels of l-alanine, which eventually leads to intracellular homeostasis of l-alanine concentrations. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  11. ALA-PDT of the normal rat esophagus: efficiency and safety largely depends on the timing of illumination

    NASA Astrophysics Data System (ADS)

    van den Boogert, Jolanda; de Bruin, Ron W. F.; van Staveren, Hugo J.; Siersema, Peter D.; van Hillegersberg, Richard

    1999-02-01

    Photodynamic therapy (PDT) is an experimental treatment modality for (pre)malignant oesophageal lesions. 5- Aminolevulinic acid (ALA)-induced, protoporphyrin IX (PpIX)- mediated photo-sensitization could be very useful as ALA- induced porphrin accumulation selectively occurs in the oesophageal epithelium. The present study aimed to optimize the time between illumination and the administration of ALA. 200 mg/kg ALA was given orally to 24 rats (allocated to 6 groups of 4 animals each). Four animals served as controls and received phosphate buffered saline orally. The animals were illuminated at various time-points (either 1, 2, 3, 4, 6, or 12 hours) after ALA administration. Illumination was performed with a cylindrical diffuser placed in a balloon catheter. The device was originally made for percutaneous transluminal coronary angioplasty and consisted of a semi-flexible catheter and an inflatable cylindric optically clear balloon. The diffuser was placed centrally in the catheter. The same illumination parameters (633 nm, 25 J radiant energy/cm diffuser, power output 100 mW/cm diffuser) were used for each animal. During illumination, fluorescence measurements and light dosimetry were performed. The animals were sacrificed at 48 hours after PDT for histological assessment. Highest PpIX fluorescence was found at 2, 3, and 4 hours after ALA administration. Dosimetric measurements showed a 2 - 3 times higher in vivo fluence rate compared to the estimated fluence rate. Histology at 48 hours after PDT showed diffuse epithelial damage at the laser site only in rats illuminated at 2 hours after ALA administration. Illumination at 3, 4, and 6 hours after ALA administration resulted in diffuse epithelial damage in only one of four rats. In none of the rats illuminated at 1 and 12 hours after administration of ALA epithelial damage was found. These results show that illumination at 2 hours after oral ALA administration provides an efficient and safe scheme for ALA-PDT in the

  12. Gene-diet-related factors of hyperglycaemia in postmenopausal women.

    PubMed

    Grygiel-Górniak, Bogna; Kaczmarek, Elżbieta; Mosor, Maria; Przysławski, Juliusz; Nowak, Jerzy

    2018-05-01

    As ageing and increased body fat are the signs of insulin resistance, we have studied whether the presence of Pro12Ala and C1431T of peroxisome proliferator-activated receptor gamma 2 gene and Trp64Arg of beta 3-adrenergic receptor gene may predispose to the hyperglycaemia development in postmenopausal women, who have never undergone hypoglycaemic treatment. The distributions of selected allele and genotype frequencies were determined by the PCR-RFLP method in normo- and hyperglycaemic, who have never been diagnosed and treated for diabetes mellitus were measured. The amount of body fat and lean body mass (LBM) were assessed by the bioimpedance method and nutritional habits by 7-day dietary recall. There were no differences between the distribution of genotypes and the allele frequencies of the Pro12Ala, C1431T and Trp64Arg polymorphisms in normo- and hyperglycaemic women. Hyperglycaemic women were characterized by visceral obesity, hypertension, higher serum insulin and triglycerides, higher intake of fat and lower consumption of complex carbohydrates and B vitamins. Normoglycaemic women with Pro12Pro polymorphism acquired higher energy from dietary fat (p < 0.0276) and lower energy from carbohydrates (p < 0.0480) than normoglycaemic Ala12 carriers. Subjects with Pro12Pro polymorphism and LBM > 58% of total body mass or with Trp64Trp and normal triglycerides have higher chance of normoglycaemia. Genotyping for Pro12Ala and Trp64Arg polymorphism in postmenopausal women may have the clinical benefit of predicting hyperglycaemia, thereby contributing to the prevention of diabetes mellitus development in the future. However, not only the genetic background but also the dietary habits (intake of fat, carbohydrates and B vitamins) determine the risk of hyperglycaemia.

  13. Impact of charged amino acid substitution in the transmembrane domain of L-alanine exporter, AlaE, of Escherichia coli on the L-alanine export.

    PubMed

    Kim, Seryoung; Ihara, Kohei; Katsube, Satoshi; Ando, Tasuke; Isogai, Emiko; Yoneyama, Hiroshi

    2017-01-01

    The Escherichia coli alaE gene encodes the L-alanine exporter, AlaE, that catalyzes active export of L-alanine using proton electrochemical potential. The transporter comprises only 149 amino acid residues and four predicted transmembrane domains (TMs), which contain three charged amino acid residues. The AlaE-deficient L-alanine non-metabolizing cells (ΔalaE cells) appeared hypersusceptible to L-alanyl-L-alanine showing a minimum inhibitory concentration (MIC) of 2.5 µg/ml for the dipeptide due to a toxic accumulation of L-alanine. To elucidate the mechanism by which AlaE exports L-alanine, we replaced charged amino acid residues in the TMs, glutamic acid-30 (TM-I), arginine-45 (TM-II), and aspartic acid-84 (TM-III) with their respective charge-conserved amino acid or a net neutral cysteine. The ΔalaE cells producing R45K or R45C appeared hypersusceptible to the dipeptide, indicating that arginine-45 is essential for AlaE activity. MIC of the dipeptide in the ΔalaE cells expressing E30D and E30C was 156 µg/ml and >10,000 µg/ml, respectively, thereby suggesting that a negative charge at this position is not essential. The ΔalaE cells expressing D84E or D84C showed an MIC >10,000 and 78 µg/ml, respectively, implying that a negative charge is required at this position. These results were generally consistent with that of the L-alanine accumulation experiments in intact cells. We therefore concluded that charged amino acid residues (R45 and D84) in the AlaE transmembrane domain play a pivotal role in L-alanine export. Replacement of three cysteine residues at C22, C28 (both in TM-I), and C135 (C-terminal region) with alanine showed only a marginal effect on L-alanine export.

  14. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  15. PPARγ gene polymorphism, C-reactive protein level, BMI and periodontitis in post-menopausal Japanese women.

    PubMed

    Wang, Yangming; Sugita, Noriko; Yoshihara, Akihiro; Iwasaki, Masanori; Miyazaki, Hideo; Nakamura, Kazutoshi; Yoshie, Hiromasa

    2016-03-01

    Several studies have reported inconsistent results regarding the association between the PPARγPro12Ala polymorphism and obesity. Obese individuals had higher C-reactive protein (CRP) levels compared with those of normal weight, and PPARγ activation could significantly reduce serum high-sensitive CRP level. We have previously suggested that the Pro12Ala polymorphism represents a susceptibility factor for periodontitis, which is a known risk factor for increased CRP level. The aim was to investigate associations between PPARγ gene polymorphism, serum CRP level, BMI and/or periodontitis among post-menopausal Japanese women. The final sample in this study comprised 359 post-menopausal Japanese women. Periodontal parameters, including PD, CAL and BOP, were measured per tooth. PPARγPro12Ala genotype was determined by PCR-RFLP. Hs-CRP value was measured by a latex nephelometry assay. No significant differences in age, BMI or periodontal parameters were found between the genotypes. The percentages of sites with PD ≥ 4 mm were significantly higher among the hsCRP ≥ 1 mg/l group than the hsCRP < 1 mg/l group (p = 0.003). Positive correlations were found between serum hsCRP levels and the percentages of sites with PD ≥ 4 mm (p = 0.043) in PPARγ Ala allele carriers, and BMI (p = 0.033) in non-carriers. After adjustment for model covariates, BMI was significantly associated with serum hsCRP level. The PPARγPro12Ala polymorphism was not independently associated with periodontitis, serum CRP level or BMI in post-menopausal Japanese women. However, serum hsCRP level correlated with periodontitis in Ala allele carriers, and with BMI in non-carriers. © 2014 John Wiley & Sons A/S and The Gerodontology Society. Published by John Wiley & Sons Ltd.

  16. Monitoring blood flow responses during topical ALA-PDT

    PubMed Central

    Becker, Theresa L.; Paquette, Anne D.; Keymel, Kenneth R.; Henderson, Barbara W.; Sunar, Ulas

    2011-01-01

    Photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular disruption early in treatment must be identified and prevented. We present blood flow responses to topical ALA-PDT in a preclinical model and basal cell carcinoma patients assessed by diffuse correlation spectroscopy (DCS). Our results show that ALA-PDT induced early blood flow changes and these changes were irradiance dependent. It is clear that there exists considerable variation in the blood flow responses in patients from lesion to lesion. Monitoring blood flow parameter may be useful for assessing ALA-PDT response and planning. PMID:21326642

  17. Vitamin D Combined with Aminolevulinate (ALA)-Mediated Photodynamic Therapy (PDT) for Human Psoriasis: A Proof-of-Principle Study

    PubMed Central

    Maytin, Edward V.; Honari, Golara; Khachemoune, Amor; Taylor, Charles R.; Ortel, Bernhard; Pogue, Brian W.; Sznycer-Taub, Nathaniel; Hasan, Tayyaba

    2012-01-01

    We previously showed that select agents (methotrexate or Vitamin D), when administered as a preconditioning regimen, are capable of promoting cellular differentiation of epithelial cancer cells while simultaneously enhancing the efficacy of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT). In solid tumors, pretreatment with Vitamin D simultaneously promotes cellular differentiation and leads to selective accumulation of target porphyrins (mainly protoporphyrin IX, PpIX) within diseased tissue. However, questions of whether or not the effects upon cellular differentiation are inexorably linked to PpIX accumulation, and whether these effects might occur in hyperproliferative noncancerous tissues, have remained unanswered. In this paper, we reasoned that psoriasis, a human skin disease in which abnormal cellular proliferation and differentiation plays a major role, could serve as a useful model to test the effects of pro-differentiating agents upon PpIX levels in a non-neoplastic setting. In particular, Vitamin D, a treatment for psoriasis that restores (increases) differentiation, might increase PpIX levels in psoriatic lesions and facilitate their responsiveness to ALA-PDT. This concept was tested in a pilot study of 7 patients with bilaterally-matched psoriatic plaques. A regimen in which calcipotriol 0.005% ointment was applied for 3 days prior to ALA-PDT with blue light, led to preferential increases in PpIX (~130%), and reductions in thickness, redness, scaling, and itching in the pretreated plaques. The results suggest that a larger clinical trial is warranted to confirm a role for combination treatments with Vitamin D and ALA-PDT for psoriasis. PMID:23264699

  18. Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

    PubMed Central

    Millikan, Robert C; Player, Jon; de Cotret, Allan René; Moorman, Patricia; Pittman, Gary; Vannappagari, Vani; Tse, Chiu-Kit J; Keku, Temitope

    2004-01-01

    Introduction A polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA. Methods We examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites). Results The odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs. Conclusions The MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer. PMID:15217492

  19. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients.

    PubMed

    Genazzani, A D; Shefer, K; Della Casa, D; Prati, A; Napolitano, A; Manzo, A; Despini, G; Simoncini, T

    2018-05-01

    To evaluate the efficacy of alpha-lipoic acid (ALA) administration on hormonal and metabolic parameters of obese PCOS patients. A group of 32 obese PCOS patients were selected after informed consent. 20 patients referred to have first grade relatives with diabetes type I or II. Hormonal and metabolic parameters as well as OGTT were evaluated before and after 12 weeks of ALA integrative administration (400 mg per os every day). ALA administration significantly decreased insulin, glucose, BMI and HOMA index. Hyperinsulinemia and insulin response to OGTT decreased both as maximal response (Δmax) and as AUC. PCOS with diabetes relatives showed the decrease also of triglyceride and GOT. Interestingly in all PCOS no changes occurred on all hormonal parameters involved in reproduction such as LH, FSH, and androstenedione. ALA integrative administration at a low dosage as 400 mg daily improved the metabolic impairment of all PCOS patients especially in those PCOS with familiar diabetes who have a higher grade of risk of NAFLD and predisposition to diabetes.

  20. THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

    PubMed

    Khan, Kamron N; Islam, Farrah; Moore, Anthony T; Michaelides, Michel

    2018-03-01

    To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

  1. Computational and experimental investigations into the conformations of cyclic tetra-α/β-peptides.

    PubMed

    Oakley, Mark T; Oheix, Emmanuel; Peacock, Anna F A; Johnston, Roy L

    2013-07-11

    We present a combined computational and experimental study of the energy landscapes of cyclic tetra-α/β-peptides. We have performed discrete path sampling calculations on a series of cyclic tetra-α/β-peptides to obtain the relative free energies and barriers to interconversion of their conformers. The most stable conformers of cyclo-[(β-Ala-Gly)2] contain all-trans peptide groups. The relative energies of the cis isomers and the cis-trans barriers are lower than in acyclic peptides but not as low as in the highly strained cyclic α-peptides. For cyclic tetra-α/β-peptides containing a single proline residue, of the type cyclo-[β-Ala-Xaa-β-Ala-Pro], the energy landscapes show that the most stable isomers containing cis and trans β-Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol(-1). We show that the underlying energy landscapes of cyclo-[β-Ala-Lys-β-Ala-Pro] and cyclo-[β-Ala-Ala-β-Ala-Pro] are similar, allowing the substitution of the flexible side chain of Lys with Ala to reduce the computational demand of our calculations. However, the steric bulk of the Val side chain in cyclo-[β-Ala-Val-β-Ala-Pro] affects the conformations of the ring, leading to significant differences between its energy landscape and that of cyclo-[β-Ala-Ala-β-Ala-Pro]. We have synthesized the cyclic peptide cyclo-[β-Ala-Lys-β-Ala-Pro], and NMR spectroscopy shows the presence of conformers that interconvert slowly on the NMR time scale at temperatures up to 80 °C. Calculated circular dichroism (CD) spectra for the proposed major isomer of cyclo-[β-Ala-Ala-β-Ala-Pro] are in good agreement with the experimental spectra of cyclo-[β-Ala-Lys-β-Ala-Pro], suggesting that the Ala cyclic tetrapeptide is a viable model for the Lys analogue.

  2. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

    PubMed

    Berkson, Burton M; Rubin, Daniel M; Berkson, Arthur J

    2009-12-01

    The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

  3. Evidence for a Contribution of ALA Synthesis to Plastid-To-Nucleus Signaling

    PubMed Central

    Czarnecki, Olaf; Gläßer, Christine; Chen, Jin-Gui; Mayer, Klaus F. X.; Grimm, Bernhard

    2012-01-01

    The formation of 5-aminolevulinic acid (ALA) in tetrapyrrole biosynthesis is widely controlled by environmental and metabolic feedback cues that determine the influx into the entire metabolic path. Because of its central role as the rate-limiting step, we hypothesized a potential role of ALA biosynthesis in tetrapyrrole-mediated retrograde signaling and exploited the direct impact of ALA biosynthesis on nuclear gene expression (NGE) by using two different approaches. Firstly, the Arabidopsis gun1, hy1 (gun2), hy2 (gun3), gun4 mutants showing uncoupled NGE from the physiological state of chloroplasts were thoroughly examined for regulatory modifications of ALA synthesis and transcriptional control in the nucleus. We found that reduced ALA-synthesizing capacity is common to analyzed gun mutants. Inhibition of ALA synthesis by gabaculine (GAB) that inactivates glutamate-1-semialdehyde aminotransferase and ALA feeding of wild-type and mutant seedlings corroborate the expression data of gun mutants. Transcript level of photosynthetic marker genes were enhanced in norflurazon (NF)-treated seedlings upon additional GAB treatment, while enhanced ALA amounts diminish these RNA levels in NF-treated wild-type in comparison to the solely NF-treated seedlings. Secondly, the impact of posttranslationally down-regulated ALA synthesis on NGE was investigated by global transcriptome analysis of GAB-treated Arabidopsis seedlings and the gun4-1 mutant, which is also characterized by reduced ALA formation. A common set of significantly modulated genes was identified indicating ALA synthesis as a potential signal emitter. The over-represented gene ontology categories of genes with decreased or increased transcript abundance highlight a few biological processes and cellular functions, which are remarkably affected in response to plastid-localized ALA biosynthesis. These results support the hypothesis that ALA biosynthesis correlates with retrograde signaling-mediated control of NGE

  4. Atg12 Maintains Skeletal Integrity by Modulating Pro-Osteoclastogenic Signals and Chondrocyte Differentiation

    NASA Technical Reports Server (NTRS)

    Tahimic, Candice; Bahl, Disha; Shirazi-Fard, Yasaman; Marsh, Timothy; Schreurs, Anne-Sofie; Rael, Victoria E.; Glikbarg, Chloe; Debnath, Jayantha; Globus, Ruth K.

    2016-01-01

    Weightlessness and radiation, two unique elements of space, profoundly decreases bone mass. This bone loss is attributed to increased activity of bone-resorbing osteoclasts and functional changes in bone-forming osteoblasts, cells that give rise to mature osteocytes. Our long-term goal is to identify signaling pathways that may be targeted to mitigate bone loss in scenarios of space exploration, radiotherapy and accidental radiation exposure. We have previously shown that exposure of MLO-Y4 osteocyte-like cells to simulated space radiation (56Fe) increased the expression of the pro-osteoclastogenic gene rankl and decreased protein levels of LC3B-II, a key player in autophagy. In this current study, we aimed to further elucidate the role of autophagy in maintaining structural integrity of the skeleton. We hypothesize that loss of autophagy in bone leads to an imbalance in pro-osteoclastogenic and pro-osteogenic signals, resulting in net bone loss. To test our hypothesis we performed global postnatal deletion of Atg12 using tamoxifeninducible Cre recombinase under the control of the CAG promoter. Six-week-old CAGCreERT2/ FloxAtg12 animals were treated daily with Tamoxifen or Vehicle (Control, oil only) for five days and euthanasia performed two weeks after the onset of treatment. Percent change in body weights (prior to treatment and at euthanasia) was not significantly different between treatment groups within the same gender. Compared to Vehicle (Control) groups, Tamoxifen (Atg12 iKO) groups showed decreased LC3B-I to II conversion and increased p62 protein levels, consistent with loss of autophagy. Quantitative PCR revealed increased expression of proosteoclastogenic cytokines mcp1 and rankl in bone and marrow respectively in male iKOs compared to male controls. Expression levels of these genes were not significantly altered in the Atg12 iKO females compared to females controls. Microcomputed tomography of tibiae revealed decreased cortical bone volume, cortical

  5. Inferior oblique muscle origin: horizontal location in relation to ala nasi and its gender difference.

    PubMed

    Takahashi, Yasuhiro; Kakizaki, Hirohiko; Kohjima, Kiwamu; Nakano, Takashi; Asamoto, Ken; Ichinose, Akihiro; Iwaki, Masayoshi

    2013-01-01

    We studied the horizontal location of the inferior oblique muscle (IOM) origin in relation to the ipsilateral ala nasi and compared the results between genders in 76 orbits of 38 Japanese cadavers. Consequently, the IOM origin was located 1.2 mm laterally to the vertical line through the lateral margin of the ipsilateral ala nasi. No significant difference was noted between genders (males, 1.3 mm; females, 0.9 mm; P = 0.257, Student t test) or between sides (right, 1.1 mm; left, 1.3 mm; P = 0.570, Student t test). In contrast, the mean interalae-nasi distance was 39.8 mm and was significantly greater in males than that in females (males, 40.8 mm; females, 38.6 mm; P = 0.049, Student t test). The ala nasi can be used as a reference point irrespective of gender or side for identifying the IOM origin during oculoplastic surgery.

  6. Dietary carotenoid-rich oil supplementation improves exercise-induced anisocytosis in runners: influences of haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms in dilutional pseudoanemia (sports anemia).

    PubMed

    Miranda-Vilela, Ana L; Akimoto, Arthur K; Alves, Penha C Z; Pereira, Luiz C S; Klautau-Guimarães, Maria N; Grisolia, Cesar K

    2010-04-01

    Physical training induces beneficial adaptation, whereas exhaustive exercises increase reactive oxygen-species generation, thereby causing oxidative damage in plasma and erythrocytes, fractions susceptible to lipid peroxidation. Pequi (Caryocar brasiliense Camb.) is a Brazilian Cerrado fruit containing a carotenoid-rich oil. The aim was to investigate the effects of pequi-oil on exercise-induced oxidative damage in plasma and erythrocytes, after running in the same environment and undergoing weekly training under the same conditions as to type, intensity and length. Evaluations were accomplished after outdoor running on flat land before and after ingestion of 400 mg pequi-oil capsules for 14 days. Blood samples were taken after running and submitted to TBARS assay and erythrogram analysis. Haptoglobin, MnSOD (Val9Ala), CAT (21A/T) and GPX1 (Pro198Leu) gene polymorphisms were priorly investigated, so as to estimate genetic influence The reduction in erythrocytes, hemoglobin and hematocrit after pequi-oil treatment was notably associated with higher plasma expansion. Except for MCHC (mean corpuscular hemoglobin concentration) and RDW (red cell distribution width), the results were influenced by the polymorphisms studied. The best response to pequi-oil was presented by MnSOD Val/Val, CAT AA or AT genotypes and the GPX1 Pro allele. The significantly lower RDW and higher MHCH values were related to pequi-oil protective effects. Pequi oil, besides possessing other nutritional properties, showed protective blood effects.

  7. ON THE RELATIONSHIPS OF SUBSTRATE ORIENTATION, HYDROGEN ABSTRACTION AND PRODUCT STEREOCHEMISTRY IN SINGLE AND DOUBLE DIOXYGENATIONS BY SOYBEAN LIPOXYGENASE-1 AND ITS ALA542GLY MUTANT*

    PubMed Central

    Coffa, Gianguido; Imber, Ann N.; Maguire, Brendan C.; Laxmikanthan, Gurunathan; Schneider, Claus; Gaffney, Betty J.; Brash, Alan R.

    2005-01-01

    Recent findings associate the control of stereochemistry in lipoxygenase (LOX) catalysis with a conserved active site alanine for S configuration hydroperoxide products, or a corresponding glycine for R stereoconfiguration. To further elucidate the mechanistic basis for this stereocontrol we compared the stereoselectivity of the initiating hydrogen abstraction in soybean LOX-1 and an Ala542Gly mutant that converts linoleic acid to both 13S and 9R configuration hydroperoxide products. Using 11R-3H- and 11S-3H-labeled linoleic acid substrates to examine the initial hydrogen abstraction, we found that all the primary hydroperoxide products were formed with an identical and highly stereoselective proS hydrogen abstraction from C-11 of the substrate (97–99% pro-S selective). This strongly suggests that 9R and 13S oxygenations occur with the same binding orientation of substrate in the active site, and as the equivalent 9R and 13S products were formed from a bulky ester derivative (1-palmitoyl-2-linoleoyl-phosphatidylcholine), one can infer that the orientation is tail-first. Both the EPR spectrum and the reaction kinetics were altered by the R product-inducing Ala-Gly mutation, indicating a substantial influence of this Ala-Gly substitution extending to the environment of the active site iron. To examine also the reversed orientation of substrate binding, we studied oxygenation of the 15S-hydroperoxide of arachidonic acid by the Ala542Gly mutant soybean LOX-1. In addition to the usual 5S,15S- and 8S,15S-dihydroperoxides, a new product was formed and identified by HPLC, UV, GC-MS and NMR as 9R , 1 5 S -dihydroperoxy-eicosa-5Z,7E,11Z,13E-tetraenoic acid, the R configuration “partner” of the normal 5S,15S product. This provides evidence that both tail-first and carboxylate end-first binding of substrate can be associated with S or R partnerships in product formation in the same active site. PMID:16157595

  8. Delta-ALA urine test

    MedlinePlus

    ... hours. Normal value ranges may vary slightly from one lab to another. Some labs use different measurements or test different samples. Talk to your provider about the meaning of your specific test results. What Abnormal Results Mean An increased level of urinary delta-ALA may ...

  9. ALA-induced fluorescence in the canine oral cavity.

    PubMed

    Vaidyanathan, Vijay; Wiggs, Robert; Stohl, Josh; Baxi, Mehul

    2006-06-01

    We examined whether 5-aminolevulinic acid (ALA) could enhance the spectroscopic contrast between normal and diseased oral tissues, without prolonged photosensitivity. ALA is a promising photosensitizing agent. Adose of 25 mg/kg of ALA was administered intravenously to five dogs with gingivitis and three dogs with oral cancer, respectively. Fluorescence was recorded from the diseased sites in the oral cavity in addition to normal sites. ALA-induced proto-porphyrin IX fluorescence at all gingivitis sites reached a peak in 2-3 h and returned to baseline in 24 h. Fluorescence from the gingivitis site was observed earlier and was higher than the fluorescence from the normal site. For dogs with cancer, fluorescence from the cancerous sites occurred earlier in time compared to gingivitis sites and was comparatively higher in intensity. The fluorescence from the diseased sites was found to be higher than the normal site. Clinical and fluorescence data suggest that a dose of 25 mg/kg may be satisfactory for diagnostic purposes and would have minimal side effects.

  10. Acquisition of pro-oxidant activity of fALS-linked SOD1 mutants as revealed using circular dichroism and UV-resonance Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Fujimaki, Nobuhiro; Nishiya, Ken; Miura, Takashi; Nakabayashi, Takakazu

    2016-11-01

    The acquisition of pro-oxidant activity of the mutated form of human Cu, Zn-superoxide dismutase (SOD1) has been investigated to clarify the relationship between mutations in SOD1 and the pathogenesis of amyotrophic lateral sclerosis (ALS). Ala4 → Val (A4V) and Gly93 → Ala (G93A) mutants, which are representative ALS-linked SOD1 mutants, have been found to exhibit both the denaturation and the gain of pro-oxidant activity after incubation in the apo-form at a physiological condition of 37 °C and pH 7.4 and the rebinding of Cu2+. These characteristics are similar to those previously reported for the His43 → Arg (H43R) mutant. UV-resonance Raman spectra indicated that the coordination structure of the Cu-binding site catalyzing the oxidation reaction is the same among the denatured A4V, G93A, and H43R. Since wild-type SOD1 does not exhibit the denaturation in its apo-form at 37 °C and pH 7.4, the instability of the protein structure due to mutation can be considered as a significant factor that induces the denaturation and the subsequent pro-oxidant activity.

  11. Genetic polymorphisms of PPAR gamma, arsenic methylation capacity and breast cancer risk in Mexican women.

    PubMed

    Pineda-Belmontes, Cristina P; Hernández-Ramírez, Raúl U; Hernández-Alcaraz, César; Cebrián, Mariano E; López-Carrillo, Lizbeth

    2016-04-01

    To evaluate whether the presence of polymorphisms of peroxisome proliferator-activated receptor gamma PPARγ (Pro 1 2Ala) and PPARGC1B (Ala203Pro) modifies the association between the inorganic arsenic (iAs) methylation capacity and breast cancer (BC). Mexican women were interviewed, and blood and urine samples were collected from them (cases/controls= 197/220). The concentration of urinary arsenic species and the polymorphisms of interest were determined by high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and polymerase chain reaction (PCR), respectively. In women with a high %MMA (urinary monomethyl arsenic) and high primary methylation ratio (PM = MMA/iAs), the risk of BC was increased (odds ratio [OR]%MMA T3 vs.T1= 3.60: 95% confidence interval [CI] 2.02-6.41, ORPMI T3 vs.T1= 3.47: 95%CI 1.95-6.17), which was maintained after adjusting for polymorphisms. No significant interactions were observed between the polymorphisms and the arsenic variables on the risk of BC. Pro 12Ala and Ala203Pro polymorphisms did not modify the association between the iAs methylation capacity and BC.

  12. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

    PubMed Central

    Kaneko, Sadahiro

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  13. ALA PDT for high grade dysplasia in Barrett's oesophagus: review of a decade's experience

    NASA Astrophysics Data System (ADS)

    Bown, Stephen G.; Mackenzie, Gary D.; Dunn, Jason M.; Thorpe, Sally M.; Lovat, Laurence B.

    2009-06-01

    We have been investigating PDT with 5 aminolaevulinic acid (ALA) for the treatment of high grade dysplasia (HGD) in Barrett's oesophagus (BO) for over a decade. This drug has inherent advantages over porfimer sodium (Photofrin), the current approved photosensitiser in the UK and USA, which causes strictures in 18-50% and light sensitivity for up to three months. ALA has a lower rate of oesophageal strictures due to its preferential activity in the mucosa, sparing the underlying muscle, and patients are only light sensitive for 1-2 days. Within a randomised controlled trial, we demonstrated that an ALA dose of 60mg/kg activated by 1000J/cm red laser light is the most effective. Using these values we achieved complete reversal of HGD at 1 year in 89% of 27 patients. A randomised controlled trial of ALA vs porfimer sodium PDT for HGD is currently under way with end points of efficacy and safety. 50 of 66 patients have been recruited. Preliminary data suggest ALA PDT is safer with a trend to higher efficacy. Late relapse can occur in 20% of patients. New prognostic markers, in particular aneuploidy, are helping us to identify and target patients at risk of late relapse. Furthermore optical biopsy techniques such as elastic scattering spectroscopy (ESS) may allow detection of nuclear abnormalities in vivo and enable us to target areas of interest whilst reducing sampling error. PDT faces new challenges for the treatment of HGD in BO, with the recent introduction of balloon based radiofrequency ablation. This technique appears simpler and as effective as PDT, but follow up is currently short and long term safety data is lacking. In our experience ALA PDT is currently the most effective minimally invasive treatment for HGD in BO. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

  14. 33 CFR 110.194 - Mobile Bay, Ala., at entrance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Mobile Bay, Ala., at entrance. 110.194 Section 110.194 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY ANCHORAGES ANCHORAGE REGULATIONS Anchorage Grounds § 110.194 Mobile Bay, Ala., at entrance. (a) The anchorage...

  15. Ex-vivo absorption study of lysine R-lipoate salt, a new pharmaceutical form of R-ALA.

    PubMed

    Amenta, Francesco; Buccioni, Michela; Ben, Diego Dal; Lambertucci, Catia; Navia, Aleix Martí; Ngouadjeu Ngnintedem, Michael A; Ricciutelli, Massimo; Spinaci, Andrea; Volpini, Rosaria; Marucci, Gabriella

    2018-06-15

    Alpha-lipoic acid (ALA) oral supplements were used in many pathologies associated with increased oxidative stress. Although only R-ALA is considered the biologically active form, R,S-ALA is used in therapeutic applications even showing poor water solubility. The aim of this work was to study the absorption and transport mechanism across the intestinal barrier of new R-ALA stable and water soluble form, consisting in the lysine R-ALA salt, in presence and absence of specific inhibitors of Na + /multivitamin (SMVT) and monocarboxylic acids (MCT). The absorption of a new ALA form was investigated at rat everted sacs in comparison with R-ALA, S-ALA, and R,S-ALA. Results showed that duodenum is the best portion of intestine for ALA forms absorption. The absorption percentage of R-ALA, S-ALA, R,S-ALA, and lysine R-ALA salt was 66%, 43%, 55%, and 70%, respectively. The modest effect of the SMVT inhibitor biotin demonstrated that this transporter system is not principally involved in the absorption of lysine R-lipoate salt across the rat intestinal barrier. On the contrary, the MCT inhibitor octanoic acid significantly reduced the transport of this salt, whit an absorption decrease of R-ALA and lysine R-lipoate salt of 28% and 24%, respectively. Since the highest concentration of these inhibitors did not completely inhibit the absorption of lysine R-lipoate salt, other transport mechanisms probably operate for its intracellular delivery. The new form of ALA, lysine R-lipoate salt, was the most absorbed respect to the other ALA forms demonstrating that this compound is more suitable for oral administration. This new salt could represent a promising candidate for ALA oral supplementation. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Evaluation of ALA-induced PpIX as a photosensitizer for PDT in cats

    NASA Astrophysics Data System (ADS)

    Lucroy, Michael D.; Edwards, Benjamin F.; Peavy, George M.; Krasieva, Tatiana B.; Griffey, Stephen M.; Madewell, Bruce R.

    1998-07-01

    Given exogenously, ALA defeats intrinsic regulatory feedback mechanisms allowing intracellular accumulation of protoporphyrin IX (PpIX), a highly efficient photosensitizer. In vivo, PpIX synthesis in neoplastic mammary tissues averages 20-fold higher than in normal mammary tissues. PpIX is retained intracellularly, unlike perivascular localization of other photosensitizers, and it is then cleared quickly from the body. In vitro, ALA induced PpIX production in our laboratory in 6 cell lines tested, including an established feline kidney cell line and dermal fibroblasts from primary skin biopsy explant, resulting in photosensitization. Fluorescent microscopy confirmed PpIX production in skin adnexae following ALA administration in a normal cat. To evaluate toxicity, three cats were treated with a single i.v. dose of ALA (either 100, 200, of 400 mg/kg) and followed for 7 days. Cats receiving 100 or 200 mg/kg ALA i.v. had elevated liver enzymes and bilirubin within 24 hours. Histopathology revealed hydropic changes in the liver and renal fibrosis. The cat receiving 400 mg/kg ALA intravenously had cutaneous flush, bradycardia and apnea associated with ALA administration; within 24 hours the cat was lethargic, anorectic and icteric. ALT, AST and bilirubin concentrations had increased significantly. At necropsy the liver had a prominent lobular pattern; histopathology revealed severe periportal hepatitis and splenic necrosis. Systemically administered ALA induces PpIX production, but toxicity may preclude its clinical application in the cat. PpIX levels seem to be more time dependent than those dependent at these three ALA doses and they are well beyond the saturation point for adequate PpIX conversion. The literature is scant regarding toxicity associated with parenteral administration of ALA.

  17. In vivo study of ALA PLGA nanoparticles-mediated PDT for treating cutaneous squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Huang, Zheng; Wang, Xiuli

    2014-09-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still a challenge. Although topical photodynamic therapy (PDT) is effective for treating in situ and superficial SCC, the effectiveness of topical ALA delivery to thick SCC can be limited by its bioavailability. Polylactic-co-glycolic acid nanopartieles (PLGA NPs) might provide a promising ALA delivery strategy. The aim of this study was to evaluate the efficacy of ALA PLGA NPs PDT for the treatment of cutaneous SCC in a mouse model. Methods: ALA loaded PLGA NPs were prepared and characterized. The therapeutic efficacy of ALA PLGA NP mediated PDT in treating UV-induced cutaneous SCC in the mice model were examined. Results: In vivo study showed that ALA PLGA NPs PDT were more effective than free ALA of the same concentration in treating mouse cutaneous SCC. Conclusion: ALA PLGA NPs provides a promising strategy for delivering ALA and treating cutaneous SCC.

  18. GIS-based accident location and analysis system (GIS-ALAS) : project report : phase I

    DOT National Transportation Integrated Search

    1998-04-06

    This report summarizes progress made in Phase I of the geographic information system (GIS) based Accident Location and Analysis System (GIS-ALAS). The GIS-ALAS project builds on PC-ALAS, a locationally-referenced highway crash database query system d...

  19. PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men.

    PubMed

    Kahara, Toshio; Takamura, Toshinari; Hayakawa, Tetsuo; Nagai, Yukihiro; Yamaguchi, Hiromi; Katsuki, Tatsuo; Katsuki, Ken-Ichi; Katsuki, Michio; Kobayashi, Ken-Ichi

    2003-02-01

    Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARgamma gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55 +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R, Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARgamma gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome. Copyright 2003, Elsevier Science (USA). All rights reserved.

  20. Potent inhibition of endopeptidase 24.16 and endopeptidase 24.15 by the phosphonamide peptide N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid.

    PubMed Central

    Barelli, H; Dive, V; Yiotakis, A; Vincent, J P; Checler, F

    1992-01-01

    A phosphonamide peptide, N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid, previously shown to block Clostridium histolyticum collagenases, was examined as a putative inhibitor of endopeptidase 24.16 and endopeptidase 24.15. Hydrolysis of two endopeptidase 24.16 substrates, i.e. 3-carboxy-7-methoxycoumarin (Mcc)-Pro-Leu-Gly-Pro-D-Lys-dinitrophenyl (Dnp) and neurotensin, were completely and dose-dependently inhibited by the phosphonamide inhibitor with KI values of 0.3 and 0.9 nM respectively. In addition, the phosphonamide peptide inhibited the hydrolysis of benzoyl (Bz)-Gly-Ala-Ala-Phe-(pAB) p-aminobenzoate and neurotensin by endopeptidase 24.15 with about a 10-fold lower potency (KI values of 5 and 7.5 nM respectively). The selectivity of this inhibitor towards several exo- and endo-peptidases belonging to the zinc-containing metallopeptidase family established that a 1 microM concentration of this inhibitor was unable to affect leucine aminopeptidase, carboxypeptidase A, angiotensin-converting enzyme and endopeptidase 24.11. The present paper therefore reports on the first hydrophilic highly potent endopeptidase 24.16 inhibitor and describes the most potent inhibitory agent directed towards endopeptidase 24.15 developed to date. These tools should allow one to assess the contribution of endopeptidase 24.16 and endopeptidase 24.15 to the physiological inactivation of neurotensin as well as other neuropeptides. PMID:1332678

  1. Frequency and Clinicopathological Characteristics of Presenilin 1 Gly206Ala Mutation in Puerto Rican Hispanics with Dementia

    PubMed Central

    Arnold, Steven E.; Vega, Irving E.; Karlawish, Jason H.; WoIk, David A.; Nunez, Jessica; Negron, Mirna; Xie, Sharon X.; Wang, Li-San; Dubroff, Jacob G.; McCarty-Wood, Elisabeth; Trojanowski, John Q.; Van Deerlin, Vivianna

    2012-01-01

    The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania’s Alzheimer’s Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly 206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study. PMID:23114514

  2. Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208).

    PubMed

    De Marco, Rossella; Bedini, Andrea; Spampinato, Santi; Cavina, Lorenzo; Pirazzoli, Edoardo; Gentilucci, Luca

    2016-10-13

    Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.

  3. Alpha-linolenic acid (ALA) is inversely related to development of adiposity in school-age children

    PubMed Central

    Perng, Wei; Villamor, Eduardo; Mora-Plazas, Mercedes; Marin, Constanza; Baylin, Ana

    2015-01-01

    Background/Objectives Studies in adults indicate that dietary polyunsaturated fatty acid (PUFA) composition may play a role in development of adiposity. Because adipocyte quantity is established between late childhood and early adolescence, understanding the impact of PUFAs on weight gain during the school-age years is crucial to developing effective interventions. Subjects/Methods We quantified N-3 and N-6 PUFAs in serum samples of 668 Colombian schoolchildren aged 5–12 years at the time of recruitment into a cohort study, using gas-liquid chromatography. Serum concentrations of N-3 (ALA, EPA, DHA) and N-6 PUFAs (LA, GLA, DGLA, AA) were determined as % total fatty acids. Children’s anthropometry was measured annually for a median of 30 months. We used mixed-effects models with restricted cubic splines to construct population body mass index-for-age z-score (BAZ) growth curves for age-and sex-specific quartiles of each PUFA. Results N-3 ALA was inversely related to BAZ gain after adjustment for sex, baseline age and weight status, and household socioeconomic level. Estimated BAZ change between 6 and 14 years among children in the highest quartile of ALA compared to those in the lowest quartile was 0.45 (95% CI: 0.07, 0.83) lower (P-trend=0.006). Conclusions N-3 ALA may be protective against weight gain in school-age children. Whether improvement in PUFA status reduces adiposity in pediatric populations deserves evaluation in randomized trials. PMID:25271016

  4. Evaluation of Partial Cut-out of Sacroiliac Screws From the Sacral Ala Slope via Pelvic Inlet and Outlet View.

    PubMed

    Zhang, Jingwei; Hamilton, Ryan; Li, Ming; Ebraheim, Nabil A; He, Xianfeng; Liu, Jiayong; Zhu, Limei

    2015-12-01

    An anatomic and radiographic study of placement of sacroiliac screws. The aim of this study was to quantitatively assess the risk of partial cut-out of sacroiliac screws from the sacral ala slope via inlet and outlet view. The partial cut-out of sacroiliac screws from the superior surface of sacral ala can jeopardize the L5 nerve root, which is difficult to identify on the pelvic inlet and outlet views. Computed tomography images of 60 patients without pelvic ring deformity or injury were used to measure the width (on inlet view) and height (on outlet view) of the sacral ala. The angle of the sacral ala slope was measured on lateral view. According to the measured parameters, the theoretical safe trajectories of screw placement were calculated using inverse trigonometric functions. Under fluoroscopic guidance, a sacroiliac screw was placed close to the midline on both inlet and outlet views, including posterosuperior, posteroinferior, anterosuperior, and anteroinferior regions to the midline. The incidence of screw partial cut-out from the superior surface of sacral ala was identified. The measured widths and heights of the sacral alas were 28.1 ± 2.8 and 29.8 ± 3.1 mm, respectively. The average angle between the superior aspect of the S1 vertebral body and the superior aspect of the sacral ala was 37.2 ± 2.5 degrees. The rate of partial cut-out of the screws from the superior surface of sacral ala slope was 12.5% (5/40) in posterosuperior, 0% (0/40) in posteroinferior, 70% (28/40) in anterosuperior, and 20% (8/40) in anteroinferior. To avoid the risk of partial cut-out from sacroiliac screw placement, more precise description should be added to the conventional description: the sacroiliac screws should be placed at the inferior half portion on outlet view and at the posterior half portion on inlet view. 4.

  5. Effects Ala54Thr polymorphism of FABP2 on obesity index and biochemical variable in response to a aerobic exercise training

    PubMed Central

    Han, Tae Kyung

    2013-01-01

    The purpose of the current study was to investigate whether or not the FABP2 gene polymorphism modulated obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers through 12-week aerobic exercise training in abdominal obesity group of Korean mid-life women. A total of 243 abdominally obese subjects of Korean mid-life women voluntarily participated in aerobic exercise training program for 12 weeks. Polymerase Chain Reaction with Restriction Fragment Length Polymorphism (PCR-RFLP) assay was used to assess the FABP2 genotype of the participants (117 of AA homozygotes, 100 of AT heterozygotes, 26 of TT homozygotes). Prior to the participation of the exercise training program, baseline obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers were measured. All the measurements were replicated following the 12-week aerobic exercise training program, and then the following results were found. After 12-week aerobic exercise training program, wild type (Ala54Ala) and mutant type (Ala54Thr+Thr54Thr) significantly decreased weight (P > .001), BMI (P > .001), %bf (P > .001), waist circumference (P > .001), WHR (P > .001), muscle mass (wild type p < .022; mutant type P > .001), RHR (P > .001), viseceral adipose area (wild type p < .005; mutant type P > .001), subcutaneous area (P > .001), insulin (wild type p < .005; mutant type P > .001) and significantly increased VO2max (P > .001). And wild type significantly decresed NEFA (P > .05), glucose (P > .05), OGTT 120min glucose (P > .05) and significantly increased HDLC (p > .005). Mutant type significantly decreased SBP (P > .001), DBP (P > .01), TC (P > .01), LPL (P > .05), LDL (P > .001), HOMA index (P > .01). The result of the present study represents that regular aerobic exercise training may beneficially prevent obesity index, blood pressure, blood lipids and insulin resistance markers independent of FABP Ala54Thr wild type and mutant type. PMID:25566432

  6. ALA-induced PpIX fluorescence in epileptogenic tissue

    NASA Astrophysics Data System (ADS)

    Kleen, Jonathan K.; Valdes, Pablo A.; Harris, Brent T.; Holmes, Gregory L.; Paulsen, Keith D.; Roberts, David W.

    2011-03-01

    Astrogliotic tissue displays markedly increased levels of ALA-induced PpIX fluorescence, making it useful for fluorescence-guided resection in glioma surgery. In patients with temporal lobe epilepsy (TLE) and corresponding animal models, there are areas of astrogliosis that often co-localize with the epileptic focus, which can be resected to eliminate seizures in the majority of treated patients. If this epileptogenic tissue can exhibit PpIX fluorescence that is sufficiently localized, it could potentially help identify margins in epilepsy surgery. We tested the hypothesis that ALA-induced PpIX fluorescence could visually accentuate epileptogenic tissue, using an established animal model of chronic TLE. An acute dose of pilocarpine was used to induce chronic seizure activity in a rat. This rat and a normal control were given ALA, euthanized, and brains examined post-mortem for PpIX fluorescence and neuropathology. Preliminary evidence indicates increased PpIX fluorescence in areas associated with chronic epileptic changes and seizure generation in TLE, including the hippocampus and parahippocampal areas. In addition, strong PpIX fluorescence was clearly observed in layer II of the piriform cortex, a region known for epileptic reorganization and involvement in the generation of seizures in animal studies. We are further investigating whether ALA-induced PpIX fluorescence can consistently identify epileptogenic zones, which could warrant the extension of this technique to clinical studies for use as an adjuvant guidance technology in the resection of epileptic tissue.

  7. Conformational analysis of α-helical polypeptide included L-proline residue by high-resolution solid-state NMR measurement and quantum chemical calculation

    NASA Astrophysics Data System (ADS)

    Souma, Hiroyuki; Shoji, Akira; Kurosu, Hiromichi

    2008-10-01

    We challenged the problem about the stabilization mechanism of an α-helix formation for polypeptides containing L-proline (Pro) residue. We computed the optimized structure of α-helical poly( L-alanine) molecules including a Pro residue, H-(Ala) 8-Pro-(Ala) 9-OH, based on the molecular orbital calculation with density functional theory, B3LYP/6-31G(d) and the 13C and 15N chemical shift values based on the GIAO-CHF method with B3LYP/6-311G(d,p), respectively. It was found that two kinds of optimized structures, 'Bent structure' and 'Included α-helix structure', were preferred structures in H-(Ala) 8-Pro-(Ala) 9-OH. In addition, based on the precise 13C and 15N chemical shift data of the simple model, we successfully analyzed the secondary structure of well-defined synthetic polypeptide H-(Phe-Leu-Ala) 3-Phe C-Pro-Ala N-(Phe-Leu-Ala) 2-OH (FLA-11P), the secondary structure of which was proven to the 'Included α-helix structure'.

  8. Computational Prediction of the Protonation Sites of Ac-Lys-(Ala)n-Lys-NH2 Peptides through Conceptual DFT Descriptors.

    PubMed

    Sastre, Sebastián; Frau, Juan; Glossman-Mitnik, Daniel

    2017-03-13

    Six density functionals (M11, M11L, MN12L, MN12SX, N12, and N12SX) in connection with the Def2TZVP basis set and the SMD solvation model (water as a solvent) have been assessed for the calculation of the molecular structure and properties of several peptides with the general formulaAc-Lys-(Ala)n-Lys-NH2,withn=0to5  [...].

  9. Stimulation of respiratory changes in alae nasi length by chemoreceptor activation.

    PubMed

    Van Lunteren, E; Haxhiu, M A; Cherniack, N S

    1986-03-01

    Respiratory-related changes in length of the nasal dilator muscle, the alae nasi muscle, were measured using sonomicrometry in ten anesthetized (pentobarbital), tracheostomized, spontaneously breathing dogs. Piezoelectric crystals were inserted 7-25 mm apart along the direction of the alae nasi muscle fibers, and the effects of progressive hyperoxic hypercapnia and a peripheral and central chemoreceptor stimulant, nicotine (10-500 micrograms intravenously), were ascertained. The alae nasi shortened during inspiration in all animals, started to lengthen again towards the end of inspiration, returned to resting length during the first portion of expiration (Te-1), and remained at resting length for the remainder of expiration (Te-2). The amount of alae nasi inspiratory shortening was increased by occluding the airway for a single breath. Progressive hypercapnia caused progressive increases in the amount and velocity of nasal muscle inspiratory shortening during both unoccluded and occluded breaths; similar stimulatory effects on inspiratory shortening were seen following nicotine administration. Furthermore, both chemoreceptor stimulants caused a delay in the return of the muscle to its resting length during expiration, resulting in a significant increase in Te-1 relative to Te (Te-1/Te), and a greater amount of nasal muscle shortening to be present during Te-1. In some animals these agents also caused tonic shortening of the alae nasi, so that the muscle never returned to its resting length. These results suggest that inspiratory shortening of the alae nasi is inhibited by vagal inputs, but that chemoreceptor activation increases the amount of muscle shortening during both inspiration and early expiration.

  10. Ala-7, His-10 and Arg-12 are crucial amino acids for activity of a synthetically engineered μ-conotoxin.

    PubMed

    Lebbe, Eline K M; Peigneur, Steve; Brullot, Ward; Verbiest, Thierry; Tytgat, Jan

    2014-03-01

    Cone snail toxins or conotoxins are often small cysteine-rich peptides which have shown to be highly selective ligands for a wide range of ion channels such as voltage-gated sodium channels (Na(V)s). Na(V)s participate in a wide range of electrophysiological processes. Consequently, their malfunction has been associated with numerous diseases. The development of subtype-selective modulators of Na(V)s remains highly important in the treatment of such disorders. In order to expand our knowledge in the search for novel therapeutics to treat Na(V)-related diseases, we explored the field of peptide engineering. In the current study, the impact of well considered point mutations into a bioactive peptide that was found to be a very potent and selective inhibitor of Na(V)s (i.e. Midi R2) was examined. We designed two peptides, named Midi R2[A7G] and Midi R2[H10A, R12A] which have mutations at position 7, and both 10 and 12, respectively. Electrophysiological recordings indicated that an Ala to Gly mutation at position 7 increased IC50-values from the nanomolar range to the micromolar range. For Midi R2[H10A, R12A] at a concentration of 10 μM, activity is even reduced to 0-10% for all of the tested Na(V)-channels. Circular dichroism measurements proved that overall structural conformations did not change. These findings suggest that the minimal space between the second and the third intercysteine loop of Midi R2 is the sequence RRWARDHSR and that His at position 10 and Arg at position 12 are crucial amino acids for the potency and specificity of Midi R2. In this way, new insights into the structure-activity relationships of μ-conotoxins were found. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Treating cutaneous squamous cell carcinoma using ALA PLGA nanoparticle-mediated photodynamic therapy in a mouse model

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Wang, Xiuli; Zhao, Feng; Luan, Hansen

    2015-03-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted ALA delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Methods: UV-induced cutaneous SCCs were established in hairless mice. ALA loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NPs-induced protoporphyrin IX (PpIX) fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results: PLGA NPs could enhance PpIX production in SCC. ALA PLGA NP mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC.

  12. The role of loop ZA and Pro371 in the function of yeast Gcn5p bromodomain revealed through molecular dynamics and experiment.

    PubMed

    Pizzitutti, Francesco; Giansanti, Andrea; Ballario, Paola; Ornaghi, Prisca; Torreri, Paola; Ciccotti, Giovanni; Filetici, Patrizia

    2006-01-01

    Biological experiments were combined with molecular dynamics simulations to understand the importance of amino acidic residues present in the bromodomain of the yeast histone acetyltransferase Gcn5p. It was found that residue Pro371 plays an important role in the molecular recognition of the acetylated histone H4 tail by Gcn5p bromodomain. Crystallographic analysis of the complex showed that this residue does not directly interact with the histone substrate. It has been demonstrated that a double mutation Pro371Thr and Met372Ala in the Gcn5p bromodomain impairs chromatin remodeling activity. It is demonstrated here that, in this double mutant and in the fully deleted bromodomain strain, there is lower growth under amino acid deprivation conditions. By in vitro surface plasmon resonance (Biacore) experiments it is shown that the binding affinity of the double mutation to acetyl lysine 16 histone H4 peptide decreases. Molecular dynamics simulations were used to explain this loss in acetyl lysine-Gcn5p bromodomain affinity, in the double mutant. By comparing nanosecond molecular dynamics trajectories of the native as well as the single and doubly mutated bromodomain, it is concluded that the presence of Pro371 is important to the functionality of the Gcn5p bromodomain. In the simulation a point mutation involving this highly conserved residue induced an increase in the flexibility of the ZA loop, which in turn modulated the exposure of the binding pocket to the acetyl lysine. The combined double mutations (Pro371Thr-Met372Ala) not only markedly perturb the motion of the ZA loop but also destabilize the entire structure of the bromodomain. Copyright 2005 John Wiley & Sons, Ltd.

  13. Application of 5-ALA for differential diagnostics of stomach diseases

    NASA Astrophysics Data System (ADS)

    Okhotnikova, Natalja L.; Dadvany, Sergey A.; Kuszin, Michail I.; Kharnas, Sergey S.; Zavodnov, Victor Y.; Sklyanskaya, Olga A.; Loschenov, Victor B.; Volkova, Anna I.; Agafonov, Valery V.

    2001-01-01

    59 patients with stomach diseases including gastric cancer or polyp, gastritis, esofagus disease were investigated. Before gastroscopy all patients were given 5-ALA in doses 5mg, 10mg and 20mg per 1kg of body weight orally. Fluorescence diagnostics which estimates concentration of ALA-induced PPIX in regular and alternated tissues of gastric mucosa were carried out in 2-4 hours. Using of 5-ALA has shown high diagnostic effectiveness for differential diagnostics of stomach diseases. This technique has proved 10 diagnosis of cancer and revealed 15 malignant stomach diseases including 4 cancer in situ for patients with preliminary diagnosis of gastric ulcer. It also revealed 5 patients with enhanced fluorescence for which aimed biopsy has shown high degree of inflammation process. The latter were assigned as a risk group.

  14. MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis.

    PubMed

    Nikzad, Hossein; Karimian, Mohammad; Sareban, Kobra; Khoshsokhan, Maryam; Hosseinzadeh Colagar, Abasalt

    2015-11-01

    Methylenetetrahydrofolate reductase (MTHFR) functions as a main regulatory enzyme in folate metabolism. The association of MTHFR gene Ala222Val polymorphism with male infertility in an Iranian population was investigated by undertaking a meta-analysis and in-silico approach. A genetic association study included 497 men; 242 had unexplained infertility and 255 were healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for genotyping MTHFR-Ala222Val. OpenMeta[Analyst] software was used to conduct the analysis; 22 studies were identified by searching PubMed and the currently reported genetic association study. A novel in-silico approach was used to analyse the effects of Ala222Val substitution on the structure of mRNA and protein. Genetic association study revealed a significant association of MTHFR-222Val/Val genotype with oligozoospermia (OR 2.32; 95% CI, 1.12 to 4.78; P = 0.0451) and azoospermia (OR 2.59; 95% CI 1.09 to 6.17; P = 0.0314). Meta-analysis for allelic, dominant and codominant models showed a significant association between Ala222Val polymorphism and the risk of male infertility (P < 0.001). In silico-analysis showed MTHFR-Ala222Val affects enzyme structure and could also change the mRNA properties (P = 0.1641; P < 0.2 is significant). The meta-analysis suggested significant association of MTHFR-Ala222Val with risk of male infertility, especially in Asian populations. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  15. Lack of association between uncoupling protein-2 Ala55Val polymorphism and incident diabetes in the atherosclerosis risk in communities study.

    PubMed

    Bielinski, Suzette J; Pankow, James S; Boerwinkle, Eric; Bray, Molly S; Kao, W H Linda; Folsom, Aaron R

    2008-09-01

    Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

  16. Latest results of 5-ALA-based fluorescence diagnosis and other medical disciplines

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold

    1999-02-01

    Preclinical and clinical studies on 5-aminolevulinic acid (5- ALA) induced Protoporphyrin IX (PPIX) are performed in various departments now following promising clinical results for the detection of bladder cancer in urology. This paper provides an overview on the progress of 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT coordinated by the Laser Research Laboratory of the Ludwig-Maximilians-University in Munich. 5-ALA can be applied either topically or systematically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor visible with naked eyes. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, should improve tumor localization in future.

  17. Conversion of the agent-oriented domain-specific language ALAS into JavaScript

    NASA Astrophysics Data System (ADS)

    Sredojević, Dejan; Vidaković, Milan; Okanović, Dušan; Mitrović, Dejan; Ivanović, Mirjana

    2016-06-01

    This paper shows generation of JavaScript code from code written in agent-oriented domain-specific language ALAS. ALAS is an agent-oriented domain-specific language for writing software agents that are executed within XJAF middleware. Since the agents can be executed on various platforms, they must be converted into a language of the target platform. We also try to utilize existing tools and technologies to make the whole conversion process as simple as possible, as well as faster and more efficient. We use the Xtext framework that is compatible with Java to implement ALAS infrastructure - editor and code generator. Since Xtext supports Java, generation of Java code from ALAS code is straightforward. To generate a JavaScript code that will be executed within the target JavaScript XJAF implementation, Google Web Toolkit (GWT) is used.

  18. Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis.

    PubMed

    Deraos, George; Rodi, Maria; Kalbacher, Hubert; Chatzantoni, Kokona; Karagiannis, Fotios; Synodinos, Loukas; Plotas, Panayiotis; Papalois, Apostolos; Dimisianos, Nikolaos; Papathanasopoulos, Panagiotis; Gatos, Dimitrios; Tselios, Theodore; Apostolopoulos, Vasso; Mouzaki, Athanasia; Matsoukas, John

    2015-08-28

    Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and it has been established that autoreactive T helper (Th) cells play a crucial role in its pathogenesis. Myelin basic protein (MBP) epitopes are major autoantigens in MS, and the sequence MBP87-99 is an immunodominant epitope. We have previously reported that MBP87-99 peptides with modifications at principal T-cell receptor (TCR) contact sites suppressed the induction of EAE symptoms in rats and SJL/J mice, diverted the immune response from Th1 to Th2 and generated antibodies that did not cross react with the native MBP protein. In this study, the linear and cyclic analogs of the MBP87-99 epitope, namely linear (Ala91,Ala96)MBP87-99 (P2) and cyclo(87-99)(Ala91,Ala96)MBP87-99 (P3), were evaluated for their binding to HLA-DR4, stability to lysosomal enzymes, their effect on cytokine secretion by peripheral blood mononuclear cells (PBMC) derived from MS patients or healthy subjects (controls), and their effect in rat EAE. P1 peptide (wild-type, MBP87-99) was used as control. P2 and P3 did not alter significantly the cytokine secretion by control PBMC, in contrast to P1 that induced moderate IL-10 production. In MS PBMC, P2 and P3 induced the production of IL-2 and IFN-γ, with a simultaneous decrease of IL-10, whereas P1 caused a reduction of IL-10 secretion only. The cellular response to P3 indicated that cyclization did not affect the critical TCR contact sites in MS PBMC. Interestingly, the cyclic P3 analog was found to be a stronger binder to HLA-DR4 compared to linear P2. Moreover, cyclic P3 was more stable to proteolysis compared to linear P2. Finally, both P2 and P3 suppressed EAE induced by an encephalitogenic guinea pig MBP74-85 epitope in Lewis rats whereas P1 failed to do so. In conclusion, cyclization of myelin altered peptide ligand (Ala91,Ala96)MBP87-99 improved binding affinity to HLA-DR4, resistance to proteolysis and antigen-specific immunomodulation

  19. Effect of Ala54Thr polymorphism of FABP2 on anthropometric and biochemical variables in response to a moderate-fat diet.

    PubMed

    Martinez-Lopez, Erika; Garcia-Garcia, Maritza R; Gonzalez-Avalos, Jorge M; Maldonado-Gonzalez, Montserrat; Ruiz-Madrigal, Bertha; Vizmanos, Barbara; Hernandez-Nazara, Zamira; Roman, Sonia; Panduro, Arturo

    2013-01-01

    To analyze the effect of the fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism on anthropometric and biochemical variables in response to a moderate-fat diet in overweight or obese subjects. One hundred nine subjects with a body mass index ≥ 25 kg/m(2) were studied. Participants underwent a dietary intervention that consisted of 30% fat (saturated fat <7% of total calories), 15% protein, and 55% carbohydrates. The FABP2 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Anthropometric and biochemical data were measured at baseline, 1 mo, and 2 mo of nutritional intervention. The mean age was 38.6 ± 11.3 y and the mean body mass index 32.7 ± 6.1 kg/m(2), with 20 men (18%) and 89 women (82%). Fifty-three patients (48.6%) had genotype Ala54Ala (wild-type group) and 56 patients had genotype Ala54Thr/Thr54Thr (51.4%, mutant group). At baseline, no significant difference was found between the FABP2 genotypes groups, except for the carbohydrate intake and resting metabolic rate, which were higher in the Ala54Thr/Thr54Thr group (P < 0.05). At 2 mo, participants had lost 6.8% of their initial weight. The Ala54Thr/Thr54Thr group compared with the Ala54Ala group showed significant decreases in the parameters of weight (-7.5 versus -4.2 kg), body mass index (-2.1 versus -1.2 kg/m(2)), waist circumference (-7.6 versus -5.2 cm), waist-to-hip ratio (-0.04 versus -0.02), and C-reactive protein (-1.4 versus -0.76 mg/L), respectively (P < 0.05). After the resting metabolic rate was adjusted, the decreases in waist circumference, waist-to-hip ratio, and C-reactive protein remained significant between the two groups. This study showed that the Thr54 allele carriers responded better to a moderate-fat diet. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. A base substitution in the donor site of intron 12 of KIT gene is responsible for the dominant white coat colour of blue fox (Alopex lagopus).

    PubMed

    Yan, S Q; Hou, J N; Bai, C Y; Jiang, Y; Zhang, X J; Ren, H L; Sun, B X; Zhao, Z H; Sun, J H

    2014-04-01

    The dominant white coat colour of farmed blue fox is inherited as a monogenic autosomal dominant trait and is suggested to be embryonic lethal in the homozygous state. In this study, the transcripts of KIT were identified by RT-PCR for a dominant white fox and a normal blue fox. Sequence analysis showed that the KIT transcript in normal blue fox contained the full-length coding sequence of 2919 bp (GenBank Acc. No KF530833), but in the dominant white individual, a truncated isoform lacking the entire exon 12 specifically co-expressed with the normal transcript. Genomic DNA sequencing revealed that a single nucleotide polymorphism (c.1867+1G>T) in intron 12 appeared only in the dominant white individuals and a 1-bp ins/del polymorphism in the same intron showed in individuals representing two different coat colours. Genotyping results of the SNP with PCR-RFLP in 185 individuals showed all 90 normal blue foxes were homozygous for the G allele, and all dominant white individuals were heterozygous. Due to the truncated protein with a deletion of 35 amino acids and an amino acid replacement (p.Pro623Ala) located in the conserved ATP binding domain, we propose that the mutant receptor had absent tyrosine kinase activity. These findings reveal that the base substitution at the first nucleotide of intron 12 of KIT gene, resulting in skipping of exon 12, is a causative mutation responsible for the dominant white phenotype of blue fox. © 2013 Stichting International Foundation for Animal Genetics.

  1. Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin.

    PubMed

    Wang, Rui-lan; Kang, Fu-xin

    2010-06-01

    Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of pro-atrial natriuretic peptide (pro-ANP) and pro-adrenomedullin (pro-ADM) levels in a cohort of medical intensive care patients and to compare it with that of other known biomarkers and physiological scores. Blood samples of 51 consecutive critically ill patients admitted to the intensive care unit and 53 age-matched healthy control people were evaluated in this prospective study. The prognostic value of pro-ANP and pro-ADM levels was compared with that of acute physiology and chronic health evaluation (APACHE) II scores and various biomarkers such as C-reactive protein, interleukin-6 and procalcitonin. Pro-ANP and pro-ADM were detected by a new sandwich immunoassay. On admission, 25 patients had systemic inflammatory response syndrome (SIRS), 12 sepsis, 9 severe sepsis and 5 septic shock. At that time, the median levels (ng/ml) of pro-ANP and pro-ADM were 87.22 and 0.34 respectively in patients with SIRS, 1533.30 and 2.23 in those with sepsis, 1098.73 and 4.57 in those with severe sepsis, and 1933.94 and 8.21 in those with septic shock. With the increasing severity of disease, the levels of pro-ANP and pro-ADM were gradually increased. On admission, the circulating levels of pro-ANP and pro-ADM in patients with sepsis, severe sepsis, or septic shock were significantly higher in non-survivors than in survivors (P less than 0.05). In a receiver operating characteristic curve analysis for the survival of patients with sepsis, the areas under the curve (AUCs) for pro-ANP and pro-ADM were 0.89 and 0.87 respectively, which was similar to the AUCs for procalcitonin and APACHE II scores. Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

  2. Thermodynamic effects of replacements of Pro residues in helix interiors of maltose-binding protein.

    PubMed

    Prajapati, R S; Lingaraju, G M; Bacchawat, Kiran; Surolia, Avadhesha; Varadarajan, Raghavan

    2003-12-01

    Introduction of Pro residues into helix interiors results in protein destabilization. It is currently unclear if the converse substitution (i.e., replacement of Pro residues that naturally occur in helix interiors would be stabilizing). Maltose-binding protein is a large 370-amino acid protein that contains 21 Pro residues. Of these, three nonconserved residues (P48, P133, and P159) occur at helix interiors. Each of the residues was replaced with Ala and Ser. Stabilities were characterized by differential scanning calorimetry (DSC) as a function of pH and by isothermal urea denaturation studies as a function of temperature. The P48S and P48A mutants were found to be marginally more stable than the wild-type protein. In the pH range of 5-9, there is an average increase in T(m) values of P48A and P48S of 0.4 degrees C and 0.2 degrees C, respectively, relative to the wild-type protein. The other mutants are less stable than the wild type. Analysis of the effects of such Pro substitutions in MBP and in three other proteins studied to date suggests that substitutions are more likely to be stabilizing if the carbonyl group i-3 or i-4 to the mutation site is not hydrogen bonded in the wild-type protein. Copyright 2003 Wiley-Liss, Inc.

  3. Alpha Lipoic Acid (ALA) effects on subchorionic hematoma: preliminary clinical results.

    PubMed

    Porcaro, G; Brillo, E; Giardina, I; Di Iorio, R

    2015-09-01

    The clinic use of alpha Lipoic Acid (ALA) is linked to its capability to exert antioxidant effects and, more interestingly, to counteract the pathologic changes of complex networks of cytokines, chemokines and growth factors, restoring their physiological state. The aim of this randomized controlled clinical trial was to test the contribution of oral supplementation of ALA to the standard treatment with Progesterone vaginal suppositories, in healing subchorionic hematomas in patients with threatened miscarriage. Controls were administered only Progesterone suppositories. Nineteen pregnant women in the first trimester of gestation, with threatened miscarriage and ultrasound evidence of subchorionic hematoma, were included in the trial and randomly divided in two groups: controls, treated with 400 mg Progesterone (200 mg 2 times per day), given by vaginal suppositories, and case study treated with the same Progesterone dosage, plus ALA, given orally at the dose of 600 mg (300 mg 2 times per day, DAV®, Lo.Li. Pharma srl, Italy). Sixteen patients completed the trial. Treatment was performed until complete resolution of the clinical picture. In both groups, the subjects improved significantly but, in general, a better and faster evolution in the major signs of threatened miscarriage was observed in the subjects treated with ALA and Progesterone. In these patients, the speed of resorption of subchorionic hematoma was significantly (p ≤ 0.05) superior compared to controls. The ALA and Progesterone group showed a faster decrease or disappearance of all symptoms than that observed in the control group, however the difference was not significant. These preliminary results suggest that ALA supplementation significantly contributes to speed up the process of restoration of physiological conditions in threatened miscarriage and ameliorates the medical conditions of both the mothers and the foetus, probably modulating the networks of cytokines, growth factors and other

  4. Glacier lake outburst floods caused by glacier shrinkage: case study of Ala-Archa valley, Kyrgyz Ala Too, northern Tian Shan, Kyrgyzstan

    NASA Astrophysics Data System (ADS)

    Petrakov, D.; Erochin, S. A.; Harbor, J.; Ivanov, M.; Rogozhina, I.; Stroeven, A. P.; Usubaliev, R.

    2012-12-01

    Changes in glacier extent and runoff in Central Asia increase socio-economic stress and may result in political conflict between donors of freshwater (Kyrgyzstan, Tajikistan) and recipients of freshwater (Uzbekistan, China). Glaciers in the Pamir and Tian Shan regions have experienced an unprecedented downwasting due to regional climate changes over the past decades. This is because air temperature increases are in some areas accompanied by a decrease in precipitation. Such conditions have already resulted in a reduction of glacier runoff, especially in the northern and western Tian Shan, and an increase of the number and area of glacial lakes in Kyrgyzstan. Even though glacial lakes in the mountains are in general relatively small and located far from densely populated areas, their outbursts often produce destructive debris flows. Such debris flows are especially common in Kyrgyzstan because of its steep river channels and abundance of Holocene and Quaternary glacier deposits that can be remobilized. The glacial lake outburst flood (GLOF) in the Shakhimardan river catchment in 1999, for example, resulted in 100 fatalities in Uzbekistan, and the GLOF from the Zyndan glacial lake led to substantial economic losses in 2009. According to the latest inventory, there are more than 350 glacial lakes in Kyrgyzstan of which about 70 occur in the Kyrgyz Ala Too. The Ala-Archa valley is among the most important glacierized catchments in Kyrgyzstan. Despite the presence of a relatively small glacier-covered area of 36 km2, the Ala-Archa river is of critical importance to the Bishkek area, its agriculture, and its population which currently exceeds one million. GLOFs are therefore a threat to both numerous settlements of touristic value in the Ala-Archa headwaters and to Bishkek. The Teztor lake in the Adygene catchment of the Ala-Archa river system experienced an outburst during 1988 and 2005. On the early morning of July 31, 2012, this lake began draining through a dam

  5. 5-Aminolevulinic Acid (ALA) Alleviated Salinity Stress in Cucumber Seedlings by Enhancing Chlorophyll Synthesis Pathway.

    PubMed

    Wu, Yue; Jin, Xin; Liao, Weibiao; Hu, Linli; Dawuda, Mohammed M; Zhao, Xingjie; Tang, Zhongqi; Gong, Tingyu; Yu, Jihua

    2018-01-01

    5-Aminolevulinic acid (ALA) is a common precursor of tetrapyrroles as well as a crucial growth regulator in higher plants. ALA has been proven to be effective in improving photosynthesis and alleviating the adverse effects of various abiotic stresses in higher plants. However, little is known about the mechanism of ALA in ameliorating the photosynthesis of plant under abiotic stress. In this paper, we studied the effects of exogenous ALA on salinity-induced damages of photosynthesis in cucumber ( Cucumis sativus L.) seedlings. We found that the morphology (plant height, leave area), light utilization capacity of PS II [qL, Y(II)] and gas exchange capacity (Pn, gs, Ci, and Tr) were significantly retarded under NaCl stress, but these parameters were all recovered by the foliar application of 25 mg L -1 ALA. Besides, salinity caused heme accumulation and up-regulation of gene expression of ferrochelatase ( HEMH ) with suppression of other genes involved in chlorophyll synthesis pathway. Exogenously application of ALA under salinity down-regulated the heme content and HEMH expression, but increased the gene expression levels of glutamyl-tRNA reductase ( HEMA1 ), Mg-chelatase ( CHLH ), and protochlorophyllide oxidoreductase ( POR ). Moreover, the contents of intermediates involved in chlorophyll branch were increased by ALA, including protoporphyrin IX (Proto IX), Mg-protoporphyrin IX (Mg-Proto IX, protochlorophyllide (Pchlide), and chlorophyll (Chl a and Chl b ) under salt stress. Ultrastructural observation of mesophyll cell showed that the damages of photosynthetic apparatus under salinity were fixed by ALA. Collectively, the chlorophyll biosynthesis pathway was enhanced by exogenous ALA to improve the tolerance of cucumber under salinity.

  6. PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells.

    PubMed

    Barbero, P; Rovère, C; De Bie, I; Seidah, N; Beaudet, A; Kitabgi, P

    1998-09-25

    Among the members of the proprotein convertase (PC) family, PC1 and PC2 have well established roles as prohormone convertases. Another good candidate for this role is PC5-A that has been shown to be present in the regulated secretory pathway of certain neuroendocrine tissues, but evidence that it can process prohormones is lacking. To determine whether PC5-A could function as a prohormone convertase and to compare its cleavage specificity with that of PC1 and PC2, we stably transfected the rat pheochromocytoma PC12 cell line with PC5-A and analyzed the biosynthesis and subcellular localization of the enzyme, as well as its ability to process pro-neurotensin/neuromedin N (pro-NT/NN) into active peptides. Our data showed that in transfected PC12 cells, PC5-A was converted from its 126-kDa precursor form into a 117-kDa mature form and, to a lesser extent, into a C-terminally truncated 65-kDa form of the 117-kDa product. Metabolic and immunochemical studies showed that PC5-A was sorted to early compartments of the regulated secretory pathway where it colocalized with immunoreactive NT. Furthermore, pro-NT/NN was processed in these compartments according to a pattern that differed from that previously described in PC1- and PC2-transfected PC12 cells. This pattern resembled that previously reported for pro-NT/NN processing in the adrenal medulla, a tissue known to express high levels of PC5-A. Altogether, these data demonstrate for the first time the ability of PC5-A to function as a prohormone convertase in the regulated secretory pathway and suggest a role for this enzyme in the physiological processing of pro-NT/NN.

  7. The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor

    PubMed Central

    2013-01-01

    Background To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. Results ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. Conclusion C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor. PMID:24341457

  8. The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor.

    PubMed

    Sanders, Jarred; Nagy, Stanislav; Fetterman, Graham; Wright, Charles; Treinin, Millet; Biron, David

    2013-12-17

    To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor.

  9. proBAMconvert: A Conversion Tool for proBAM/proBed.

    PubMed

    Olexiouk, Volodimir; Menschaert, Gerben

    2017-07-07

    The introduction of new standard formats, proBAM and proBed, improves the integration of genomics and proteomics information, thus aiding proteogenomics applications. These novel formats enable peptide spectrum matches (PSM) to be stored, inspected, and analyzed within the context of the genome. However, an easy-to-use and transparent tool to convert mass spectrometry identification files to these new formats is indispensable. proBAMconvert enables the conversion of common identification file formats (mzIdentML, mzTab, and pepXML) to proBAM/proBed using an intuitive interface. Furthermore, ProBAMconvert enables information to be output both at the PSM and peptide levels and has a command line interface next to the graphical user interface. Detailed documentation and a completely worked-out tutorial is available at http://probam.biobix.be .

  10. Improve efficacy of topical ALA-PDT by calcipotriol through up-regulation of coproporphyrinogen oxidase.

    PubMed

    Yang, Deng-Fu; Chen, Jia-Haur; Chiang, Chun-Pin; Huang, Zheng; Lee, Jeng-Woei; Liu, Chung-Ji; Chang, Junn-Liang; Hsu, Yih-Chih

    2014-09-01

    Topical 5-aminolevulinic acid-mediated photodynamic therapy (topical ALA-PDT) is effective for treating oral precancerous lesions. The aim of this in vivo and in vitro study was to examine whether the efficacy of topical ALA-PDT could be further improved by calcipotriol (CAL). Precancerous lesions in the buccal pouch of hamsters were induced by dimethylbenz(a)anthracene (DMBA). Lesions were treated with multiple topical ALA-PDT with or without CAL pretreatment. ALA-induced protoporphyrine IX (PpIX) was monitored by in situ fluorescence measurement. The effect of CAL on heme-related enzymes (CPOX, PPOX, and FECH) were examined in an in vitro model using human squamous cell carcinoma (SCC) cells (SCC4, SAS) using Western blots. Fluorescence spectroscopy revealed that PpIX reached its peak level in precancerous epithelial cells of buccal pouch at 2.5 or 3.5h without or with CAL pretreatment, respectively. Both treatment regimens showed similar response rates, but the complete response was achieved after 5 times of ALA-PDT and 3 times of CAL-ALA-PDT (p<0.001). Pretreatment of SCC cells with 10(-8) or 10(-7)M CAL could result in a significant cell death (p<0.05) and an elevation of CPOX protein level. Topical CAL can improve the efficacy of ALA-PDT in treating precancerous lesions, likely through the increase in CPOX level and in PpIX production. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. In vitro antioxidant activities of the novel pentapeptides Ser-His-Glu-Cys-Asn and Leu-Pro-Phe-Ala-Met and the relationship between activity and peptide secondary structure.

    PubMed

    Yang, Ruiwen; Wang, Jia; Lin, Songyi; Ye, Haiqing; Chen, Feng

    2017-04-01

    Using high-performance liquid chromatography/tandem mass spectrometry, two novel antioxidant pentapeptides [Ser-His-Glu-Cys-Asn (SHECN) and Leu-Pro-Phe-Ala-Met (LPFAM)] were identified from 1-3-kDa soybean protein hydrolysates (SPH). The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was used to evaluate cytotoxicity in HepG2 cells. Antioxidant activity was measured using in vitro assays, including the cellular antioxidant activity assay (CAA), 2,2-diphenyl-1-picrylhydrazyl or 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) inhibition, and oxygen radical absorbance capacity (ORAC) assays. Finally, the secondary structure was determined using circular dichroism (CD). The results revealed that two novel peptides were nontoxic and possessed antioxidant activity. SHECN had significantly higher antioxidant activity than LPFAM (P < 0.05). The CAA value of SHECN was 776.22 µmol QE 100 g -1 . SHECN also showed significant DPPH inhibition (70.18 ± 4.06%) and ABTS inhibition (88.16 ± 0.76%). It had normalized ORAC values of 0.3000 ± 0.0070 µmol GE mg -1 and 0.0900 ± 0.0020 µmol TE mg -1 , respectively. The results of the CD analysis demonstrated that, compared to LPFAM, which had much lower antioxidant activity, SHECN had a high β-sheet content and reduced α-helix content. The results indicated that SHECN possessed high antioxidant activity. A higher β-sheet content and lower content levels of α-helix appear to be correlated with antioxidant activity. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  12. Temperature- and Length-Dependent Energetics of Formation for Polyalanine Helices in Water: Assignment of wAla(n,T) and Temperature-Dependent CD Ellipticity Standards

    PubMed Central

    Job, Gabriel E.; Kennedy, Robert J.; Heitmann, Björn; Miller, Justin S.; Walker, Sharon M.; Kemp*, Daniel S.

    2006-01-01

    Length-dependent helical propensities wAla(n,T) at T = 10, 25, and 60 °C are assigned from t/c values and NMR 13C chemical shifts for series 1 peptides TrpLysmInp2tLeu–AlantLeuInp2LysmNH2, n = 15, 19, and 25, m = 5, in water. Van’t Hoff analysis of wAla(n,T) show that α-helix formation is primarily enthalpy-driven. For series 2 peptides Ac–Trp Lys5Inp2tLeu–βAspHel–Alan–beta–tLeuInp2Lys5NH2, n = 12 and 22, which contain exceptionally helical Alan cores, protection factor-derived fractional helicities FH are assigned in the range 10–30 °C in water and used to calibrate temperature-dependent CD ellipticities [θ]λ,H,n,T. These are applied to CD data for series 1 peptides, 12 ≤ n ≤ 45, to confirm the wAla(n,T) assignments at T = 25 and 60 °C. The [θ]λ,H,n,T are temperature dependent within the wavelength region, 222 ± 12 nm, and yield a temperature correction for calculation of FH from experimental values of [θ]222,n,T,Exp. PMID:16787087

  13. 5-ALA photopreparation using pulsed NIR enhances skin fluorescence via temperature-independent cell signaling pathways

    NASA Astrophysics Data System (ADS)

    Barolet, Augustin C.; Cormack, Gregory; Barolet, Daniel

    2018-02-01

    The effect of near infrared light (940 nm) on the conversion of 5-aminolevulinic acid (5-ALA) to PpIX, a compound involved in photodynamic therapy (PDT), was examined. The back skin of three test subjects was irradiated with continuous wavelength and pulsed infrared light at 940 nm. These irradiations took place 50-53, 24-29, and 8-14 hours prior to the application of the 5-ALA. After a three-hour incubation period with 5-ALA, a FluoDerm™device was used to measure the fluorescence of the skin (emitting wavelength: 400-420 nm; measuring excitation wavelength: 610-720 nm), a direct indication of the activity of 5-ALA. 5-ALA must penetrate the skin and then be converted to PpIX before any fluorescence increase can be observed. Results: For two patients (one was disqualified), the continuous wavelength, 50 hour pre-irradiation condition, the FluoDerm readings showed a 19 to 23% increase in fluorescence (p = 0.05) compared to the no-irradiation, 5-ALA only control.

  14. Pro-Anorexia and Anti-Pro-Anorexia Videos on YouTube: Sentiment Analysis of User Responses.

    PubMed

    Oksanen, Atte; Garcia, David; Sirola, Anu; Näsi, Matti; Kaakinen, Markus; Keipi, Teo; Räsänen, Pekka

    2015-11-12

    Pro-anorexia communities exist online and encourage harmful weight loss and weight control practices, often through emotional content that enforces social ties within these communities. User-generated responses to videos that directly oppose pro-anorexia communities have not yet been researched in depth. The aim was to study emotional reactions to pro-anorexia and anti-pro-anorexia online content on YouTube using sentiment analysis. Using the 50 most popular YouTube pro-anorexia and anti-pro-anorexia user channels as a starting point, we gathered data on users, their videos, and their commentators. A total of 395 anorexia videos and 12,161 comments were analyzed using positive and negative sentiments and ratings submitted by the viewers of the videos. The emotional information was automatically extracted with an automatic sentiment detection tool whose reliability was tested with human coders. Ordinary least squares regression models were used to estimate the strength of sentiments. The models controlled for the number of video views and comments, number of months the video had been on YouTube, duration of the video, uploader's activity as a video commentator, and uploader's physical location by country. The 395 videos had more than 6 million views and comments by almost 8000 users. Anti-pro-anorexia video comments expressed more positive sentiments on a scale of 1 to 5 (adjusted prediction [AP] 2.15, 95% CI 2.11-2.19) than did those of pro-anorexia videos (AP 2.02, 95% CI 1.98-2.06). Anti-pro-anorexia videos also received more likes (AP 181.02, 95% CI 155.19-206.85) than pro-anorexia videos (AP 31.22, 95% CI 31.22-37.81). Negative sentiments and video dislikes were equally distributed in responses to both pro-anorexia and anti-pro-anorexia videos. Despite pro-anorexia content being widespread on YouTube, videos promoting help for anorexia and opposing the pro-anorexia community were more popular, gaining more positive feedback and comments than pro-anorexia videos

  15. Surviving the Tremors: ALA in San Francisco.

    ERIC Educational Resources Information Center

    Wilson Library Bulletin, 1992

    1992-01-01

    Reports on the American Library Association (ALA) 1992 Annual Conference. Highlights include awards given; libraries' futures; bibliographic instruction; NREN (National Research and Education Network); telecommunications; lack of status in librarianship; proposed guidelines for patron behavior; interlibrary loan; the Americans with Disabilities…

  16. Topical application of ALA PDT for the treatment of moderate to severe acne vulgaris

    NASA Astrophysics Data System (ADS)

    Wang, Xiu-Li; Wang, Hong-Wei; Zhang, Ling-Lin; Su, Lina; Guo, Ming-Xia; Huang, Zheng

    2009-06-01

    Objectives: To evaluate the effectiveness of topical 5-aminolevulinic acid (ALA)- medicated photodynamic therapy (ALA PDT) for the treatment of moderate to severe acne vulgaris. Methods: Sixteen Chinese patients with moderate to severe facial acne were treated with 1-3 courses of ALA PDT. ALA cream (3%) was freshly prepared and applied to acne lesions for 3-4 h. The lesions were irradiated by a 635 nm diode laser at dose levels of 60 - 80 J/cm2 at 100 mW/cm2. Clinical assessments were conducted before and after treatment up to 3 months. Results: All patents showed response to ALA PDT. Complete clearance was seen in 10 patients (62.5%) and partial clearance in 6 patients (37.5%). One case showed recurrence after complete clearance at 2 months and another two showed recurrence after complete clearance at 3 months. However, the number of new lesions were significantly reduced. Adverse effects were minimal. Conclusions: The results of this preliminary clinical study is encouraging. ALA PDT is a simple, safe and useful therapeutic option for the treatment of moderate to severe acne. Further studies to evaluate the treatment with a larger number of patients and for a longer period of follow-up are needed.

  17. 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.

  18. Synthesis and characterization of 12-aminolauric acid-modified montmorillonite for catalytic application

    NASA Astrophysics Data System (ADS)

    Pagtalunan, Cris Angelo M.; Sumera, Florentino C.; Conato, Marlon T.

    2018-05-01

    The simple cation-exchange preparation of 12-aminolauric acid-modified montmorillonite (ALA-Mt), an aluminosilicate clay modified with the alkylammonium surfactant, is reported. Different loadings of 12-aminolauric acid (12-ALA) from 100 to 400 times the cation exchange capacity (CEC) in montmorillonite (Mt) was prepared and studied. Successful intercalation of the organic surfactant was monitored by the increase in basal (d001) spacing of the organoclay compared to the pure Mt. The clay mineral composite have increased surfactant loading resulting to lower degradation temperatures, rougher surface morphology, increased particle size, and increased organophilicity of the organoclay compared to the native Mt. The improved properties of ALA-Mt present it as an attractive catalyst material for polymerization reactions.

  19. The 1993 AIA/ALA Building Award Recipients.

    ERIC Educational Resources Information Center

    Muller, Karen

    1993-01-01

    Describes the eight library buildings that won the 1993 Awards of Excellence for Library Architecture from the American Institute of Architects (AIA) and the American Library Association (ALA) including one adaptive reuse, four expansions, two new buildings, and one temporary building. (EAM)

  20. Preparation of antioxidative corn protein hydrolysates, purification and evaluation of three novel corn antioxidant peptides.

    PubMed

    Jin, Du-Xin; Liu, Xiao-Lan; Zheng, Xi-Qun; Wang, Xiao-Jie; He, Jun-Fang

    2016-08-01

    Corn gluten meal is a major co-product of corn wet milling. Corn gluten meal was hydrolyzed with Alcalase, Flavourzyme, Alcalase+Flavourzyme and Flavourzyme+Alcalase. At the substrate concentration of 10%, corn protein hydrolysate catalyzed by Alcalase had a degree of hydrolysis of 17.83%, which was higher than that by Flavourzyme (3.65%). The hydrolysate catalyzed by Alcalase+Flavourzyme exhibited better antioxidant activities and was further purified. Three novel antioxidant peptides were purified by a series of chromatographic techniques. Sequences of the three peptides were identified as Cys-Ser-Gln-Ala-Pro-Leu-Ala, Tyr-Pro-Lys-Leu-Ala-Pro-Asn-Glu and Tyr-Pro-Gln-Leu-Leu-Pro-Asn-Glu, respectively. Among the three peptides, Cys-Ser-Gln-Ala-Pro-Leu-Ala exhibited good reducing power and excellent scavenging capacities for DPPH radical and superoxide anion radical, with IC50 values of 0.116 and 0.39mg/ml, respectively. The results from our study indicate antioxidant potency of corn protein hydrolysates and peptides separated from corn gluten meal and can provide basic understanding for the application of corn protein hydrolysates as natural antioxidants. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Purification and Characterization of an X-Prolyl-Dipeptidyl Peptidase from Lactobacillus sakei

    PubMed Central

    Sanz, Yolanda; Toldrá, Fidel

    2001-01-01

    An X-prolyl-dipeptidyl peptidase has been purified from Lactobacillus sakei by ammonium sulfate fractionation and five chromatographic steps, which included hydrophobic interaction, anion-exchange chromatography, and gel filtration chromatography. This procedure resulted in a recovery yield of 7% and an increase in specificity of 737-fold. The enzyme appeared to be a dimer with a subunit molecular mass of approximately 88 kDa. Optimal activity was shown at pH 7.5 and 55°C. The enzyme was inhibited by serine proteinase inhibitors and several divalent cations (Cu2+, Hg2+, and Zn2+). The enzyme almost exclusively hydrolyzed X-Pro from the N terminus of each peptide as well as fluorescent and colorimetric substrates; it also hydrolyzed X-Ala at the N terminus, albeit at lower rates. Km s for Gly-Pro- and Lys-Ala-7-amido-4-methylcoumarin were 29 and 88 μM, respectively; those for Gly-Pro- and Ala-Pro-p-nitroanilide were 192 and 50 μM, respectively. Among peptides, β-casomorphin 1-3 was hydrolyzed at the highest rates, while the relative hydrolysis of the other tested peptides was only 1 to 12%. The potential role of the purified enzyme in the proteolytic pathway by catalyzing the hydrolysis of peptide bonds involving proline is discussed. PMID:11282638

  2. New developments in fluorescence detection of ALA-induced protoporphyrin IX for cancer localization

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Baumgartner, Reinhold; Betz, Christian; Bise, Karl; Brand, P.; Gamarra, Fernando; Haeussinger, Karl; Hillemanns, Peter; Huber, Rudolf M.; Knuechel, Ruth; Kriegmair, M.; Leunig, Andreas; Pichler, J.; Rick, Kai; Schulz, H.; Stanzel, F.; Stocker, Susanne; Wagner, Simon; Weigandt, H.

    1997-12-01

    After the very promising clinical results for the detection of bladder cancer in urology, preclinical and clinical studies on aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) are preformed in various disciplines now. This paper provides a brief overview of the progress on 5-ALA assisted fluorescence diagnosis in urology, pulmonology, neurosurgery, gynecology and ENT performed in collaboration with the Laser Research Laboratory at the Department of Urology of the Ludwig-Maximilians-University in Munich. Five-ALA can be applied either topically or systemically to induce an intracellular accumulation of fluorescing PPIX. With appropriate dosage of 5-ALA, malignant tissue can be stained selectively, and irradiation with violet light excites a bright red fluorescence of the tumor. Optical properties of the tissue tend to hamper the precise identification and demarcation of suspect areas in fluorescence images. Multicolor remission and fluorescence imaging, therefore, seems to be indispensable for a reliable tumor localization.

  3. The Thr92Ala 5′ Type 2 Deiodinase Gene Polymorphism Is Associated with a Delayed Triiodothyronine Secretion in Response to the Thyrotropin-Releasing Hormone–Stimulation Test: A Pharmacogenomic Study

    PubMed Central

    Butler, Peter W.; Smith, Sheila M.; Linderman, Joyce D.; Brychta, Robert J.; Alberobello, Anna Teresa; Dubaz, Ornella M.; Luzon, Javier A.; Skarulis, Monica C.; Cochran, Craig S.; Wesley, Robert A.; Pucino, Frank

    2010-01-01

    Background The common Thr92Ala D2 polymorphism has been associated with changes in pituitary–thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)–mediated TSH stimulation of the thyroid gland. Methods Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. Results No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups. Conclusions The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis. PMID:21054208

  4. Scavengers modifying the phototoxicity induced by ALA-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Casas, Adriana; Perotti, Christian; Fukuda, Haydee; Batlle, Alcira

    2001-04-01

    The exogenously stimulated formation of intracellularly generated Protoporphyrin IX, a precursor of heme, is becoming one of the fastest developing areas in the field of Photodynamic Therapy (PDT). We have examined the degree of protection of several scavengers, aminoacids and compounds related to glutathione metabolism, to the photodamage induced by 5-aminolevulinic acid (ALA)-mediated PDT, employing the LM2 cell line, derived from a mammary murine adenocarcinoma. We have exposed the cells to different concentrations of the scavengers, 24 before PDT, during PDT, and 19 hr after treatment. We defined the protection grade (PG) as the ratio between cell survival after ALA-PDT treatment in the presence of the protector and cell survival after ALA-PDT treatment. We found that L-tryptophan (PG=8.3 at 2mM), N-acetyl-L-cysteine (PG= 7.9 at 30 mM), L-cysteine (PG=7.81 at 8mM), S-adenosyl-L-methionine (PG= 7.86 at 8mM), melatonin (PG=6.81 at 8mM) and glycine (PG=6.8 at 40 mM) are the best protectors to PDT damage, followed by L-methionine (PG=4.38 at 0.8 mM), mannitol (PG=2.32 at 2 mM) and reduced glutathione (PG=3.41 at 0.8 mM), whereas oxidized glutathione does not exert any protection. The implications of these results in the photodamage induced by ALA-PDT is discussed.

  5. Bacterial resistance to vancomycin: overproduction, purification, and characterization of VanC2 from Enterococcus casseliflavus as a D-Ala-D-Ser ligase.

    PubMed

    Park, I S; Lin, C H; Walsh, C T

    1997-09-16

    The VanC phenotype for clinical resistance of enterococci to vancomycin is exhibited by Enterococcus gallinarum and Enterococcus casseliflavus. Based on the detection of the cell precursor UDP-N-acetylmuramic acid pentapeptide intermediate terminating in D-Ala-D-Ser instead of D-Ala-D-Ala, it has been predicted that the VanC ligase would be a D-Ala-D-Ser rather than a D-Ala-D-Ala ligase. Overproduction of the E. casseliflavus ATCC 25788 vanC2 gene in Escherichia coli and its purification to homogeneity allowed demonstration of ATP-dependent D-Ala-D-Ser ligase activity. The kcat/Km2 (Km2 = Km for D-Ser or C-terminal D-Ala) ratio for D-Ala-D-Ser/D-Ala-D-Ala dipeptide formation is 270/0.69 for a 400-fold selection against D-Ala in the C-terminal position. VanC2 also has substantial D-Ala-D-Asn ligase activity (kcat/Km2 = 74 mM-1min-1).

  6. Gene-gene interaction between PPAR gamma 2 and ADR beta 3 increases obesity risk in children and adolescents.

    PubMed

    Ochoa, M C; Marti, A; Azcona, C; Chueca, M; Oyarzábal, M; Pelach, R; Patiño, A; Moreno-Aliaga, M J; Martínez-González, M A; Martínez, J A

    2004-11-01

    Multiple genes are likely to be involved in obesity and these genes may interact with environmental factors to influence obesity risk. Our aim was to explore the synergistic contribution of the two polymorphisms: Pro12Ala of the PPAR gamma 2 gene and Trp64Arg of the ADR beta 3 gene to obesity risk in a Spanish children and adolescent population. We designed a sex- and age-matched case-control study. Participants were 185 obese and 185 control children (aged 5-18 y) from the Navarra region, recruited through Departments of Pediatrics (Hospital Virgen del Camino, Navarra University Clinic and several Primary Health Centers). The obesity criterion (case definition) was BMI above the 97th percentile according to Spanish BMI reference data for age and gender. Anthropometric parameters were measured by standard protocols. The genotype was assessed by PCR-RFLP after digestion with BstUI for PPAR gamma 2 mutation and BstNI for ADR beta 3 variants. Face-to-face interviews were conducted to assess the physical activity. Using a validated physical activity questionnaire, we computed an activity metabolic equivalent index (METs h/week), which represents the physical exercise during the week for each participant. Statistical analysis was performed by conditional logistic regression, taking into account the matching between cases and controls. Carriers of the polymorphism Pro12Ala of the PPAR gamma 2 gene had a significantly higher obesity risk than noncarriers (odds ratio (OR)=2.18, 95% CI=1.09-4.36) when we adjusted for sex, age and physical activity. Moreover, the risk of obesity was higher (OR=2.59, 95% CI=1.17-5.34) when family history of obesity was also taken into account in the model. The OR for obesity linked to both polymorphisms (PPAR gamma 2 and ADR beta 3) was 5.30 (95% CI=1.08-25.97) when we adjusted for sex, age and physical activity. After adjustment for family history of obesity, the OR for carriers of both polymorphisms was 19.5 (95% CI=2.43-146.8). A

  7. Pro-Anorexia and Anti-Pro-Anorexia Videos on YouTube: Sentiment Analysis of User Responses

    PubMed Central

    Garcia, David; Sirola, Anu; Näsi, Matti; Kaakinen, Markus; Keipi, Teo; Räsänen, Pekka

    2015-01-01

    Background Pro-anorexia communities exist online and encourage harmful weight loss and weight control practices, often through emotional content that enforces social ties within these communities. User-generated responses to videos that directly oppose pro-anorexia communities have not yet been researched in depth. Objective The aim was to study emotional reactions to pro-anorexia and anti-pro-anorexia online content on YouTube using sentiment analysis. Methods Using the 50 most popular YouTube pro-anorexia and anti-pro-anorexia user channels as a starting point, we gathered data on users, their videos, and their commentators. A total of 395 anorexia videos and 12,161 comments were analyzed using positive and negative sentiments and ratings submitted by the viewers of the videos. The emotional information was automatically extracted with an automatic sentiment detection tool whose reliability was tested with human coders. Ordinary least squares regression models were used to estimate the strength of sentiments. The models controlled for the number of video views and comments, number of months the video had been on YouTube, duration of the video, uploader’s activity as a video commentator, and uploader’s physical location by country. Results The 395 videos had more than 6 million views and comments by almost 8000 users. Anti-pro-anorexia video comments expressed more positive sentiments on a scale of 1 to 5 (adjusted prediction [AP] 2.15, 95% CI 2.11-2.19) than did those of pro-anorexia videos (AP 2.02, 95% CI 1.98-2.06). Anti-pro-anorexia videos also received more likes (AP 181.02, 95% CI 155.19-206.85) than pro-anorexia videos (AP 31.22, 95% CI 31.22-37.81). Negative sentiments and video dislikes were equally distributed in responses to both pro-anorexia and anti-pro-anorexia videos. Conclusions Despite pro-anorexia content being widespread on YouTube, videos promoting help for anorexia and opposing the pro-anorexia community were more popular, gaining more

  8. Effect of oscillation dynamics on long-range electron transfer in a helical peptide monolayer.

    PubMed

    Matsushita, Daisuke; Uji, Hirotaka; Kimura, Shunsaku

    2018-06-06

    Electron transfer (ET) reactions via helical peptides composed of -(Aib-Pro)n- were studied in self-assembled monolayers and compared with -(Ala-Aib)n- peptides. Short Aib-Pro peptides showed slightly higher ET rates due to the better electronic coupling of the Pro residue. But, the 24mer Aib-Pro peptide showed a smaller ET rate than the corresponding Ala-Aib peptide. On the basis of DFT calculations, the deceleration of the ET rate of the longer Aib-Pro peptide is considered to be due to the smaller number of active modes of accordion-like oscillations than the Ala-Aib peptide, which has a strong influence on a long-range ET reaction.

  9. Primary structure of pancreatic polypeptide from four species of Perissodactyla (Przewalski's horse, zebra, rhino, tapir).

    PubMed

    Henry, J S; Lance, V A; Conlon, J M

    1991-12-01

    Pancreatic polypeptide (PP) has been purified from extracts of the pancreas of four species of odd-toed ungulates (Perissodactyla): Przewalski's horse, mountain zebra, white rhinoceros, and mountain tapir. The amino acid sequence of Przewalski's horse pancreatic polypeptide was established as Ala-Pro-Met-Glu-Pro-Val-Tyr-Pro-Gly-Asp10-Asn- Ala-Thr-Pro-Glu-Gln-Met-Ala-Gln-Tyr20-Ala-Ala-Glu-Leu-Arg-Arg-Tyr- Ile-Asn-Met30 - Leu-Thr-Arg-Pro-Arg-Tyr.NH2. Zebra PP was identical to Przewalski's horse PP, rhinoceros PP contained three substitutions relative to the horse (Ser for Ala1, Leu for Met3, and Glu for Gln16), and tapir PP contained one substitution relative to the horse (Leu for Met3). On the basis of morphological characteristics and the fossil record, the rhinocerotids are classified with the tapirids in the suborder Ceratomorpha, whereas the horse and zebra belong to a separate suborder, Hippomorpha. On the basis of structural similarity of the PP molecules, however, it would appear that the tapir is more closely related to the horse than to the rhinoceros. These observations provide a further example of the need for extreme caution when inferring taxonomic or phylogenetic relationships between species from the structures of homologous peptides.

  10. D2-Thr92Ala, thyroid hormone levels and biochemical hypothyroidism in preeclampsia.

    PubMed

    Procopciuc, Lucia Maria; Caracostea, Gabriela; Hazi, Georgeta; Nemeti, Georgiana; Stamatian, Florin

    2017-02-01

    To identify if there is a relationship between the deiodinase D2-Thr92Ala genetic variant, thyroid hormone levels and biochemical hypothyroidism in preeclampsia. We genotyped 125 women with preeclampsia and 131 normal pregnant women using PCR-RFLP. Serum thyroid hormone levels were determined using ELISA. Our study showed higher TSH and FT4 levels and lower FT3 levels in women with preeclampsia compared to normal pregnant women, with statistical significance for women with mild and severe preeclampsia. The risk to develop pregnancy-induced hypertension (PIH), mild or severe preeclampsia was increased in carriers of at least one D2-Ala92 allele. TSH and FT4 levels were significantly higher and FT3 levels were significantly lower in preeclamptic women with severe preeclampsia if they carried the D2-Ala92 allele compared to non-carriers. Pregnant women with PIH and mild preeclampsia, carriers of at least one D2-Ala92 allele, delivered at lower gestational age neonates with a lower birth weight compared to non-carriers, but the results were statistically significant only in severe preeclampsia. The D2-Thr92Ala genetic variant is associated with the severity and the obstetric outcome of preeclampsia, and it also influences thyroid hormone levels. The study demonstrates non-thyroidal biochemical hypothyroidism - as a result of deiodination effects due to D2 genotypes.

  11. Shark island pedicle flap for repair of combined nasal ala-perialar defects.

    PubMed

    Cvancara, Joseph L; Wentzell, J Michael

    2006-05-01

    The combined nasal ala-perialar defect involving the concave intersection of the lateral nasal ala, nasal sidewall, cheek, and upper cutaneous lip is a problem for reconstructive surgery. During repair of combined cheek and nose defects, it is important not to blunt the alar facial sulcus. Defects involving these adjacent cosmetic units can be repaired by using combination procedures such as a flap/graft. Our purpose is to introduce, describe, and illustrate a one-stage flap repair descriptively named the "shark" island pedicle flap (SIPF). The SIPF was developed for a specific combined nasal ala-perialar defect. This reconstruction restores the natural contours, preserves cosmetic boundaries, and eliminates the need for pexing sutures and graft/flap combinations. The SIPF is an island pedicle flap with a superior arm that rotates 90 degrees into the wound. This arm repairs the alar portion of the defect. The advancing island pedicle flap repairs the alar facial sulcus. The 90 degrees rotation of the superior arm forces the alar portion of the flap to tilt 90 degrees relative to the remaining body of the flap, forming an inverted cone of redundancy. Natural re-creation of the lateral ala and the alar facial sulcus results. Illustrative examples with a descriptive technique are provided for the SIPF. A well-planned SIPF reconstruction can provide exceptional cosmetic and functional results. Cutaneous reconstructive surgeons will find the SIPF useful and reproducible in their armamentarium for single-stage aesthetic and functional repair of a specific combined lateral ala-adjacent perialar tissue defect.

  12. Using the ALA's "Evaluating Library Instruction" (1996).

    ERIC Educational Resources Information Center

    Roselle, Ann

    1997-01-01

    Using a multi-method approach--student and faculty surveys and a comparison of bibliographies from senior nursing students--to evaluate the Information Literacy Skills Program at the University of Botswana, this study found that information about the impact of instruction can be discovered through more open-ended questions; the ALA's…

  13. The complex filling of alae crater, Kilauea Volcano, Hawaii

    USGS Publications Warehouse

    Swanson, D.A.; Duffield, W.A.; Jackson, D.B.; Peterson, D.W.

    1972-01-01

    Since February 1969 Alae Crater, a 165-m-deep pit crater on the east rift of Kilauea Volcano, has been completely filled with about 18 million m3 of lava. The filling was episodic and complex. It involved 13 major periods of addition of lava to the crater, including spectacular lava falls as high as 100 m, and three major periods of draining of lava from the crater. Alae was nearly filled by August 3, 1969, largely drained during a violent ground-cracking event on August 4, 1969, and then filled to the low point on its rim on October 10, 1969. From August 1970 to May 1971, the crater acted as a reservoir for lava that entered through subsurface tubes leading from the vent fissure 150 m away. Another tube system drained the crater and carried lava as far as the sea, 11 km to the south. Much of the lava entered Alae by invading the lava lake beneath its crust and buoying the crust upward. This process, together with the overall complexity of the filling, results in a highly complicated lava lake that would doubtless be misinterpreted if found in the fossil record. ?? 1972 Stabilimento Tipografico Francesco Giannini & Figli.

  14. Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium

    PubMed Central

    Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Objective Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). Materials and Methods In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Results Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. Conclusion ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions. PMID:27540524

  15. Overexpression of Annexin A1 Suppresses Pro-Inflammatory Factors in PC12 Cells Induced by 1-Methyl-4-Phenylpyridinium.

    PubMed

    Kiani-Esfahani, Abbas; Kazemi Sheykhshabani, Sedigheh; Peymani, Maryam; Hashemi, Motahare-Sadat; Ghaedi, Kamran; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Annexin A1 (ANXA1) is suggested to have anti-inflammatory function. However, the precise function of ANXA1 has remained unclear. In this study, we therefore examined the potency of ANXA1 in regulating reactive oxygen species (ROS) production and suppressing pro-inflammatory responses in PC12 cells induced by 1-methyl-4-phenylpyridinium (MPP+). In this experimental study, cDNA of ANXA1 was cloned and inserted to the PGL268 pEpi-FGM18F vector to produce a recombinant PGL/ANXA1 vector for transfection into the PC12 cells. ANXA1 transfected cells were then treated with MPP+. Apoptosis and the content of pro-inflammatory factors including ROS, Interlukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were assessed by flow-cytometry, real-time quantitative polymerase chain reaction (RT-qPCR) and western blot in ANXA1-transfected cells and the data were compared with those obtained from mock and control cells. Data revealed that overexpression of ANXA1 is associated with decreased levels of ROS and expression level of IL-6 and iNOS transcripts, and NF-κB protein in MPP+ treated PC12 cells. ANXA1 may be considered as an agent for prevention of neurodegenerative or inflammatory conditions.

  16. Conformational and chemical selection by a trans-acting editing domain

    PubMed Central

    Danhart, Eric M.; Bakhtina, Marina; Cantara, William A.; Kuzmishin, Alexandra B.; Ma, Xiao; Sanford, Brianne L.; Vargas-Rodriguez, Oscar; Košutić, Marija; Goto, Yuki; Suga, Hiroaki; Nakanishi, Kotaro; Micura, Ronald; Musier-Forsyth, Karin

    2017-01-01

    Molecular sieves ensure proper pairing of tRNAs and amino acids during aminoacyl-tRNA biosynthesis, thereby avoiding detrimental effects of mistranslation on cell growth and viability. Mischarging errors are often corrected through the activity of specialized editing domains present in some aminoacyl-tRNA synthetases or via single-domain trans-editing proteins. ProXp-ala is a ubiquitous trans-editing enzyme that edits Ala-tRNAPro, the product of Ala mischarging by prolyl-tRNA synthetase, although the structural basis for discrimination between correctly charged Pro-tRNAPro and mischarged Ala-tRNAAla is unclear. Deacylation assays using substrate analogs reveal that size discrimination is only one component of selectivity. We used NMR spectroscopy and sequence conservation to guide extensive site-directed mutagenesis of Caulobacter crescentus ProXp-ala, along with binding and deacylation assays to map specificity determinants. Chemical shift perturbations induced by an uncharged tRNAPro acceptor stem mimic, microhelixPro, or a nonhydrolyzable mischarged Ala-microhelixPro substrate analog identified residues important for binding and deacylation. Backbone 15N NMR relaxation experiments revealed dynamics for a helix flanking the substrate binding site in free ProXp-ala, likely reflecting sampling of open and closed conformations. Dynamics persist on binding to the uncharged microhelix, but are attenuated when the stably mischarged analog is bound. Computational docking and molecular dynamics simulations provide structural context for these findings and predict a role for the substrate primary α-amine group in substrate recognition. Overall, our results illuminate strategies used by a trans-editing domain to ensure acceptance of only mischarged Ala-tRNAPro, including conformational selection by a dynamic helix, size-based exclusion, and optimal positioning of substrate chemical groups. PMID:28768811

  17. ALA 2010: Where to Eat in DC

    ERIC Educational Resources Information Center

    Library Journal, 2010

    2010-01-01

    As host to visitors and transplants from around the world, Washington, DC, benefits from the constant infusion of different cultures. Although most neighborhoods lack a unified culinary flavor, make no mistake: DC is a city of distinctive areas, each with its own style, ensuring that hungry American Library Association (ALA) 2010 conference…

  18. A Prospective Open-label Pilot Study of Fluvastatin on Pro-inflammatory and Pro-thrombotic Biomarkers in Antiphospholipid Antibody Positive Patients

    PubMed Central

    Erkan, Doruk; Willis, Rohan; Murthy, Vijaya L.; Basra, Gurjot; Vega, JoAnn; Ruiz Limón, Patricia; Carrera, Ana Laura; Papalardo, Elizabeth; Martínez-Martínez, Laura Aline; González, Emilio B.; Pierangeli, Silvia S.

    2014-01-01

    Objective: To determine if pro-inflammatory and pro-thrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers. Methods: Four groups of patients (age 18-65) were recruited: a) Primary Antiphospholipid Syndrome (PAPS); b) Systemic Lupus Erythematosus (SLE) with APS (SLE/APS); c) Persistent aPL positivity without SLE or APS (Primary aPL); and d) Persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for three months. At three months, patients stopped the study medication and they were followed for another three months. Blood samples for 12 pro-inflammatory and pro-thrombotic biomarkers were collected monthly for six months. Results: Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin [IL]-6, IL1β, vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF]-□α, interferon [IFN]-α, inducible protein-10 [IP10], soluble CD40 ligand [sCD40L], soluble tissue factor [sTF], and intracellular cellular adhesion molecule [ICAM]-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L, and sTF). Conclusion: Our prospective mechanistic study demonstrates that pro-inflammatory and pro-thrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin-induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients. PMID:23933625

  19. Recombinant Brucella abortus gene expressing immunogenic protein

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

    Mayfield, J.E.; Tabatabai, L.B.

    This patent describes a synthetic recombinant DNA molecule containing a DNA sequence. It comprises a gene of Brucella abortus encoding an immunogenic protein having a molecular weight of approximately 31,000 daltons as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis under denaturing conditions, the protein having an isoelectric point around 4.9, and containing a twenty-five amino acid sequence from its amino terminal end consisting of Gln-Ala-Pro-Thr-Phe-Phe-Arg-Ile-Gly-Thr-Gly-Gly-Thr-Ala-Gly-Thr-Tyr-Tyr-Pro-Ile-Gly-Gly-Leu-Ile-Ala, wherein Gln, Ala, Pro, Thr, Phe, Arg, Ile, Gly, Tyr, and Leu, respectively, represent glutamine, alanine, proline, threonine, phenylalanine, arginine, isolecuine, glycine, tyrosine, and leucine.

  20. Furosemide loading test in a case of homozygous solute carrier family 12, member 1 (SLC12A1) mutation (g.62382825G>A, p.Pro372Leu) in Japanese Black cattle.

    PubMed

    Hasegawa, Kiyotoshi; Sasaki, Shinji; Sakamoto, Yoichi; Takano, Akifumi; Takayama, Megumi; Higashi, Tomoko; Sugimoto, Yoshikazu; Yasuda, Yasuaki

    2017-10-01

    Hydrallantois is the excessive accumulation of fluid in the allantoic cavity in a pregnant animal and is associated with fetal death. We recently identified a recessive missense mutation in the solute carrier family 12, member 1 (SLC12A1) gene (g.62382825G>A, p.Pro372Leu) that is associated with hydrallantois in Japanese Black cattle. Unexpectedly, we found a case of the homozygous risk-allele for SLC12A1 in a calf, using a PCR-based direct DNA sequencing test. The homozygote was outwardly healthy up to 3 months of age and the mother did not exhibit any clinical symptoms of hydrallantois. In order to validate these observations, we performed confirmation tests for the genotype and a diuretic loading test using furosemide, which inhibits the transporter activity of the SLC12A1 protein. The results showed that the calf was really homozygous for the risk-allele. In the homozygous calf, administration of furosemide did not alter urinary Na + or Cl - levels, in contrast to the heterozygote and wild-type calves in which these were significantly increased. These results demonstrate that the SLC12A1 (g.62382825G>A, p.Pro372Leu) is a hypomorphic or loss-of-function mutation and the hydrallantois with this mutation shows incomplete penetrance in Japanese Black cattle. © 2017 Japanese Society of Animal Science.

  1. The importance of being kinked: role of Pro residues in the selectivity of the helical antimicrobial peptide P5.

    PubMed

    Bobone, Sara; Bocchinfuso, Gianfranco; Park, Yoonkyung; Palleschi, Antonio; Hahm, Kyung-Soo; Stella, Lorenzo

    2013-12-01

    Antimicrobial peptides (AMPs) are promising compounds for developing new antibiotic drugs against drug-resistant bacteria. Many of them kill bacteria by perturbing their membranes but exhibit no significant toxicity towards eukaryotic cells. The identification of the features responsible for this selectivity is essential for their pharmacological development. AMPs exhibit few conserved features, but a statistical analysis of an AMP sequence database indicated that many α-helical AMPs surprisingly have a helix-breaking Pro residue in the middle of their sequence. To discriminate among the different possible hypotheses for the functional role of this feature, we designed an analogue of the antimicrobial peptide P5, in which the central Pro was deleted (analogue P5Del). Pro removal resulted in a dramatic increase of toxicity. This was explained by the observation that P5Del binds both charged and neutral membranes, whereas P5 has no appreciable affinity towards neutral bilayers. CD and simulative data provided a rationalization of this behavior. In solution P5, due to the presence of Pro, attains compact conformations, in which its apolar residues are partially shielded from the solvent, whereas P5Del is more helical. These structural differences reduce the hydrophobic driving force for association of P5 to neutral membranes, whereas its binding to anionic bilayers can still take place because of electrostatic attraction. After membrane binding, the Pro residue does not preclude the attainment of a membrane-active amphiphilic helical conformation. These findings shed light on the role of Pro residues in the selectivity of AMPs and provide hints for the design of new, highly selective compounds. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

  2. Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): current clinical and development status

    NASA Astrophysics Data System (ADS)

    Marcus, Stuart L.; Sobel, Russel S.; Golub, Allyn L.; Carroll, Ronald L.; Lundahl, Scott L.; Shulman, D. Geoffrey

    1996-04-01

    Exogenous provision of ALA to many tissues results in the accumulation of sufficient quantities of the endogenous photosensitizer protoporphyrin IX, (PpIX), to produce a photodynamic effect. Therefore, ALA may be considered the only current PDT agent in clinical development which is a biochemical precursor of a photosensitizer. Topical ALA application, followed by exposure to activating light (ALA PDT), has been reported effective for the treatment of a variety of dermatologic diseases including cutaneous T-cell lymphoma, superficial basal cell carcinoma, Bowen's disease, and actinic (solar) keratoses, and is also being examined for treatment of acne and hirsutism. PpIX induced by ALA application also may serve as a fluorescence detection marker for photodiagnosis (PD) of malignant and pre- malignant conditions of the urinary bladder and other organs. Local internal application of ALA has also been used for selective endometrial ablation in animal model systems and is beginning to be examined in human clinical studies. Systemic, oral administration of ALA has been used for ALA PDT of superficial head and neck cancer, various gastrointestinal cancers, and the condition known as Barrett's esophagus. This brief paper reviews the current clinical and development status of ALA PDT.

  3. Potentiation of ALA-PDT antitumor activity in mice using topical DMXAA

    NASA Astrophysics Data System (ADS)

    Marrero, Allison; Sunar, Ulas; Sands, Theresa; Oseroff, Allan; Bellnier, David

    2009-06-01

    Photodynamic treatment of subcutaneously implanted Colon 26 tumors in BALB/c mice using the aminolevulinic acid (ALA)-induced photosensitizer protoporphyrin IX (PpIX) was shown to be enhanced by the addition of the vascular disrupting agent 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA; Novartis ASA404). DMXAA increases vascular permeability and decreases blood flow in both murine and human tumors. Sufficiently high parenteral DMXAA doses can lead to tumor collapse and necrosis. We have previously reported marked enhancement of antitumor activity when PDT, using either Photofrin or HPPH, is combined with low-dose intraperitoneal DMXAA. We now describe the first attempt to combine topically-applied DMXAA with PDT. For this, DMXAA was applied two hours before PpIX-activating light delivery. PDT with ALA-PDT alone (ALA 20%; 80 J/cm2 delivered at 75 mW/cm2) caused a 39% decrease in tumor volume compared to unirradiated controls. Addition of topical DMXAA to ALA-PDT resulted in a 74% reduction in tumor volume. Diffuse correlation spectroscopy (DCS), a non-invasive blood flow imaging method, is being used to understand the mechanism of this effect and to aid in the proper design of the therapy. For instance, our most recent DCS data suggests that the 2-hour interval between the DMXAA and light applications may not be optimum. This preliminary study suggests a potential role for topical DMXAA in combination with PDT for dermatologic tumors.

  4. Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients.

    PubMed

    Adlbrecht, Christopher; Hülsmann, Martin; Strunk, Guido; Berger, Rudolf; Mörtl, Deddo; Struck, Joachim; Morgenthaler, Nils G; Bergmann, Andreas; Jakowitsch, Johannes; Maurer, Gerald; Lang, Irene M; Pacher, Richard

    2009-04-01

    The identification of chronic heart failure (CHF) patients at high risk of adverse outcome remains a challenge. New peptides are emerging that may give additional information. In CHF patients, endothelin (ET) levels predict mortality risk. Adrenomedullin has been shown to predict mortality in ischaemic heart failure, but not in unselected or non-ischaemic CHF patients. Moreover, ADM and ET have never been assessed in one model. The aim of the present study was to assess the prognostic value of midregional-pro-adrenomedullin (MR-proADM) and C-terminal-pro-endothelin-1 (CT-proET-1) in outpatients with CHF. We measured plasma MR-proADM and CT-proET-1 levels in 786 consecutive CHF outpatients and compared them with B-type natriuretic peptide (BNP) levels. At 24-month follow-up, 233 patients had died. A stepwise forward Cox regression model with age, sex, estimated glomerular filtration rate, NYHA > II, left ventricular ejection fraction (LVEF), MR-proADM, CT-proET-1, and BNP as possible predictors revealed that MR-proADM levels [hazard ratio (HR) = 1.77, P < 0.001] in addition to age (HR = 1.02, P = 0.004), ejection fraction (HR = 0.98, P = 0.004), and NYHA > II (HR = 1.86, P < 0.001) were predictors of death at 24 months. When the analysis was repeated dependent on NYHA-stage, MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers, but only in patients with mild/moderate CHF. Our data suggest that MR-proADM may be an important prognostic humoral marker, especially in mild/moderately symptomatic and non-ischaemic CHF patients.

  5. CHEK2*1100delC Variant and BRCA1/2-Negative Familial Breast Cancer - A Family-Based Genetic Association Study

    DTIC Science & Technology

    2007-10-01

    AD_________________ Award Number: DAMD17-03-1-0774 TITLE: CHEK2 *1100delC Variant and BRCA1/2...NUMBER CHEK2 *1100delC Variant and BRCA1/2-Negative Familial Breast Cancer - A Family- Based Genetic Association Study 5b. GRANT NUMBER DAMD17...association between the CHEK2 *1100delC gene variant and breast cancer among BRCA1/2-negative families. Vital to DNA replication and normal growth of breast

  6. Fluorescence spectroscopy of gastrointestinal tumors using δ-ALA

    NASA Astrophysics Data System (ADS)

    Borisova, E. G.; Vladimirov, B. G.; Angelov, I. G.; Avramov, L. A.

    2007-03-01

    In the recent study delta-aminolevulinic acid/Protoporphyrin IX (δ-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The δ-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Mucosa autofluorescence lies at 450-600 nm region. The fluorescence of PpIX is clearly pronounced at the 630-710 nm region. Deep minima in the tumor fluorescence signals are observed in the region 540-575 nm, related to hemoglobin re-absorption. Such high hemoglobin content is an indication of the tumors neovascularisation and it is clearly pronounced in all dysplastic and tumor sites investigated. The lack of fluorescence peaks in the red spectral area for normal mucosa is an indication for selective accumulation of δ-ALA/PpIX only in abnormal sites and gives high contrast when lesion borders are determined from clinicians during video observation in the process of diagnostic procedure. Very good correlation between fluorescence signals and histology examination results of the lesions investigated is achieved.

  7. A periplasmic D-alanyl-D-alanine dipeptidase in the gram-negative bacterium Salmonella enterica.

    PubMed

    Hilbert, F; García-del Portillo, F; Groisman, E A

    1999-04-01

    The VanX protein is a D-alanyl-D-alanine (D-Ala-D-Ala) dipeptidase essential for resistance to the glycopeptide antibiotic vancomycin. While this enzymatic activity has been typically associated with vancomycin- and teicoplainin-resistant enterococci, we now report the identification of a D-Ala-D-Ala dipeptidase in the gram-negative species Salmonella enterica. The Salmonella enzyme is only 36% identical to VanX but exhibits a similar substrate specificity: it hydrolyzes D-Ala-D-Ala, DL-Ala-DL-Phe, and D-Ala-Gly but not the tripeptides D-Ala-D-Ala-D-Ala and DL-Ala-DL-Lys-Gly or the dipeptides L-Ala-L-Ala, N-acetyl-D-Ala-D-Ala, and L-Leu-Pro. The Salmonella dipeptidase gene, designated pcgL, appears to have been acquired by horizontal gene transfer because pcgL-hybridizing sequences were not detected in related bacterial species and the G+C content of the pcgL-containing region (41%) is much lower than the overall G+C content of the Salmonella chromosome (52%). In contrast to wild-type Salmonella, a pcgL mutant was unable to use D-Ala-D-Ala as a sole carbon source. The pcgL gene conferred D-Ala-D-Ala dipeptidase activity upon Escherichia coli K-12 but did not allow growth on D-Ala-D-Ala. The PcgL protein localizes to the periplasmic space of Salmonella, suggesting that this dipeptidase participates in peptidoglycan metabolism.

  8. 5-ALA-induced fluorescence as a marker for diagnostic tissue in stereotactic biopsies of intracranial lymphomas: experience in 41 patients.

    PubMed

    Kiesel, Barbara; Millesi, Matthias; Woehrer, Adelheid; Furtner, Julia; Bavand, Anahita; Roetzer, Thomas; Mischkulnig, Mario; Wolfsberger, Stefan; Preusser, Matthias; Knosp, Engelbert; Widhalm, Georg

    2018-06-01

    (57%) and inhomogeneous intratumoral fluorescence in 12 (43%). According to histopathological analysis, all samples with strong or vague fluorescence contained diagnostic lymphoma tissue, resulting in a positive predictive value of 100%. Analysis showed no influence of preoperative corticosteroids or immunosuppression on fluorescence. CONCLUSIONS The data obtained in this study demonstrate the technical and clinical utility of 5-ALA-induced fluorescence in stereotactic biopsies of intracranial lymphomas. Thus, 5-ALA can serve as a useful tool to select patients not requiring intraoperative histopathology, and its application should markedly reduce operation time and related costs in the future.

  9. A determination of occlusal plane comparing different levels of the tragus to form ala-tragal line or Camper's line: A photographic study.

    PubMed

    Kumar, Sandeep; Garg, Sandeep; Gupta, Seema

    2013-02-01

    The purpose of this study was to determine accurately the part of the tragus to be used to form the Ala-Tragal line or Camper's line in orthognathic profile patients. 150 dentate subjects with age of 18-40 years with orthognathic profile were sampled. Life-size lateral digital photographs of the face with fox plane were taken in natural head position. Different angles between Eye-Ear plane and occlusal plane (OT1-OP), Eye-Ear plane and ala-superior border of tragus (OT1-AT1), Eye-Ear plane and ala-middle border of tragus (OT1-AT2) and Eye-Ear plane and ala-inferior border of tragus (OT1-AT3) were calculated using computer software package, AutoCAD 2004. From the three angles formed by the Eye-ear plane (OT1 or FH plane) and the ala-tragal lines, the one closest to the angle formed between Eye-Ear plane (OT1) and occlusal plane (OP) was used to determine the occlusal plane of orientation. The obtained results were subjected to ANOVA F test, Tukey's Honestly significant difference test, followed by Karl Pearson coefficient of correlation test. P values of less than 0.05 were taken as statistically significant. The mean of base line angle i.e. OT1-OP angle (11.96 ± 4.36) was found to be close to OT1-AT2 angle (13.67 ± 1.93) and OT1-AT3 angle (10.31 ± 2.03), but OT1-OP angle was found to be more closer to OT1-AT3 angle. Comparison of mean angles showed that OT1-OP angle in both males (11.68) and females (12.51) is close to OT1-AT3 angle (males- 11.01, females- 11.95). The line joining from ala to the lower border of the tragus was parallel to the occlusal plane in 53.3% of the subjects. There was no influence of the sex on the level of occlusal plane.

  10. A determination of occlusal plane comparing different levels of the tragus to form ala-tragal line or Camper's line: A photographic study

    PubMed Central

    Garg, Sandeep; Gupta, Seema

    2013-01-01

    PURPOSE The purpose of this study was to determine accurately the part of the tragus to be used to form the Ala-Tragal line or Camper's line in orthognathic profile patients. MATERIALS AND METHODS 150 dentate subjects with age of 18-40 years with orthognathic profile were sampled. Life-size lateral digital photographs of the face with fox plane were taken in natural head position. Different angles between Eye-Ear plane and occlusal plane (OT1-OP), Eye-Ear plane and ala-superior border of tragus (OT1-AT1), Eye-Ear plane and ala-middle border of tragus (OT1-AT2) and Eye-Ear plane and ala-inferior border of tragus (OT1-AT3) were calculated using computer software package, AutoCAD 2004. From the three angles formed by the Eye-ear plane (OT1 or FH plane) and the ala-tragal lines, the one closest to the angle formed between Eye-Ear plane (OT1) and occlusal plane (OP) was used to determine the occlusal plane of orientation. The obtained results were subjected to ANOVA F test, Tukey's Honestly significant difference test, followed by Karl Pearson coefficient of correlation test. P values of less than 0.05 were taken as statistically significant. RESULTS The mean of base line angle i.e. OT1-OP angle (11.96 ± 4.36) was found to be close to OT1-AT2 angle (13.67 ± 1.93) and OT1-AT3 angle (10.31 ± 2.03), but OT1-OP angle was found to be more closer to OT1-AT3 angle. Comparison of mean angles showed that OT1-OP angle in both males (11.68) and females (12.51) is close to OT1-AT3 angle (males- 11.01, females- 11.95). CONCLUSION The line joining from ala to the lower border of the tragus was parallel to the occlusal plane in 53.3% of the subjects. There was no influence of the sex on the level of occlusal plane. PMID:23508203

  11. Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey.

    PubMed

    Stummer, Walter; Rodrigues, Floriano; Schucht, Philippe; Preuss, Matthias; Wiewrodt, Dorothee; Nestler, Ulf; Stein, Marco; Artero, José Manuel Cabezudo; Platania, Nunzio; Skjøth-Rasmussen, Jane; Della Puppa, Alessandro; Caird, John; Cortnum, Søren; Eljamel, Sam; Ewald, Christian; González-García, Laura; Martin, Andrew J; Melada, Ante; Peraud, Aurelia; Brentrup, Angela; Santarius, Thomas; Steiner, Hans Herbert

    2014-12-01

    Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children. Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence. Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %). Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.

  12. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system

    PubMed Central

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-01-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. PMID:27903595

  13. Basic principles of fluorescence detection with use of 5-ALA

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold; Stepp, Herbert G.

    2000-06-01

    5-Aminolevulinic acid (5-ALA) has been proven to induce selective accumulation of flourescent Protoporphyrin IX (PPIX) in many types of malignant tissue. According to the target to treatment different routes of topical and systemical application of 5-ALA can be chosen. They include techniques like inhalation, installation and rinsing. For fluorescence detection a lamp based system have been developed in the laser-Forschungslabor in Munich together with Storz company. By skillful balancing of excitation filter centered around 400 nm and the observation filter with transmission above 450 nm images with high color contrast can be obtained. The universal application of the D-LIGHT could be demonstrated in different clinical disciplines like urology, neurosurgery, ENT clinic, gynecology and others.

  14. Delta-aminolevulinic acid dehydratase (ALAD) polymorphism in lead exposed Bangladeshi children and its effect on urinary aminolevulinic acid (ALA)

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

    Tasmin, Saira, E-mail: rimzim1612@yahoo.com; Furusawa, Hana; Ahmad, Sk. Akhtar

    Background and objective: Lead has long been recognized as a harmful environmental pollutant. People in developing countries like Bangladesh still have a higher risk of lead exposure. Previous research has suggested that the delta-aminolevulinic acid dehydratase (ALAD) genotype can modify lead toxicity and individual susceptibility. As children are more susceptible to lead-induced toxicity, this study investigated whether the ALAD genotype influenced urinary excretion of delta-aminolevulinic acid (U-ALA) among children exposed to environmental lead in Bangladesh. Methods: Subjects were elementary schoolchildren from a semi-urban industrialized area in Bangladesh. A total of 222 children were studied. Blood and urine were collected tomore » determine ALAD genotypes, blood lead levels and urinary aminolevulinic acid (U-ALA). Results: The mean BPb level was 9.7 µg/dl for the study children. BPb was significantly positively correlated with hemoglobin (p<0.01). In total, allele frequency for ALAD 1 and 2 was 0.83 and 0.17 respectively. The mean U-ALA concentration was lower in ALAD1-2/2-2 carriers than ALAD1-1 carriers for boys (p=0.001). But for girls, U-ALA did not differ significantly by genotype (p=0.26). When U-ALA was compared by genotype at the same exposure level in a multiple linear regression analysis, boys who were ALAD1-2/2-2 carriers still had a lower level of U-ALA compared to ALAD1-1carriers. Conclusion: This study provides information about the influence of ALAD polymorphism and its association with U-ALA in Bangladeshi children. Our results indicate that the ALAD1-2/2-2 genotype may have a protective effect in terms of U-ALA for environmentally lead exposed boys. - Highlights: • High blood lead level for the environmentally exposed schoolchildren. • BPb was significantly correlated with U-ALA and Hb. • Effect of ALAD genotype on U-ALA is differed by sex. • Lower U-ALA in ALAD2 than ALAD1 carriers only for boys at same exposure.« less

  15. Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia-like syndrome

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

    Nagai, T.; Kato, R.; Hasegawa, T.

    1995-01-02

    We describe a 5-year-old Japanese boy who has some radiographic findings characteristic of asphyxiating thoracic dystrophy (ATD)-chondroectodermal dysplasia with a de novo chromosome abnormality. He also has mild mental retardation, short stature, hypoplastic hair and skin, oligodontia, small thoracic cage, hypoplastic pelvis and cone-shaped epiphyses of hands. On cytogenetic studies he was found to have a de novo del(12)(p11.21p12.2). These results suggest that the locus of the gene associated with ATD-chondroectodermal dysplasia may be situated at 12p11.21p12.2. 11 refs., 2 figs.

  16. Comparsion of light dose on topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Tseng, Meng-Ke; Liu, Chung-Ji; Hsu, Yih-Chih

    2012-03-01

    Oral cancer has becomes the most prominent male cancer disease due to the local betel nut chewing habit combing with smoking and alcohol-drinking lifestyle. In order to minimize the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch cancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA -mediated PDT. We found that ALA reached its peak level in cancerous lesions about 2.5 hrs after topical application of ALA gel. The precancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 75 and 100 J/cm2 using LED 635 nm Wonderlight device. It is suggesting that optimization of the given light dose is critical to the success of PDT results.

  17. Alpha-lipoic acid (ALA) as a supplementation for weight loss: results from a meta-analysis of randomized controlled trials.

    PubMed

    Kucukgoncu, S; Zhou, E; Lucas, K B; Tek, C

    2017-05-01

    Obesity is associated with significant morbidity and mortality rates. Even modest weight loss may be associated with health benefits. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant. Studies have suggested anti-obesity properties of ALA; however, results are inconsistent. The purpose of this study is to conduct a meta-analysis of the effect of ALA on weight and body mass index (BMI). A comprehensive, systematic literature search identified 10 articles on randomized, double-blind, placebo-controlled studies involving ALA. We conducted a meta-analysis of mean weight and BMI change differences between ALA and placebo treatment groups. Alpha-lipoic acid treatment coincided with a statistically significant 1.27 kg (confidence interval = 0.25 to 2.29) greater mean weight loss compared with the placebo group. A significant overall mean BMI difference of -0.43 kg/ m 2 (confidence interval = -0.82 to -0.03) was found between the ALA and placebo groups. Meta-regression analysis showed no significance in ALA dose on BMI and weight changes. Study duration significantly affected BMI change, but not weight change. Alpha-lipoic acid treatment showed small, yet significant short-term weight loss compared with placebo. Further research is needed to examine the effect of different doses and the long-term benefits of ALA on weight management. © 2017 World Obesity Federation.

  18. Arg-Phe-Phe D-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xaa-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles.

    PubMed

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

    2018-06-20

    The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally-occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding D-isomer(s), generating a 14 compound library. While L-to-D inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.

  19. 40 CFR 721.7780 - Poly[oxy(methyl-1,2-ethane-diyl)], α,α′-(2,2-dimethyl-1,3-pro-pan-ediyl)bis[ω-(oxi-rany-me-thoxy)-.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...±,αâ²-(2,2-dimethyl-1,3-pro-pan-ediyl)bis[Ï-(oxi-rany-me-thoxy)-. 721.7780 Section 721.7780... Poly[oxy(methyl-1,2-ethane-diyl)], α,α′-(2,2-dimethyl-1,3-pro-pan-ediyl)bis[ω-(oxi-rany-me-thoxy)-. (a... technologies in § 721.90(a)(2)(ii): Oil and grease separation. (b) Specific requirements. The provisions of...

  20. ALA-PDT elicits oxidative damage and apoptosis in UVB-induced premature senescence of human skin fibroblasts.

    PubMed

    Zhou, Bing-Rong; Zhang, Li-Chao; Permatasari, Felicia; Liu, Juan; Xu, Yang; Luo, Dan

    2016-06-01

    5-Aminolevulinic acid photodynamic therapy (ALA-PDT) has been used for the treatment of skin photoaging. It can significantly improve the appearance of fine lines, dotted pigmentation, and roughness of photoaged skin. However, the mechanisms by which ALA-PDT yields rejuvenating effects on photoaged skin have not been well elucidated. Thus, in this study we explored the effects of ALA-PDT in photoaged fibroblasts. We established a stress-induced premature senescence (SIPS) model by repeated exposures of human dermal fibroblasts (HDFs) to ultraviolet B (UVB) irradiation. Cells were irradiated by red light laser at 635nm wavelength (50mW/cm(2)). Intracellular protoporphyrin IX (PpIX) was detected by confocal microscopy. Intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) change were detected by fluorescence microscopy and flow cytometry. Morphological changes were observed by optical microscopy. Proliferative activity was measured by a cell counting kit-8 (CCK-8). Cell apoptosis was detected by fluorescence microscopy using Hoechst staining and flow cytometry using annexin V/propidium Iodide double staining. Intracellular PpIX fluorescence in UVB-induced premature senescent HDFs (UVB-SIPS-HDFs) reached the highest intensity after incubation with 1.00mmol/L ALA for 6h (P<0.05). Compared with control group, intracellular ROS level, MMP, and apoptotic rate were increased (P<0.05) and proliferative activity was decreased (P<0.05) in UVB-SIPS-HDFs treated with ALA-PDT, which were positively correlated to ALA incubation time and red light laser dose. Our study demonstrated that ALA-PDT elicits oxidative damage and apoptosis in photoaged fibroblasts in vitro, which may be the basis for the rejuvenating effects on photoaged skin. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system.

    PubMed

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-02-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  2. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.

    PubMed

    Yasuda, Makiko; Gan, Lin; Chen, Brenden; Kadirvel, Senkottuvelan; Yu, Chunli; Phillips, John D; New, Maria I; Liebow, Abigail; Fitzgerald, Kevin; Querbes, William; Desnick, Robert J

    2014-05-27

    The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.

  3. Desleucyl-Oritavancin with a Damaged d-Ala-d-Ala Binding Site Inhibits the Transpeptidation Step of Cell-Wall Biosynthesis in Whole Cells of Staphylococcus aureus.

    PubMed

    Kim, Sung Joon; Singh, Manmilan; Sharif, Shasad; Schaefer, Jacob

    2017-03-14

    We have used solid-state nuclear magnetic resonance to characterize the exact nature of the dual mode of action of oritavancin in preventing cell-wall assembly in Staphylococcus aureus. Measurements performed on whole cells labeled selectively in vivo have established that des-N-methylleucyl-N-4-(4-fluorophenyl)benzyl-chloroeremomycin, an Edman degradation product of [ 19 F]oritavancin, which has a damaged d-Ala-d-Ala binding aglycon, is a potent inhibitor of the transpeptidase activity of cell-wall biosynthesis. The desleucyl drug binds to partially cross-linked peptidoglycan by a cleft formed between the drug aglycon and its biphenyl hydrophobic side chain. This type of binding site is present in other oritavancin-like glycopeptides, which suggests that for these drugs a similar transpeptidase inhibition occurs.

  4. Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.

    PubMed

    Batissoco, Ana Carla; Abreu-Silva, Ronaldo Serafim; Braga, Maria Cristina Célia; Lezirovitz, Karina; Della-Rosa, Valter; Alfredo, Tabith; Otto, Paulo Alberto; Mingroni-Netto, Regina Célia

    2009-02-01

    Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness. Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes. We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found. Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6-D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected c.167delT, p.Trp24X, p.Val37Ile, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro. Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27Ile, p.Met34Thr, p.Ala40Ala, and p.Gly160Ser. Two previously reported mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both

  5. Specificity of the collagenolytic serine proteinase from the pancreas of the catfish (Parasilurus asotus).

    PubMed

    Yoshinaka, R; Sato, M; Yamashita, M; Itoko, M; Ikeda, S

    1987-01-01

    The collagenolytic serine proteinase from the pancreas of the catfish (Parasilus asotus) had a pH optimum of 7.5 for native, reconstituted calf skin collagen fibrils. The enzyme was most stable at pH 6-9. The enzyme hydrolyzed heat-denatured collagen (gelatin), casein, hemoglobin and elastin in addition to native collagen but not virtually Tos-Arg-OEe, Bz-Tyr-OEe and Suc-(Ala)3-NA. The enzyme cleaved Leu-Gly (or Gln-Gly), Gly-Ile and Ile-Ala bonds on DNP-Pro-Leu-Gly-Ile-Ala-Gly-Arg-NH2 and DNP-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg.

  6. Human melioidosis reported by ProMED.

    PubMed

    Nasner-Posso, Katherinn Melissa; Cruz-Calderón, Stefania; Montúfar-Andrade, Franco E; Dance, David A B; Rodriguez-Morales, Alfonso J

    2015-06-01

    There are limited sources describing the global burden of emerging diseases. A review of human melioidosis reported by ProMED was performed and the reliability of the data retrieved assessed in comparison to published reports. The effectiveness of ProMED was evaluated as a source of epidemiological data by focusing on melioidosis. Using the keyword 'melioidosis' in the ProMED search engine, all of the information from the reports and collected data was reviewed using a structured form, including the year, country, gender, occupation, number of infected individuals, and number of fatal cases. One hundred and twenty-four entries reported between January 1995 and October 2014 were identified. A total of 4630 cases were reported, with death reported in 505 cases, suggesting a misleadingly low overall case fatality rate (CFR) of 11%. Of 20 cases for which the gender was reported, 12 (60%) were male. Most of the cases were reported from Australia, Thailand, Singapore, Vietnam, and Malaysia, with sporadic reports from other countries. Internet-based reporting systems such as ProMED are useful to gather information and synthesize knowledge on emerging infections. Although certain areas need to be improved, ProMED provided good information about melioidosis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Dietary ALA, EPA and DHA have distinct effects on oxylipin profiles in female and male rat kidney, liver and serum.

    PubMed

    Leng, Shan; Winter, Tanja; Aukema, Harold M

    2018-04-18

    There is much data on the effects of dietary n-3 fatty acids on tissue fatty acid compositions, but comparable comprehensive data on their oxygenated metabolites (oxylipins) is limited. The effects of providing female and male rats with diets high in α-linolenic acid (ALA), EPA or DHA for 6 weeks on oxylipins and fatty acids in kidney, liver and serum were therefore examined. The oxylipin profile generally reflected fatty acids, but it also revealed unique effects of individual n-3 fatty acids that were not apparent from fatty acid data alone. Dietary ALA increased renal and serum DHA oxylipins even though DHA itself did not increase, while dietary EPA did not increase DHA oxylipins in kidney or liver, suggesting that high EPA may inhibit this conversion. Oxylipin data generally corroborated fatty acid data that indicated that DHA can be retroconverted to EPA and that further retroconversion to ALA is limited. Dietary n-3 fatty acids decreased n-6 fatty acids and their oxylipins (except linoleic acid and its oxylipins), in order of effectiveness of DHA > EPA > ALA, with some exceptions: several arachidonic acid oxylipins modified at carbon 15 were not lower in all three sites, and EPA had a greater effect on 12-hydroxy-eicosatetraenoic acid and its metabolites in the liver. Oxylipins were predominantly higher in males, which was not reflective of fatty acids. Tissue-specific oxylipin profiles, therefore, provide further information on individual dietary n-3 fatty acid and sex effects that may help explain their unique physiological effects and have implications for dietary recommendations. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. A multicenter, randomized, vehicle-controlled phase 2 study of blue light photodynamic therapy with aminolevulinic acid HCl 20% topical solution for the treatment of actinic keratoses on the upper extremities: the effect of occlusion during the drug incubation period.

    PubMed

    Schmieder, George J; Huang, Eugene Y; Jarratt, Michael

    2012-12-01

    Photodynamic therapy (PDT) with aminolevulinic acid (ALA) has been shown to be safe and effective in the treatment of actinic keratoses (AKs) of the face and scalp. A recent small study has suggested that ALA-PDT can be effective for AKs of the dorsal hands/forearms. However, studies designed to provide sufficient statistical power to test this hypothesis are lacking in the literature. To determine and compare the safety and efficacy of blue light ALA-PDT vs blue light placebo vehicle (VEH) in the treatment of AKs of the upper extremities and to evaluate the effect of occlusion after application of ALA vs VEH. ALA or VEH was applied to both dorsal hands/forearms for the 3-hour incubation period before blue light treatment (10 J/ cm2). One extremity of each subject was covered with occlusive dressing during the incubation period. Treatment was repeated at week 8 if any AK lesions remained. The median AK lesion clearance rate at week 12 was 88.7% for extremities treated with occluded ALA (ALA+OCC), 70.0% for extremities treated with nonoccluded ALA, 16.7% for extremities treated with occluded VEH (VEH+OCC), and 5.6% for extremities treated with nonoccluded VEH (P<.0001). ALA+OCC resulted in a significantly higher clearance rate compared with the nonoccluded extremity at weeks 8 (P=.0006) and 12 (P=.0029). Thirty-four percent (12/35) of extremities treated with ALA+OCC had complete clearance of lesions at week 12 compared with 0% (0/35) of extremities treated with VEH+OCC (P=.0002). The safety pro!le in this study is consistent with previously reported side effects of the therapy. Blue light ALA-PDT following a 3-hour incubation appears efficacious for AK clearance of the upper extremities. Incubation using an occlusive dressing significantly increases the efficacy of the procedure and also increases the incidence and severity of some acute inflammatory side effects of PDT.

  9. Microfilarial reduction following ProHeart® 6 and ProHeart® SR-12 treatment in dogs experimentally inoculated with a resistant isolate of Dirofilaria immitis.

    PubMed

    McTier, Tom L; Pullins, Aleah; Inskeep, Gregory A; Gagnon, Genevieve; Fan, Huihao; Schoell, Adam; Bidgood, Tara; Login, Joyce; Meeus, Patrick

    2017-11-09

    Emerging resistance of heartworms (Dirofilaria immitis) to macrocyclic lactone (ML) preventives is an increasing concern for veterinarians, pet owners and animal health companies that supply heartworm preventives, with recent reports of resistant isolates identified from the Mississippi Delta region of the United States. Products that are effective in eliminating microfilariae (MF) in dogs harboring resistant heartworm infections could be important in reducing the spread of heartworm resistance. The current study was conducted to investigate the potential for ProHeart® 6 (PH 6; Zoetis) and ProHeart® SR-12 (PH 12; Zoetis) to reduce MF in dogs experimentally inoculated with an isolate of D. immitis (ZoeMo-2012) confirmed to be resistant to MLs. Twenty-three dogs with preexisting heartworm infections (via surgical transplantation) were randomly allocated to four groups based on pretreatment (Day -14) MF counts. On Day 0, dogs received a subcutaneous injection of either saline (placebo-treated control, 6 dogs), PH 6 (0.17 mg/kg, 6 dogs), PH 12 (0.5 mg/kg, 5 dogs) or a single oral dose of moxidectin powder in a gelatin capsule (0.25 mg/kg, 6 dogs). All dogs were bled for MF counts (modified Knott's test) on Days 0 (pretreatment), 1, 3, 7, 14, 21, 28, 42, 56, and 84. Dogs in control and PH 6 groups were also bled for MF counts on Days 112, 140, and 168. No adverse events associated with treatment were observed for any dog. Average reductions in MF counts compared with controls for PH 6 were 9.7% on Day 1, increasing to 75.0% on Day 7, and further to 86.5% on Day 28. On Day 42, average MF reduction increased to 90.3%. Reductions increased further over the next several months with reductions of 91.3, 96.8, 96.6, and 98.9% on Days 56, 84, 112, and 140, respectively. On Day 168, the reduction was 99.3% (P < 0.0001). Average reductions in MF counts compared with controls for PH 12 were 20.9% on Day 1, increasing to 78.9% on Day 7, and further to 91.2% on Day 28. On Day 84

  10. 12 CFR 602.12 - Fees.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Fees. 602.12 Section 602.12 Banks and Banking FARM CREDIT ADMINISTRATION ADMINISTRATIVE PROVISIONS RELEASING INFORMATION FOIA Fees § 602.12 Fees. (a) FCA may charge: (1) For manual searches for records and for review, the pro rated cost of the salary...

  11. ALA 2010 Midwinter Meeting: The Price to Participate

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    While the library economy continues its downward slide, the cost of attending the American Library Association (ALA) Midwinter Meeting seems as high as ever. That is the price of professional participation. These days it seems a bit too high and tends to limit involvement in the old association to librarians in the higher echelons of the field.…

  12. Thermally activated persistent photoconductivity & donor binding energy in high mobility AlAs QWs

    NASA Astrophysics Data System (ADS)

    Dasgupta, S.; Knaak, C.; Fontcuberta, A.; Bichler, M.; Abstreiter, G.; Grayson, M.

    2008-03-01

    In AlAs, valley index is important quantum number which can help understand interactions. However, important parameters for growth such as donor binding energy and Si δ-doping efficiency were unknown and AlAs quantum wells (QWs) typically did not conduct in dark. We grew series of (001) and (110) oriented double-sided doped n-type AlAs QWs and deduced Si donor binding energy δ in Al0.45Ga0.55 As and doping efficiency η. They work in dark possibly because dilute charge traps in substrate are screened by backside doping. From dark saturation density for doping series we deduced δdk=65.2 meV [1]. Our studies show thermally activated PPC where sample is illuminated at 4 K and returned to dark without appreciable density increase. As temperature is increased to 30 K, density doubles, indicating shallow binding energy δPIA=0 meV post-illumination anneal (PIA). Doping efficiency after illumination for (001) facet was found to be η=n2D/nSi=35% and for (110) η=17%. With this understanding, we designed (001) AlAs QW with PIA density n=2.4 x 10^11 cm-2 and mobility μ=4.3 x 10^5 cm^2/Vs(330 mK), improvement of almost an order of magnitude over published results. [1] Dasgupta, et al. APL (2007)

  13. Proteomics and SSH Analyses of ALA-Promoted Fruit Coloration and Evidence for the Involvement of a MADS-Box Gene, MdMADS1

    PubMed Central

    Feng, Xinxin; An, Yuyan; Zheng, Jie; Sun, Miao; Wang, Liangju

    2016-01-01

    Skin color is a key quality attribute of fruits and how to improve fruit coloration has long been a major concern. 5-Aminolevulinic acid (ALA), a natural plant growth regulator, can significantly increase anthocyanin accumulation in fruit skin and therefore effectively improve coloration of many fruits, including apple. However, the molecular mechanism how ALA stimulates anthocyanin accumulation in fruit skin remains unknown. Here, we investigated the impact of ALA on apple skin at the protein and mRNA levels. A total of 85 differentially expressed proteins in apple skins between ALA and water treatment (control) were identified by complementary gel-based and gel-free separation techniques. Most of these differentially expressed proteins were up-regulated by ALA. Function analysis suggested that 87.06% of the ALA-responsive proteins were associated with fruit ripening. To further screen ALA-responsive regulators, we constructed a subtracted cDNA library (tester: ALA treatment; driver: control) and obtained 104 differentially expressed unigenes, of which 38 unigenes were indicators for the fruit ripening-related genes. The differentially changed proteins and transcripts did not correspond well at an individual level, but showed similar regulated direction in function at the pathway level. Among the identified fruit ripening-related genes, the expression of MdMADS1, a developmental transcription regulator of fruit ripening, was positively correlated with expression of anthocyanin biosynthetic genes (MdCHS, MdDFR, MdLDOX, and MdUFGT) in apple skin under ALA treatment. Moreover, overexpression of MdMADS1 enhanced anthocyanin content in transformed apple calli, which was further enhanced by ALA. The anthocyanin content in MdMADS1-silenced calli was less than that in the control with ALA treatment, but higher than that without ALA treatment. These results indicated that MdMADS1 is involved in ALA-induced anthocyanin accumulation. In addition, anthocyanin

  14. Accumulation of polyubiquitylated proteins in response to Ala-Ala-Phe-chloromethylketone is independent of the inhibition of Tripeptidyl peptidase II.

    PubMed

    Villasevil, Eugenia M; Guil, Sara; López-Ferreras, Lorena; Sánchez, Carlos; Del Val, Margarita; Antón, Luis C

    2010-09-01

    In the present study we have addressed the issue of proteasome independent cytosolic protein degradation. Tripeptidyl peptidase II (TPPII) has been suggested to compensate for a reduced proteasome activity, partly based on evidence using the inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk). Here we show that AAF-cmk induces the formation of polyubiquitin-containing accumulations in osteosarcoma and Burkitt's lymphoma cell lines. These accumulations meet many of the landmarks of the aggresomes that form after proteasome inhibition. Using a combination of experiments with chemical inhibitors and interference of gene expression, we show that TPPII inhibition is not responsible for these accumulations. Our evidence suggests that the relevant target(s) is/are in the ubiquitin-proteasome pathway, most likely upstream the proteasome. We obtained evidence supporting this model by inhibition of Hsp90, which also acts upstream the proteasome. Although our data suggest that Hsp90 is not a target of AAF-cmk, its inhibition resulted in accumulations similar to those obtained with AAF-cmk. Therefore, our results question the proposed role for TPPII as a prominent alternative to the proteasome in cellular proteolysis. Copyright 2010 Elsevier B.V. All rights reserved.

  15. Effects of Pro-Gly-Pro tripeptide on the dopamine system.

    PubMed

    Meshavkin, V K; Batishcheva, E Yu; Kost, N V; Sokolov, O Yu; Trufanova, A V; Samonina, G E

    2011-08-01

    Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D(2)and D(3)receptors.

  16. Laser-induced fluorescence diagnostics of basal cell carcinomas of the skin following topical ALA application

    NASA Astrophysics Data System (ADS)

    af Klinteberg, Claes; Nilsson, Annika M.; Wang-Nordman, Ingrid; Andersson-Engels, Stefan; Svanberg, Sune; Svanberg, Katarina

    1996-12-01

    Fourteen patients with superficial basal cell carcinomas (BCCs) and fifteen patients with nodular BCCs were investigated by means of laser-induced fluorescence (LIF) in connection with photodynamic therapy (PDT). Topical application of (delta) -amino levulinic acid (ALA) was performed six hours prior to the treatment session. Fluorescence spectra were recorded, using a point-monitoring system with an excitation wavelength of 405 nm. The measurements were performed in scans over the lesion and the surrounding normal skin before application of ALA, and immediately before and after the laser treatment. The selective uptake of the photosensitive resulted in a fluorescence intensity ratio of 2.4:1 for superficial BCCs and 2.5:1 for nodular BCCs. If the fluorescence intensity was divided by the autofluorescence, this resulted in a contrast enhancement of about a factor 6 for tumor tissue. In seven patients (five with nodular BCC and two with superficial BCC), additional fluorescence measurements were performed two and four hours following the ALA application, and two hours after the PDT procedure. Thus, the kinetics of the transformation of ALA to protoporphyrin IX (PpIX) could be followed, which indicated that the synthesis of PpIX was more rapid in the tumor than in the normal tissue. After four hours, the PpIX level inside the tumour was saturated, while there still was an accumulation in the surrounding skin. The highest contrast between tumor and normal skin was reached within two hours after the ALA application.

  17. Screening of Pro-Asp Sequences Exposed on Bacteriophage M13 as an Ideal Anchor for Gold Nanocubes.

    PubMed

    Lee, Hwa Kyoung; Lee, Yujean; Kim, Hyori; Lee, Hye-Eun; Chang, Hyejin; Nam, Ki Tae; Jeong, Dae Hong; Chung, Junho

    2017-09-15

    Bacteriophages are thought to be ideal vehicles for linking antibodies to nanoparticles. Here, we define the sequence of peptides exposed as a fusion protein on M13 bacteriophages to yield optimal binding of gold nanocubes and efficient bacteriophage amplification. We generated five helper bacteriophage libraries using AE(X) 2 DP, AE(X) 3 DP, AE(X) 4 DP, AE(X) 5 DP, and AE(X) 6 DP as the exposed portion of pVIII, in which X was a randomized amino acid residue encoded by the nucleotide sequence NNK. Efficient phage amplification was achievable only in the AE(X) 2 DP, AE(X) 3 DP, and AE(X) 4 DP libraries. Through biopanning with gold nanocubes, we enriched the phage clones and selected the clone with the highest fold change after enrichment. This clone displayed Pro-Asp on the surface of the bacteriophage and had amplification yields similar to those of the wild-type helper bacteriophage (VCSM13). The clone displayed even binding of gold nanocubes along its length and minimal aggregation after binding. We conclude that, for efficient amplification, the exposed pVIII amino acid length should be limited to six residues and Ala-Glu-Pro-Asp-Asp-Pro (AEPDDP) is the ideal fusion protein sequence for guaranteeing the optimal formation of a complex with gold nanocubes.

  18. Direct Immunochemiluminescent Assay for proBNP and Total BNP in Human Plasma proBNP and Total BNP Levels in Normal and Heart Failure

    PubMed Central

    Nishikimi, Toshio; Okamoto, Hiroyuki; Nakamura, Masahiro; Ogawa, Naoko; Horii, Kazukiyo; Nagata, Kiyoshi; Nakagawa, Yasuaki; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakao, Kazuhiro; Minami, Takeya; Kuwabara, Yoshihiro; Kuwahara, Koichiro; Masuda, Izuru; Kangawa, Kenji; Minamino, Naoto; Nakao, Kazuwa

    2013-01-01

    Background Recent studies have shown that in addition to brain (or B-type) natriuretic peptide (BNP) and the N-terminal proBNP fragment, levels of intact proBNP are also increased in heart failure. Moreover, present BNP immunoassays also measure proBNP, as the anti-BNP antibody cross-reacts with proBNP. It is important to know the exact levels of proBNP in heart failure, because elevation of the low-activity proBNP may be associated with the development of heart failure. Methodology/Principal Findings We therefore established a two-step immunochemiluminescent assay for total BNP (BNP+proBNP) and proBNP using monoclonal antibodies and glycosylated proBNP as a standard. The assay enables measurement of plasma total BNP and proBNP within only 7 h, without prior extraction of the plasma. The detection limit was 0.4 pmol/L for a 50-µl plasma sample. Within-run CVs ranged from 5.2%–8.0% in proBNP assay and from 7.0%–8.4% in total BNP assay, and between-run CVs ranged from 5.3–7.4% in proBNP assay and from 2.9%–9.5% in total BNP assay, respectively. The dilution curves for plasma samples showed good linearity (correlation coefficients = 0.998–1.00), and analytical recovery was 90–101%. The mean total BNP and proBNP in plasma from 116 healthy subjects were 1.4±1.2 pM and 1.0±0.7 pM, respectively, and were 80±129 pM and 42±70 pM in 32 heart failure patients. Plasma proBNP levels significantly correlate with age in normal subjects. Conclusions/Significance Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma. PMID:23365636

  19. Clinical evaluation of the FreeStyle Precision Pro system.

    PubMed

    Brazg, Ronald; Hughes, Kristen; Martin, Pamela; Coard, Julie; Toffaletti, John; McDonnell, Elizabeth; Taylor, Elizabeth; Farrell, Lausanne; Patel, Mona; Ward, Jeanne; Chen, Ting; Alva, Shridhara; Ng, Ronald

    2013-06-05

    A new version of international standard (ISO 15197) and CLSI Guideline (POCT12) with more stringent accuracy criteria are near publication. We evaluated the glucose test performance of the FreeStyle Precision Pro system, a new blood glucose monitoring system (BGMS) designed to enhance accuracy for point-of-care testing (POCT). Precision, interference and system accuracy with 503 blood samples from capillary, venous and arterial sources were evaluated in a multicenter study. Study results were analyzed and presented in accordance with the specifications and recommendations of the final draft ISO 15197 and the new POCT12. The FreeStyle Precision Pro system demonstrated acceptable precision (CV <5%), no interference across a hematocrit range of 15-65%, and, except for xylose, no interference from 24 of 25 potentially interfering substances. It also met all accuracy criteria specified in the final draft ISO 15197 and POCT12, with 97.3-98.9% of the individual results of various blood sample types agreeing within ±12 mg/dl of the laboratory analyzer values at glucose concentrations <100mg/dl and within ±12.5% of the laboratory analyzer values at glucose concentrations ≥100 mg/dl. The FreeStyle Precision Pro system met the tighter accuracy requirements, providing a means for enhancing accuracy for point-of-care blood glucose monitoring. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. A new optical intra-tissue fiber irradiation ALA-PDT in the treatment of acne vulgaris in rabbit model: improved safety and tolerability.

    PubMed

    Wang, Qian; Jiang, Can; Liu, Wei; Chen, Jin; Lin, Xinyu; Huang, Xiangning; Duan, Xiling

    2017-01-01

    Photodynamic therapy with topical aminolevulinic acid (ALA-PDT) has been suggested to be effective in treatment of acne vulgaris. However, adverse events occur during and after treatment. To compare the efficacy and tolerability of optical intra-tissue fiber irradiation (OFI) ALA-PDT versus traditional ALA-PDT in treatment of acne vulgaris in rabbit models. Twenty-five rabbits of clean grade were used. Twenty rabbits were randomly selected to establish acne model and the other five were used as control. Rabbits in model group (40 ears) were further divided into four groups (10 ears/group): I, OFI-ALA-PDT with the head of optical fiber inserted into the target lesion (intra-tissue); II, traditional ALA-PDT group; III, OFI group; IV, blank control group without any treatment. Uncomfortable symptoms, adverse events, and effectiveness rates were recorded on post-treatment day 14, 30, and 45. On post-treatment day 14, the effectiveness rate in OFI-ALA-PDT group was obviously higher than that of the other three groups (P<0.05). However, no improved effects were observed in OFI-ALA-PDT group on day 30 and 45. During the period of treatment, the frequencies of uncomfortable symptoms in ALA-PDT group were obviously higher than those in the other three groups (P<0.05). The adverse event rate in OFI-ALA-PDT group was obviously lower than that of the ALA-PDT group (P<0.05). The unblindness of the study and temporary animal models of acne induced may hamper the assessment and monitoring of the results, and future studies are still needed to clarify it further. The OFI-ALA-PDT group (intra-tissue irradiation) showed no improved efficacy on treating rabbit ear acne but had higher safety and better tolerability.

  1. NT-proBNP in severe chronic heart failure: rationale, design and preliminary results of the COPERNICUS NT-proBNP substudy.

    PubMed

    Hartmann, Franz; Packer, Milton; Coats, Andrew J S; Fowler, Michael B; Krum, Henry; Mohacsi, Paul; Rouleau, Jean L; Tendera, Michal; Castaigne, Alain; Trawinski, Jürgen; Amann-Zalan, Ildiko; Hoersch, Silke; Katus, Hugo A

    2004-03-15

    Neither profiles nor prognostic value of cardiac N-terminal proBNP (NT-proBNP) have been prospectively evaluated in a sufficient number of patients with severe chronic heart failure (CHF) treated with carvedilol or placebo. Baseline and follow-up plasma concentrations of NT-proBNP were measured in the European part of the COPERNICUS Trial. This study enrolled patients with an ejection fraction <25% and symptoms of CHF at rest or on minimal exertion, equally randomized to placebo or carvedilol. NT-proBNP concentrations were increased at baseline (mean+/-S.D.=579+/-822 pmol/l, median=322.5 pmol/l) with a marked decrease during follow-up in the carvedilol, but not in the placebo group. One-year mortality rates were 3.9, 12 and 27.9% in the lower, middle and upper tertiles of NT-proBNP, respectively. When mortality was calculated separately in the placebo and carvedilol group, rates were 0.8, 6.3 and 19.1% in the carvedilol treated but 6.7, 17.9 and 36.9% in the placebo treated patients. NT-proBNP was a powerful predictor of subsequent all-cause mortality in patients with severe CHF. This marker should therefore be further evaluated for risk stratification and monitoring of therapy in CHF.

  2. Modification of the photodynamic action of delta-aminolaevulinic acid (ALA) on rat pancreatoma cells by mitochondrial benzodiazepine receptor ligands.

    PubMed Central

    Ratcliffe, S. L.; Matthews, E. K.

    1995-01-01

    We have shown that addition of exogenous delta-aminolaevulinic acid (ALA) to rat pancreatoma AR4-2J cells in culture leads to the increased production of porphobilinogen (PBG) and the accumulation of photoactive protoporphyrin IX (PPix) in these cells. Exposure to light (lambda > 400 nm) at an intensity of 0.2 mW cm-2 for 8 min resulted in an ALA dose-dependent cytolysis of the cells, with an EC50 of 6.6 +/- 0.7 microM. This cytolytic effect was light intensity dependent, with greater cell destruction after exposure to light at an intensity of 0.47 mW cm-2 than at 0.2 mW cm-2; it was also dependent on the duration of illumination, cell survival decreasing with increasing illumination times. The photodestruction of the AR4-2J cells following exposure to ALA can be attributed to the production of endogenous PPix, a photoactive porphyrin that we have shown to generate singlet oxygen upon illumination, whereas ALA itself does not. Further investigation of the molecular mechanisms underlying the photodynamic action of ALA demonstrated the involvement of the mitochondrial (peripheral) benzodiazepine receptor (MBR), a high-affinity recognition site for dicarboxylic porphyrins, and especially PPix. The centrally acting benzodiazepine compounds clonazepam and flumazenil, which have negligible affinities for the MBR, had no effect on ALA-mediated phototoxicity. In contrast, both the isoquinoline carboxamide PK11195 and the benzodiazepine Ro 5-4864 ligands, displaying a high affinity for the MBR, did affect ALA-mediated phototoxicity, each markedly increasing the EC50 for cell photodestruction and thus exerting a photoprotective effect. It is concluded that the MBR may play an important role in the expression of ALA-mediated PPix phototoxicity and that MBR ligands, by diminishing the actions of endogenous PPix, have the potential to rescue cells from porphyrin-induced photolysis. PMID:7841044

  3. 5-ALA based photodynamic management of glioblastoma

    NASA Astrophysics Data System (ADS)

    Rühm, Adrian; Stepp, Herbert; Beyer, Wolfgang; Hennig, Georg; Pongratz, Thomas; Sroka, Ronald; Schnell, Oliver; Tonn, Jörg-Christian; Kreth, Friedrich-Wilhelm

    2014-03-01

    Objective: Improvement of the clinical outcome of glioblastoma (GBM) patients by employment of fluorescence and photosensitization on the basis of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX). Methods: In this report the focus is laid on the use of tumor selective PpIX fluorescence for stereotactic biopsy sampling and intra-operative treatment monitoring. In addition, our current concept for treatment planning is presented. For stereotactic interstitial photodynamic therapy (iPDT), radial diffusers were implanted into the contrast enhancing tumor volume. Spectroscopic measurements of laser light transmission and fluorescence between adjacent fibers were performed prior, during and post PDT. Results: PpIX concentrations in primary glioblastoma tissue show high intra- and inter-patient variability, but are usually sufficient for an effective PDT. During individual treatment attempts with 5-ALA based GBM-iPDT, transmission and fluorescence measurements between radial diffusers gave the following results: 1. In some cases, transmission after PDT is considerably reduced compared to the value before PDT, which may be attributable to a depletion of oxygenated hemoglobin and/or diffuse bleeding. 2. PpIX fluorescence is efficiently photobleached during PDT in all cases. Conclusion: iPDT with assessment of PpIX fluorescence and photobleaching is a promising treatment option. Individualization of treatment parameters appears to bear a potential to further improve clinical outcomes.

  4. Duplication polymorphisms in exon 4 of κ-casein gene in yak breeds/populations.

    PubMed

    Pingcuo, S; Gao, J; Jiang, Z R; Jin, S Y; Fu, C Y; Liu, X; Huang, L; Zheng, Y C

    2015-08-28

    The objective of this study was to compare 12 bp-duplication polymorphisms in exon 4 of the κ-casein gene among 3 breeds/populations of yak (Bos grunniens). Genomic DNA was extracted from yak blood or muscle samples (N = 211) and a partial sequence of exon 4 of κ-casein gene was amplified by polymerase chain reaction. A polyacrylamide gel electrophoresis assay of the products (169 bp) revealed 2 variants. These variants differed in a 12-bp duplication of the nucleotide sequence corresponding to amino acids 147-150 (Glu-Ala-Ser-Pro) or 148-151 (Ala-Ser-Pro-Glu). The genotype frequency and gene frequency of the 2 κ-casein variants differed among the 3 yak breeds/populations. The long form of the κ-casein gene was the predominant allele, and the Jiulong yak showed the highest frequency of the short form variant of the κ-casein gene. In addition, 2 nucleotide differences resulting in amino acid substitutions were also identified in yaks. These results are significant for designing a breeding strategy to improve the genetic makeup of yak herds.

  5. Leading by Example? ALA Division Publications, Open Access, and Sustainability

    ERIC Educational Resources Information Center

    Hall, Nathan; Arnold-Garza, Sara; Gong, Regina; Shorish, Yasmeen

    2016-01-01

    This investigation explores scholarly communication business models in American Library Association (ALA) division peer-reviewed academic journals. Previous studies reveal the numerous issues organizations and publishers face in the academic publishing environment. Through an analysis of documented procedures, policies, and finances of five ALA…

  6. Pressure dependence of side chain 13C chemical shifts in model peptides Ac-Gly-Gly-Xxx-Ala-NH2.

    PubMed

    Beck Erlach, Markus; Koehler, Joerg; Crusca, Edson; Munte, Claudia E; Kainosho, Masatsune; Kremer, Werner; Kalbitzer, Hans Robert

    2017-10-01

    For evaluating the pressure responses of folded as well as intrinsically unfolded proteins detectable by NMR spectroscopy the availability of data from well-defined model systems is indispensable. In this work we report the pressure dependence of 13 C chemical shifts of the side chain atoms in the protected tetrapeptides Ac-Gly-Gly-Xxx-Ala-NH 2 (Xxx, one of the 20 canonical amino acids). Contrary to expectation the chemical shifts of a number of nuclei have a nonlinear dependence on pressure in the range from 0.1 to 200 MPa. The size of the polynomial pressure coefficients B 1 and B 2 is dependent on the type of atom and amino acid studied. For H N , N and C α the first order pressure coefficient B 1 is also correlated to the chemical shift at atmospheric pressure. The first and second order pressure coefficients of a given type of carbon atom show significant linear correlations suggesting that the NMR observable pressure effects in the different amino acids have at least partly the same physical cause. In line with this observation the magnitude of the second order coefficients of nuclei being direct neighbors in the chemical structure also are weakly correlated. The downfield shifts of the methyl resonances suggest that gauche conformers of the side chains are not preferred with pressure. The valine and leucine methyl groups in the model peptides were assigned using stereospecifically 13 C enriched amino acids with the pro-R carbons downfield shifted relative to the pro-S carbons.

  7. Viewership of pro-anorexia websites in seventh, ninth and eleventh graders.

    PubMed

    Custers, Kathleen; Van den Bulck, Jan

    2009-05-01

    To examine the prevalence of visiting pro-anorexia websites by 13-, 15- and 17-year old adolescents and to explore correlates of visiting such websites and predictors of anorexia nervosa (AN). Questionnaire in a sample of 711 secondary school children from the 7th, 9th and 11th grade in Flanders, Belgium. 12.6% of the girls and 5.9% of the boys had visited such websites. In girls, visiting pro-anorexia websites was associated with a higher drive for thinness, worse perception of appearance and more perfectionism. The prevalence of visiting pro-anorexia sites is non-trivial and the significant correlations between viewership of pro-ana sites and predictors of AN suggest a potential for negative impact of exposure to pro-ana sites. We conclude with some speculative remarks on the potential threat of the existence of pro-ana sites to organized health care.

  8. Histone-like DNA binding protein of Streptococcus intermedius induces the expression of pro-inflammatory cytokines in human monocytes via activation of ERK1/2 and JNK pathways.

    PubMed

    Liu, Dali; Yumoto, Hiromichi; Hirota, Katsuhiko; Murakami, Keiji; Takahashi, Kanako; Hirao, Kouji; Matsuo, Takashi; Ohkura, Kazuto; Nagamune, Hideaki; Miyake, Yoichiro

    2008-01-01

    Streptococcus intermedius is a commensal associated with serious, deep-seated purulent infections in major organs, such as the brain and liver. Histone-like DNA binding protein (HLP) is an accessory architectural protein in a variety of bacterial cellular processes. In this study, we investigated the mechanisms of pro-inflammatory cytokine inductions in THP-1 cells by stimulation with recombinant HLP of S. intermedius (rSi-HLP). rSi-HLP stimulation-induced production of pro-inflammatory cytokines (IL-8, IL-1 beta and TNF-alpha) occurred in a time- and dose-dependent manner. In contrast with the heat-stable activity of DNA binding, the induction activity of rSi-HLP was heat-unstable. In subsequent studies, rSi-HLP acted cooperatively with lipoteichoic acid, the synthetic Toll-like receptor 2 agonist, Pam3CSK4, and the cytosolic nucleotide binding oligomerization domain 2 receptor agonist, muramyldipeptide. Furthermore, Western blot and blocking assays with specific inhibitors showed that rSi-HLP stimulation induced the activation of cell signal transduction pathways, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). In addition to its physiological role in bacterial growth through DNA binding, these results indicate that Si-HLP can trigger a cascade of events that induce pro-inflammatory responses via ERK1/2 and JNK signal pathways, and suggest that bacterial HLP may contribute to the activation of host innate immunity during bacterial infection.

  9. Adjunctive α-lipoic acid reduces weight gain compared with placebo at 12 weeks in schizophrenic patients treated with atypical antipsychotics: a double-blind randomized placebo-controlled study.

    PubMed

    Kim, Nam Wook; Song, Yul-Mai; Kim, Eosu; Cho, Hyun-Sang; Cheon, Keun-Ah; Kim, Su Jin; Park, Jin Young

    2016-09-01

    α-Lipoic acid (ALA) has been reported to be effective in reducing body weight in rodents and obese patients. Our previous open trial showed that ALA may play a role in reducing weight gain in patients with schizophrenia on atypical antipsychotics. The present study evaluated the efficacy of ALA in reducing weight and BMI in patients with schizophrenia who had experienced significant weight gain since taking atypical antipsychotics. In a 12-week, double-blind randomized placebo-controlled study, 22 overweight and clinically stable patients with schizophrenia were randomly assigned to receive ALA or placebo. ALA was administered at 600-1800 mg, as tolerated. Weight, BMI, abdomen fat area measured by computed tomography, and metabolic values were determined. Adverse effects were also assessed to examine safety. Overall, 15 patients completed 12 weeks of treatment. There was significant weight loss and decreased visceral fat levels in the ALA group compared with the placebo group. There were no instances of psychopathologic aggravation or severe ALA-associated adverse effects. ALA was effective in reducing weight and abdominal obesity in patients with schizophrenia who had experienced significant weight gain since beginning an atypical antipsychotic regimen. Moreover, ALA was well tolerated throughout this study. ALA might play an important role as an adjunctive treatment in decreasing obesity in patients who take atypical antipsychotics.

  10. LJ Q&A "ALA Candidates": Library Advocacy x 2

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    Library advocacy in one of two directions is the top priority of both Camila Alire and J. Linda Williams, the candidates campaigning to capture the 2009-10 term as president of the American Library Association (ALA). Alire, dean emeritus of the libraries of both the University of New Mexico and Colorado State University, will push for enhancements…

  11. Sperm quality after swim up and density gradient centrifugation sperm preparation with supplementation of alpha lipoic acid (ALA): A preliminary study

    NASA Astrophysics Data System (ADS)

    Lestari, Silvia W.; Lestari, Sarah H.; Pujianto, Dwi A.

    2018-02-01

    Intra uterine insemination (IUI) as one of the treatment for infertility, persists low success rate. A factor that contributes to the unsuccessful of IUI is sperm preparation, performed through Swim-up (SU) and Density Gradient Centrifugation (DGC) methods. Furthermore, studies have shown that Alpha Lipoic Acid (ALA) is a potent antioxidant that could enhance the sperm motility and protect the DNA integrity of the sperm [1]. This study is aimed to re-evaluate the efficiency of the DGC and SU methods in selecting sperm before being transferred for IUI by the supplementation of ALA based on the sperm DNA integrity. Semen samples were obtained from 13 men from partners of women who are infertile (normozoospermia) and underwent IUI. Semen analysis based on the guideline of World Health Organization (WHO) 2010 was performed to measure the sperm motility and velocity, before and after sperm preparation. Then, samples were incubated with Alpha Lipoic Acid (ALA) in 0.625 mg (ALA 1), 1.25 mg (ALA 2) and 2.5 mg (ALA 3). The Sperm Chromatin Dispersion (SCD) test was performed to evaluate the sperm DNA Fragmentation Index (DFI). The percentage of motile sperm was higher in prepared sperm (post-DGC and post-SU) than in whole semen. Furthermore, the percentage of motile sperm was higher in post-DGC compared to post-SU. The level of DFI after the supplementation of ALA was decreased in prepared sperm compared to the whole semen. ALA was proved capable to select the better sperm quality with decreased sperm DNA fragmentation of prepared sperm in the all of DFI category.

  12. Challenges for community-based forest management in the KoloAla site Manompana.

    PubMed

    Urech, Zora Lea; Sorg, Jean-Pierre; Felber, Hans Rudolph

    2013-03-01

    Following the IUCN 5th World Congress on Protected Areas in 2003, the then-President of Madagascar decided to increase the area of Madagascar's protected areas from 1.7 to 6 million ha. To combine the aims of protection and timber production, a new concept was developed through the establishment of community-based forest management (CBFM) sites, called KoloAla. However, experience shows that similar management transfers to communities in Madagascar have only been successful in a very few cases. We aimed to explore the success to be expected of this new approach in the particular case of the Manompana corridor at Madagascar's eastern coast. In a first step, the readiness of the corridor's resource users for CBFM has been analysed according to the seven resource users' attributes developed by Ostrom that predict an effective self-organized resource management. In a second step, we explored how KoloAla addresses known challenges of Madagascar's CBFM. Analyses lead in a rather sober conclusion. Although KoloAla attempts to address the goals of poverty alleviation, biodiversity conservation and timber production under a single umbrella, it does so in a rather non-innovative way. Challenges with regard to the state's environmental governance, agricultural inefficiency and thus deforestation remain unsolved.

  13. Challenges for Community-Based Forest Management in the KoloAla Site Manompana

    NASA Astrophysics Data System (ADS)

    Urech, Zora Lea; Sorg, Jean-Pierre; Felber, Hans Rudolph

    2013-03-01

    Following the IUCN 5th World Congress on Protected Areas in 2003, the then-President of Madagascar decided to increase the area of Madagascar's protected areas from 1.7 to 6 million ha. To combine the aims of protection and timber production, a new concept was developed through the establishment of community-based forest management (CBFM) sites, called KoloAla. However, experience shows that similar management transfers to communities in Madagascar have only been successful in a very few cases. We aimed to explore the success to be expected of this new approach in the particular case of the Manompana corridor at Madagascar's eastern coast. In a first step, the readiness of the corridor's resource users for CBFM has been analysed according to the seven resource users' attributes developed by Ostrom that predict an effective self-organized resource management. In a second step, we explored how KoloAla addresses known challenges of Madagascar's CBFM. Analyses lead in a rather sober conclusion. Although KoloAla attempts to address the goals of poverty alleviation, biodiversity conservation and timber production under a single umbrella, it does so in a rather non-innovative way. Challenges with regard to the state's environmental governance, agricultural inefficiency and thus deforestation remain unsolved.

  14. Theoretical and experimental studies on alpha/epsilon-hybrid peptides: design of a 14/12-helix from peptides with alternating (S)-C-linked carbo-epsilon-amino acid [(S)-epsilon-Caa((x))] and L-ala.

    PubMed

    Sharma, Gangavaram V M; Babu, Bommagani Shoban; Chatterjee, Deepak; Ramakrishna, Kallaganti V S; Kunwar, Ajit C; Schramm, Peter; Hofmann, Hans-Jörg

    2009-09-04

    An (S)-C-linked carbo-epsilon-amino acid [(S)-epsilon-Caa((x))] was prepared from the known (S)-delta-Caa. This monomer was utilized together with l-Ala to give novel alpha/epsilon-hybrid peptides in 1:1 alternation. Conformational analysis on penta- and hexapeptides by NMR (in CDCl(3)), CD, and MD studies led to the identification of robust 14/12-mixed helices. This is in agreement with the data from a theoretical conformational analysis on the basis of ab initio MO theory providing a complete overview on all formally possible hydrogen-bonded helix patterns of alpha/epsilon-hybrid peptides with 1:1 backbone alternation. The "new motif" of a mixed 14/12-helix was predicted as most stable in vacuum. Obviously, the formation of ordered secondary structures is also possible in peptide foldamers with amino acid constituents of considerable backbone lengths. Thus, alpha/epsilon-hybrid peptides expand the domain of foldamers and allow the introduction of desired functionalities via the alpha-amino acid constituents.

  15. Pro-anorexia and pro-recovery photo sharing: a tale of two warring tribes.

    PubMed

    Yom-Tov, Elad; Fernandez-Luque, Luis; Weber, Ingmar; Crain, Steven P

    2012-11-07

    There is widespread use of the Internet to promote anorexia as a lifestyle choice. Pro-anorexia content can be harmful for people affected or at risk of having anorexia. That movement is actively engaged in sharing photos on social networks such as Flickr. To study the characteristics of the online communities engaged in disseminating content that encourages eating disorders (known as "pro-anorexia") and to investigate if the posting of such content is discouraged by the posting of recovery-oriented content. The extraction of pro-anorexia and pro-recovery photographs from the photo sharing site Flickr pertaining to 242,710 photos from 491 users and analyzing four separate social networks therein. Pro-anorexia and pro-recovery communities interact to a much higher degree among themselves than what is expected from the distribution of contacts (only 59-72% of contacts but 74-83% of comments are made to members inside the community). Pro-recovery users employ similar words to those used by pro-anorexia users to describe their photographs, possibly in order to ensure that their content appears when pro-anorexia users search for images. Pro-anorexia users who are exposed to comments from the opposite camp are less likely to cease posting pro-anorexia photographs than those who do not receive such comments (46% versus 61%), and if they cease, they do so approximately three months later. Our observations show two highly active communities, where most interaction is within each community. However, the pro-recovery community takes steps to ensure that their content is visible to the pro-anorexia community, both by using textual descriptions of their photographs that are similar to those used by the pro-anorexia group and by commenting to pro-anorexia content. The latter activity is, however, counterproductive, as it entrenches pro-anorexia users in their stance. Our results highlight the nature of pro-anorexia and pro-recovery photo sharing and accentuate the need for

  16. Pro-Anorexia and Pro-Recovery Photo Sharing: A Tale of Two Warring Tribes

    PubMed Central

    Yom-Tov, Elad; Weber, Ingmar; Crain, Steven P

    2012-01-01

    Background There is widespread use of the Internet to promote anorexia as a lifestyle choice. Pro-anorexia content can be harmful for people affected or at risk of having anorexia. That movement is actively engaged in sharing photos on social networks such as Flickr. Objective To study the characteristics of the online communities engaged in disseminating content that encourages eating disorders (known as “pro-anorexia”) and to investigate if the posting of such content is discouraged by the posting of recovery-oriented content. Methods The extraction of pro-anorexia and pro-recovery photographs from the photo sharing site Flickr pertaining to 242,710 photos from 491 users and analyzing four separate social networks therein. Results Pro-anorexia and pro-recovery communities interact to a much higher degree among themselves than what is expected from the distribution of contacts (only 59-72% of contacts but 74-83% of comments are made to members inside the community). Pro-recovery users employ similar words to those used by pro-anorexia users to describe their photographs, possibly in order to ensure that their content appears when pro-anorexia users search for images. Pro-anorexia users who are exposed to comments from the opposite camp are less likely to cease posting pro-anorexia photographs than those who do not receive such comments (46% versus 61%), and if they cease, they do so approximately three months later. Our observations show two highly active communities, where most interaction is within each community. However, the pro-recovery community takes steps to ensure that their content is visible to the pro-anorexia community, both by using textual descriptions of their photographs that are similar to those used by the pro-anorexia group and by commenting to pro-anorexia content. The latter activity is, however, counterproductive, as it entrenches pro-anorexia users in their stance. Conclusions Our results highlight the nature of pro-anorexia and pro

  17. Ala397Asp mutation of myosin VIIA gene segregating in a Spanish family with type-Ib Usher syndrome.

    PubMed

    Espinós, C; Millán, J M; Sánchez, F; Beneyto, M; Nájera, C

    1998-06-01

    In the current study, 12 Spanish families affected by type-I Usher syndrome, that was previously linked to chromosome 11q, were screened for the presence of mutations in the N-terminal coding portion of the motor domain of the myosin VIIA gene by single-strand conformation polymorphism analysis of the first 14 exons. A mutation (Ala397Asp) segregating with the disease was identified, and several polymorphisms were also detected. It is presumed that the other USHIB mutations in these families could be located in the unscreened regions of the gene.

  18. Effects of Ala-Gln feeding strategies on growth, metabolism, and crowding stress resistance of juvenile Cyprinus carpio var. Jian.

    PubMed

    Chen, Xiu-Mei; Guo, Gui-Liang; Sun, Li; Yang, Qiu-Shi; Wang, Gui-Qin; Qin, Gui-Xin; Zhang, Dong-Ming

    2016-04-01

    The present study was conducted to evaluate the effects of different L-alanyl-l-glutamine (Ala-Gln) feeding strategies on the growth performance, metabolism and crowding stress resistance related parameters in juvenile Jian carp (Cyprinus carpio var. Jian) under crowded condition (80 g/L). Juvenile Jian carp (initial weight 26.1 ± 0.6 g) were distributed into five groups which fed with graded concentrations (0% or 1.0%) of Ala-Gln for eight weeks. Control group (I, 0/0) fed with control diet (0% Ala-Gln) throughout the feeding trial. The other four groups employed different control and experimental diet feeding strategies ranging from two weeks control diet fed and two weeks experimental diet (1% Ala-Gln) fed (II, 0/2) to eight weeks experimental diet fed (V, 4/4). Results revealed that Mean weight gain (MEG) under all different feeding strategies of Ala-Gln were significantly higher than that of the control group (p < 0.05), and MEG of group II (201.90%) was even higher than that of group IV (184.70%). Liver glycogen and blood total protein of groups II, III and V were significantly higher than that in groups I and IV (p < 0.05). The highest level of serum thyroxine (10.07 ng/ml), insulin-like growth factor-I (52.40 ng/ml) and insulin (9.73 μ IU/mL) were observed in group V. However, diet supplemented with Ala-Gln did not affect the levels of serum glucose, cortisol and catecholamine in fish. The mRNA expression of GR1a, GR1b and GR2 were also significantly changed in Ala-Gln supplementation groups compared with control group (p < 0.05). After fish intraperitoneally injected with virulent Aeromonas hydrophila, the fish survival rates were significantly increased in all Ala-Gln supplementation groups compared with control group (p < 0.05). Results from the present experiment showed the importance of dietary supplementation of Ala-Gln in benefaction of the growth performance, metabolism and crowding stress resistance in Jian carp breeding. The

  19. Optimization and validation of FePro cell labeling method.

    PubMed

    Janic, Branislava; Rad, Ali M; Jordan, Elaine K; Iskander, A S M; Ali, Md M; Varma, N Ravi S; Frank, Joseph A; Arbab, Ali S

    2009-06-11

    Current method to magnetically label cells using ferumoxides (Fe)-protamine (Pro) sulfate (FePro) is based on generating FePro complexes in a serum free media that are then incubated overnight with cells for the efficient labeling. However, this labeling technique requires long (>12-16 hours) incubation time and uses relatively high dose of Pro (5-6 microg/ml) that makes large extracellular FePro complexes. These complexes can be difficult to clean with simple cell washes and may create low signal intensity on T2* weighted MRI that is not desirable. The purpose of this study was to revise the current labeling method by using low dose of Pro and adding Fe and Pro directly to the cells before generating any FePro complexes. Human tumor glioma (U251) and human monocytic leukemia cell (THP-1) lines were used as model systems for attached and suspension cell types, respectively and dose dependent (Fe 25 to 100 microg/ml and Pro 0.75 to 3 microg/ml) and time dependent (2 to 48 h) labeling experiments were performed. Labeling efficiency and cell viability of these cells were assessed. Prussian blue staining revealed that more than 95% of cells were labeled. Intracellular iron concentration in U251 cells reached approximately 30-35 pg-iron/cell at 24 h when labeled with 100 microg/ml of Fe and 3 microg/ml of Pro. However, comparable labeling was observed after 4 h across the described FePro concentrations. Similarly, THP-1 cells achieved approximately 10 pg-iron/cell at 48 h when labeled with 100 microg/ml of Fe and 3 microg/ml of Pro. Again, comparable labeling was observed after 4 h for the described FePro concentrations. FePro labeling did not significantly affect cell viability. There was almost no extracellular FePro complexes observed after simple cell washes. To validate and to determine the effectiveness of the revised technique, human T-cells, human hematopoietic stem cells (hHSC), human bone marrow stromal cells (hMSC) and mouse neuronal stem cells (mNSC C17

  20. Novel domain-specific POU3F4 mutations are associated with X-linked deafness: examples from different populations.

    PubMed

    Bademci, Guney; Lasisi, Akeem; Yariz, Kemal O; Montenegro, Paola; Menendez, Ibis; Vinueza, Rodrigo; Paredes, Rosario; Moreta, Germania; Subasioglu, Asli; Blanton, Susan; Fitoz, Suat; Incesulu, Armagan; Sennaroglu, Levent; Tekin, Mustafa

    2015-02-25

    Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co-segregated with deafness in all families. Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals.

  1. Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency.

    PubMed

    Acuña, Mariana; Castro-Fernández, Víctor; Latorre, Mauricio; Castro, Juan; Schuchman, Edward H; Guixé, Victoria; González, Mauricio; Zanlungo, Silvana

    2016-10-21

    Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). The p.Ala359Asp mutation has been described in several patients but its functional and structural effects in the protein are unknown. In order to characterize this mutation, we modeled the three-dimensional ASM structure using the recent available crystal of the mammalian ASM as a template. We found that the p.Ala359Asp mutation is localized in the hydrophobic core and far from the sphingomyelin binding site. However, energy function calculations using statistical potentials indicate that the mutation causes a decrease in ASM stability. Therefore, we investigated the functional effect of the p.Ala359Asp mutation in ASM expression, secretion, localization and activity in human fibroblasts. We found a 3.8% residual ASM activity compared to the wild-type enzyme, without changes in the other parameters evaluated. These results support the hypothesis that the p.Ala359Asp mutation causes structural alterations in the hydrophobic environment where ASM is located, decreasing its enzymatic activity. A similar effect was observed in other previously described NPDB mutations located outside the active site of the enzyme. This work shows the first full size ASM mutant model describe at date, providing a complete analysis of the structural and functional effects of the p.Ala359Asp mutation over the stability and activity of the enzyme. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Development of the Flu-PRO: a patient-reported outcome (PRO) instrument to evaluate symptoms of influenza.

    PubMed

    Powers, John H; Guerrero, M Lourdes; Leidy, Nancy Kline; Fairchok, Mary P; Rosenberg, Alice; Hernández, Andrés; Stringer, Sonja; Schofield, Christina; Rodríguez-Zulueta, Patricia; Kim, Katherine; Danaher, Patrick J; Ortega-Gallegos, Hilda; Bacci, Elizabeth Dansie; Stepp, Nathaniel; Galindo-Fraga, Arturo; St Clair, Kristina; Rajnik, Michael; McDonough, Erin A; Ridoré, Michelande; Arnold, John C; Millar, Eugene V; Ruiz-Palacios, Guillermo M

    2016-01-05

    To develop content validity of a comprehensive patient-reported outcome (PRO) measure following current best scientific methodology to standardize assessment of influenza (flu) symptoms in clinical research. Stage I (Concept Elicitation): 1:1 telephone interviews with influenza-positive adults (≥18 years) in the US and Mexico within 7 days of diagnosis. Participants described symptom type, character, severity, and duration. Content analysis identified themes and developed the draft Flu-PRO instrument. Stage II (Cognitive Interviewing): The Flu-PRO was administered to a unique set of influenza-positive adults within 14 days of diagnosis; telephone interviews addressed completeness, respondent interpretation of items and ease of use. Samples: Stage I: N = 46 adults (16 US, 30 Mexico); mean (SD) age: 38 (19), 39 (14) years; % female: 56%, 73%; race: 69% White, 97% Mestizo. Stage II: N = 34 adults (12 US, 22 Mexico); age: 37 (14), 39 (11) years; % female: 50%, 50%; race: 58% White, 100% Mestizo. Symptoms identified by >50%: coughing, weak or tired, throat symptoms, congestion, headache, weakness, sweating, chills, general discomfort, runny nose, chest (trouble breathing), difficulty sleeping, and body aches or pains. No new content was uncovered during Stage II; participants easily understood the instrument. Results show the 37-item Flu-PRO is a content valid measure of influenza symptoms in adults with a confirmed diagnosis of influenza. Research is underway to evaluate the suitability of the instrument for children and adolescents. This work can form the basis for future quantitative tests of reliability, validity, and responsiveness to evaluate the measurement properties of Flu-PRO for use in clinical trials and epidemiology studies.

  3. An organic solvent-stable lipase from a newly isolated Staphylococcus aureus ALA1 strain with potential for use as an industrial biocatalyst.

    PubMed

    Ben Bacha, Abir; Moubayed, Nadine Ms; Al-Assaf, Alaa

    2016-05-01

    In this study, a new strain, ALA1, was identified as Staphylococcus aureus by biochemical tests, and its 16S ribosomal DNA sequence was isolated from dromedary milk. ALA1 lipase production was optimized in shake flask experiments and measured with varying pH (3-11), temperature (20-55 °C) and substrate concentrations. The maximum lipase production was recorded at pH 8 and 30 °C for up to 30 H of culture period for the S. aureus ALA1 strain. Among the substrates tested, selected carbon sources, xylose, nitrogen source, yeast extract, and olive oil (1%) were suitable for maximizing lipase production. The effects of surfactants were investigated and showed that Tween 20, Tween 80, and Triton X-100 prevented lipase production. Interestingly, isolate ALA1 was able to grow in high concentrations of benzene or toluene (up to 50% (v/v)). Moreover, the lipolytic activity of the S. aureus ALA1 lipase was stimulated by diethyl ether, whereas almost 100% of S. aureus ALA1 lipase activity was retained in 25% acetone, acetonitrile, benzene, 2-propanol, ethanol, methanol, or toluene. Because of its stability in organic solvent, the S. aureus ALA1 lipase was used as a biocatalyst to synthesize high levels of added value molecules. S. aureus ALA1 lipase could be considered as an ideal choice for applications in detergent formulations because of its high stability and compatibility with various surfactants, oxidizing agents, and commercial detergents. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

  4. A novel tumor-activated ALA fusion protein for specific inhibition on the growth and invasion of breast cancer cells MDA-MB-231.

    PubMed

    Liu, Xiufeng; Liu, Xintong; Sunchen, Suwen; Liu, Meixia; Shen, Chen; Wu, Juanjuan; Zhao, Wanli; Yu, Boyang; Liu, Jihua

    2017-11-01

    The aim of this research was to develop a novel ALA fusion protein for target to the malignant cells surface with high uPAR expression and locally release of the scorpion toxin AGAP in an uPA-cleavable manner. It will provide an effective approach for controlled release of the peptide toxins to treat cancerous cells. The ALA fusion proteins were expressed in pichia pastoris, and the recombinant proteins were purified by Ni-NTA affinity chromatography. The proteins were added to human breast cancer cells (MDA-MB-231) and human embryonic kidney cells (HEK-293) in order to investigate the characteristic of selective targeting and releasing of scorpion toxin AGAP in cancer cells with high uPAR expression. The inhibitory effect of ALA on MDA-MB-231, MCF7, LO2 and HEK-293 was evaluated by MTT assay. Moreover, the antiproliferation mechanism of ALA was determined by flow cytometric and western blot analysis. The results showed that ALA could target MDA-MB-231 cells and the scorpion toxin AGAP could be released with high efficiency and selectivity. ALA inhibited the growth and invasion of breast cancer cells MDA-MB231. Also, cell apoptosis pathway was found to be associated with the inhibition mechanism of ALA according to the data of flow cytometric and western blot analysis. Therefore, ALA could be a novel antitumor candidate for targeting treatment of malignant cell. This study successfully demonstrated that fusion of biotoxins with tumor target domain could provide a simple yet effective way to delivery of peptide or protein drugs.

  5. Infraorbital foramen: horizontal location in relation to ala nasi.

    PubMed

    Takahashi, Yasuhiro; Kakizaki, Hirohiko; Nakano, Takashi

    2011-01-01

    To examine the horizontal location of the infraorbital foramen in relation to the ala nasi. Fifty-six orbits of 28 Japanese cadavers (18 male and 10 female cadavers; average death age, 79.7 years), fixed in 10% buffered formalin, were used. The horizontal distance from the vertical line through the lateral margin of the ala nasi to the medial margin of the infraorbital foramen (the horizontal distance) and the transverse diameter of the infraorbital foramen (the transverse diameter) were examined. Values were compared between genders and sides using Student's t test. The mean horizontal distance was 4.9 mm, with no significant difference between genders (male, 5.2 mm; female, 4.4 mm; p = 0.150) or sides (right, 4.9 mm; left, 4.9 mm; p = 0.944). The mean transverse diameter was 5.5 mm. Although there was no significant difference in this diameter between sides (right, 5.3 mm; left, 5.6 mm; p = 0.358), there was a significant difference between genders (male, 5.7 mm; female, 5.1 mm; p = 0.033). The horizontal distance had no gender difference. This value is available irrespective of gender in surgery.

  6. Inhibitory effect of collagen-derived tripeptides on dipeptidylpeptidase-IV activity.

    PubMed

    Hatanaka, Tadashi; Kawakami, Kayoko; Uraji, Misugi

    2014-12-01

    The collagen tripeptide fragments Gly-Ala-Hyp, Gly-Pro-Ala and Gly-Pro-Hyp were generated by hydrolyzing collagen from pig-skin, cattle-skin, fish-scales and chicken-feet, respectively, with Streptomyces collagenase. Collagenase treatment increased the concentration of tripeptides in the hydrolysates by 13-15% (w/w). Of the three peptides, Gly-Pro-Hyp was a true peptidic inhibitor of dipeptidylpeptidase-IV (DPP-IV), because DPP-IV could not hydrolyze the bond between Pro-Hyp. This tripeptide was a moderately competitive inhibitor (Ki=4.5 mM) of DPP-IV, and its level in the collagen hydrolysates could be greatly increased (4-9% [w/w]) using Streptomyces collagenase.

  7. ALA-induced PpIX spectroscopy for brain tumor image-guided surgery

    NASA Astrophysics Data System (ADS)

    Valdes, Pablo A.; Leblond, Frederic; Kim, Anthony; Harris, Brent T.; Wilson, Brian C.; Paulsen, Keith D.; Roberts, David W.

    2011-03-01

    Maximizing the extent of brain tumor resection correlates with improved survival and quality of life outcomes in patients. Optimal surgical resection requires accurate discrimination between normal and abnormal, cancerous tissue. We present our recent experience using quantitative optical spectroscopy in 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided resection. Exogenous administration of ALA leads to preferential accumulation in tumor tissue of the fluorescent compound, PpIX, which can be used for in vivo surgical guidance. Using the state of the art approach with a fluorescence surgical microscope, we have been able to visualize a subset of brain tumors, but the sensitivity and accuracy of fluorescence detection for tumor tissue with this system are low. To take full advantage of the biological selectivity of PpIX accumulation in brain tumors, we used a quantitative optical spectroscopy system for in vivo measurements of PpIX tissue concentrations. We have shown that, using our quantitative approach for determination of biomarker concentrations, ALA-induced PpIX fluorescence-guidance can achieve accuracies of greater than 90% for most tumor histologies. Here we show multivariate analysis of fluorescence and diffuse reflectance signals in brain tumors with comparable diagnostic performance to our previously reported quantitative approach. These results are promising, since they show that technological improvements in current fluorescence-guided surgical technologies and more biologically relevant approaches are required to take full advantage of fluorescent biomarkers, achieve better tumor identification, increase extent of resection, and subsequently, lead to improve survival and quality of life in patients.

  8. A Circle of Colleagues Meet in the Loop: ALA Midwinter Report.

    ERIC Educational Resources Information Center

    Wilson Library Bulletin, 1987

    1987-01-01

    Highlights the American Library Association (ALA) 1987 Midwinter Conference, including the aftermath of the Attorney General's report on pornography; Congressional pay equity bills; library copying rights; federal librarians' decline in membership and privatization; public library planning, role setting, and output measures manuals; and summaries…

  9. ALA-based fluorescent diagnosis of malignant oral lesions in the presence of bacterial porphyrin formation

    NASA Astrophysics Data System (ADS)

    Schleier, P.; Berndt, A.; Zinner, K.; Zenk, W.; Dietel, W.; Pfister, W.

    2006-02-01

    The aminolevulinic acid (5-ALA) -based fluorescence diagnosis has been found to be promising for an early detection and demarcation of superficial oral squamous cell carcinomas (OSCC). This method has previously demonstrated high sensitivity, however this clinical trial showed a specificity of approximately 62 %. This specificity was mainly restricted by tumor detection in the oral cavity in the presence of bacteria. After topical ALA application in the mouth of patients with previously diagnosed OSSC, red fluorescent areas were observed which did not correlate to confirm histological findings. Swabs and plaque samples were taken from 44 patients and cultivated microbiologically. Fluorescence was investigated (OMA-system) from 32 different bacteria strains found naturally in the oral cavity. After ALA incubation, 30 of 32 strains were found to synthesize fluorescent porphyrins, mainly Protoporphyrin IX. Also multiple fluorescent spectra were obtained having peak wavelengths of 636 nm and around 618 nm - 620 nm indicating synthesis of different porphyrins, such as the lipophylic Protoporphyrin IX (PpIX) and hydrophylic porphyrins (water soluble porphyrins, wsp). Of the 32 fluorescent bacterial strains, 18 produced wsp, often in combination with PpIX, and 5 produced solely wsp. These results clarify that ALA-based fluorescence diagnosis without consideration or suppression of bacteria fluorescence may lead to false-positive findings. It is necessary to suppress bacteria fluorescence with suitable antiseptics before starting the procedure. In this study, when specific antiseptic pre-treatment was performed bacterial associated fluorescence was significantly reduced.

  10. A prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer.

    PubMed

    Wang, Jianzhang; Man, Gene Chi Wai; Chan, Tak Hang; Kwong, Joseph; Wang, Chi Chiu

    2018-01-01

    Anti-angiogenesis effect of a prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining. Next, we investigated how HIF1α/VEGFA was down-regulated and how the reduction of CXCL12 inhibited tumor angiogenesis. We found that VEGFA secretion from endometrial cancer cells was decreased by Pro-EGCG treatment through inhibiting PI3K/AKT/mTOR/HIF1α pathway. Furthermore, the down-regulation of CXCL12 in stromal cells by Pro-EGCG treatment restricted migration and differentiation of macrophages thereby inhibited infiltration of VEGFA-expressing tumor-associated macrophages (TAMs). Taken together, we demonstrated that treatment with Pro-EGCG not only decreases cancer cell-secreted VEGFA but also inhibits TAM-secreted VEGFA in endometrial cancer. These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Intestinal fatty acid binding protein Ala54Thr polymorphism is associated with peripheral atherosclerosis combined with type 2 diabetes mellitus.

    PubMed

    Khattab, Salma A; Abo-Elmatty, Dina M; Ghattas, Maivel H; Mesbah, Noha M; Mehanna, Eman T

    2017-09-01

    Intestinal fatty acid-binding protein 2 (FABP2) is expressed in enterocytes and binds saturated and unsaturated long-chain fatty acids. The FABP2 Ala54Thr polymorphism has been reported to effect lipid metabolism. The aim of the present study was to assess the relationship between this polymorphism and peripheral atherosclerosis combined with type 2 diabetes mellitus (T2DM) in an Egyptian population. The study was performed on 100 T2DM patients with peripheral atherosclerosis and 100 control subjects. The Ala54Thr polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism, whereas serum FABP2 levels were determined using ELISA. Fasting blood glucose, fasting serum insulin concentrations, HbA1c, lipid profile, body mass index (BMI) and systolic and diastolic blood pressure (SBP and DBP, respectively) were determined. There was a higher frequency of the Thr54 allele among the patient group (P = 0.002). In Ala54/Thr54 heterozygotes and carriers of the rare Thr54/Thr54 genotype, there were significant increases in BMI and FABP2. Those with the Thr54/Thr54 genotype had significantly decreased high-density lipoprotein cholesterol (HDL-C) concentrations; in addition, those with the Thr54/Thr54 genotype had significantly higher SBP and DBP than subjects with the Ala54/Ala54 and Ala54/Thr54 genotypes. There was a positive correlation between FABP2 levels and BMI, SBP and DBP, and a negative correlation with HDL-C. The Thr54 allele of the FABP2 Ala54Thr polymorphism was associated with an increased incidence of peripheral atherosclerosis combined with T2DM in the population studied. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  12. Pro-Inflammatory and Pro-Oxidant Status of Pancreatic Islet In Vitro Is Controlled by TLR-4 and HO-1 Pathways

    PubMed Central

    Vivot, Kevin; Langlois, Allan; Bietiger, William; Dal, Stéphanie; Seyfritz, Elodie; Pinget, Michel; Jeandidier, Nathalie; Maillard, Elisa; Gies, Jean-Pierre; Sigrist, Séverine

    2014-01-01

    Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation. PMID:25343247

  13. ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana1

    PubMed Central

    Sautron, Emeline; Boudiere, Laurence; Michaud, Morgane; Dubots, Emmanuelle; Albrieux, Catherine; Marechal, Eric; Jouhet, Juliette

    2016-01-01

    The biogenesis of photosynthetic membranes relies on galactoglycerolipids, which are synthesized via pathways that are dispatched over several cell compartments. This membrane biogenesis requires both trafficking of lipid intermediates and a tight homeostatic regulation. In this work, we address the role of ALA10 (for aminophospholipid ATPase), a P4-type ATPase, in a process counteracting the monogalactosyldiacylglycerol (MGDG) shortage in Arabidopsis (Arabidopsis thaliana) leaves. ALA10 can interact with protein partners, ALIS1 (for ALA-interacting subunit1) or ALIS5, leading to differential endomembrane localizations of the interacting proteins, close to the plasma membrane with ALIS1 or to chloroplasts with ALIS5. ALA10 interacts also with FATTY ACID DESATURASE2 (FAD2), and modification of ALA10 expression affects phosphatidylcholine (PC) fatty acyl desaturation by disturbing the balance between FAD2 and FAD3 activities. Modulation of ALA10 expression downstream impacts the fatty acyl composition of chloroplast PC. ALA10 expression also enhances leaf growth and improves the MGDG-PC ratio, possibly through MGDG SYNTHASE1 (MGD1) activation by phosphatidic acid. The positive effect of ALA10 on leaf development is significant in conditions such as upon treatment of plants with Galvestine-1, an inhibitor of MGDG synthases, or when plants are grown at chilling temperature. PMID:26620528

  14. [Peptide Ala-Glu-Asp-Gly and interferon gamma: their role in immune response during aging].

    PubMed

    Lin'kova, N S; Kuznik, B I; Khavinson, V Kh

    2012-01-01

    The decrease of lymphocyte interferon gamma expression during aging is one of the main mechanisms leading to the immunodeficiency state in the elderly. Cell penetrating geroprotective peptide Ala-Glu-Asp-Gly has the capability to activate the proliferation of lymphocytes in thymus during its aging. The nucleotide sequence which is complementary contacted with peptide Ala-Glu-Asp-Gly was found in promoter region of interferon gamma gene. Thus, the immune protection of this peptide can be explained by its activation of the interferon gamma production in T-cells.

  15. Teacher and Peer Responsivity to Pro-Social Behaviour of High Aggressors in Preschool

    ERIC Educational Resources Information Center

    McComas, Jennifer J.; Johnson, LeAnne; Symons, Frank J.

    2005-01-01

    Naturally occurring aggressive and pro-social behaviour among 12 preschool children was examined in relation to teacher and peer responsiveness. A standardized real-time direct observational protocol was used in the context of a repeated measures design to measure the frequency and sequences of aggressive and pro-social behaviour of target…

  16. Femtosecond laser induced photodynamic therapy on 5-ALA treated SKMEL-30 cells: an efficient theranostic strategy to combat melanoma.

    PubMed

    Kars, Meltem Demirel; Kara, Reyhan; Gündoğdu, Yasemin; Kepceoğlu, Abdullah; Kılıç, Hamdi Şükür

    2014-06-01

    Photodynamic therapy (PDT) is a type of photo-chemotherapy that is based on the application of photosensitizer and irradiation of the region by laser sources. Photosensitizer and light interaction will develop reactive oxygen radicals ((1)O2) in the cells and elimination of cells by apoptosis or necrosis. Metastatic skin cancer cells SKMEL-30 were treated by 5-ALA in dark and then they were irradiated by 90-femtosecond (fs) laser with different pulse powers for different durations. The effects of 5-ALA mediated photodynamic therapy on the cells were determined by XTT proliferation kit and by flow cytometry measurements of Annexin V, 7-AAD and mitochondrial membrane potential alterations. Fluorescent accumulation of protoporphyrin IX was investigated by fluorometry and confocal laser microscope. The viability tests for SKMEL-30 cells treated with different 5-ALA doses and femtosecond laser power and durations demonstrated that 635 nm, 45 mW pulse energy at 90 fs laser pulse applications for 60 sec to 1mM 5-ALA exposed cells decreased the cell proliferation by 30%. Flow cytometric measurements exhibit that PDT caused 63% of mitochondria membrane potential alteration, 30% of cell death in the population by apoptosis and 39% of cells by necrosis. There was 1mM 5-ALA exposure that also exhibited about 32% accumulation of fluorescence in the cells. The pretreatment of the cells with the precursor 5-ALA lets the imaging due to increased protoporphyrin IX fluorescence. This treatment method may be proposed as an effective theranostic strategy for melanoma because of its rapid and effective anticancer consequences. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  17. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

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

    Nitz, Inke; Ewert, Agnes; Klapper, Maja

    2007-02-09

    Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha}more » and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.« less

  18. Folding and conformational consequences of glycine to alanine replacements at different positions in a collagen model peptide.

    PubMed

    Bhate, Manjiri; Wang, Xin; Baum, Jean; Brodsky, Barbara

    2002-05-21

    The collagen model peptide T1-892 includes a C-terminal nucleation domain, (Gly-Pro-Hyp)(4), and an N-terminal (Gly-X-Y)(6) sequence taken from type I collagen. In osteogenesis imperfecta (OI) and other collagen diseases, single base mutations often convert one Gly to a larger residue, and T1-892 homologues modeling such mutations were synthesized with Gly to Ala substitutions in either the (Gly-Pro-Hyp)(4) domain, Gly25Ala, or the (Gly-X-Y)(6) domain, Gly10Ala. CD and NMR studies show the Gly10Ala peptide forms a normal triple-helix at the C-terminal end and propagates from the C- to the N-terminus until the Gly --> Ala substitution is encountered. At this point, triple-helix folding is terminated and cannot be reinitiated, leaving a nonhelical N-terminus. A decreased thermal stability is observed as a result of the shorter length of the triple-helix. In contrast, introduction of the Gly to Ala replacement at position 25, in the nucleation domain, shifts the monomer/trimer equilibrium toward the monomer form. The increased monomer and lower trimer populations are reflected in the dramatic decrease in triple-helix content and stability. Unlike the Ala replacement at position 10, the Ala substitution in the (Gly-Pro-Hyp)(4) region can still be incorporated into a triple-helix, but at a greatly decreased rate of folding, since the original efficient nucleation site is no longer operative. The specific consequences of Gly to Ala replacements in two distinctive sequences in this triple-helical peptide may help clarify the variability in OI clinical severity resulting from mutations at different sites along type I collagen chains.

  19. Relationship Between Occlusal Plane and Three Levels of Ala Tragus line in Dentulous and Partially Dentulous Patients in Different Age Groups: A Pilot Study

    PubMed Central

    Shaikh, Saquib Ahmed; K, Lekha

    2015-01-01

    Statement of problem: Correct orientation of the occlusal plane plays a vital role in achieving optimal aesthetics, occlusal balance and function of complete dentures. The use of ala tragus line for determination of occlusal plane has been a topic of debate over past many years. Also, the effect of age on level of ala tragal line has not been investigated in the past. Purpose: To determine the effect of age on location of Ala-Tragus line. Materials and Methods: A total of 180 patients (90 males and 90 females) were selected with complete dentition and were grouped according to their age in three age groups with 60 subjects in each age group (Group A: 20-35 y, Group B: 36-50 y, Group C: 51-65 y). Right lateral profile photographs were taken with subjects having fox plane placed intraorally parallel to occlusal plane. Reference points corresponding to inferior border, middle or superior border of tragus and inferior border of ala of nose were marked on photographs. These were joined to get three different levels of Ala-Tragus line. Images were analysed photometrically and most parallel relationship was determined in between arms of fox plane (that represented the occlusal plane) and three different levels of ala tragus line. Data obtained was subjected to statistical analysis using Pearson chi-square and Likelihood-ratio chi-square test. Results: Significant correlation was found between age and level of Ala-Tragus line. The occlusal plane was found to be more parallel to Ala-tragus line when inferior border of tragus was considered as posterior reference point in young adult age group (20-35 y). In older age groups, occlusal plane was found to be more parallel to Ala-tragus line when middle of tragus was considered as posterior reference point. Conclusion: Within the limitations of this study, it can be concluded that a definite relationship exists in between age and level of ala tragus line. PMID:25859523

  20. Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin.

    PubMed

    Jimenez-Sousa, Maria Angeles; Almansa, Raquel; de la Fuente, Concha; Caro-Paton, Agustín; Ruiz, Lourdes; Sanchez-Antolín, Gloria; Gonzalez, Jose Manuel; Aller, Rocio; Alcaide, Noelia; Largo, Pilar; Resino, Salvador; de Lejarazu, Raul Ortiz; Bermejo-Martin, Jesus F

    2010-06-01

    Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF

  1. Copyright Updates for K-12 Librarians

    ERIC Educational Resources Information Center

    Johnson, Wendell G.

    2016-01-01

    Copyright concerns continue to bedevil K-12 librarians, who are often called upon to act as the copyright officers in public schools. This article describes recent copyright developments of concern to these librarians in three areas: a recent court case involving a university library, pending legislation supported by ALA, and a regulatory update.…

  2. Enhancement of tumor responsiveness to aminolevulinate-photodynamic therapy (ALA-PDT) using differentiation-promoting agents in mouse models of skin carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Sanjay; Honari, Golara; Paliwal, Akshat; Hasan, Tayyaba; Maytin, Edward V.

    2009-06-01

    Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is an emerging treatment for cancers. ALA, given as a prodrug, selectively accumulates and is metabolized in cancer cells to form protoporphyrin IX (PpIX). Targeted local irradiation with light induces cell death. Since the efficacy of ALA-PDT for large or deep tumors is currently limited, we are developing a new approach that combines differentiation-inducing agents with ALA-PDT to improve the clinical response. Here, we tested this new combination paradigm in the following two models of skin carcinoma in mice: 1) tumors generated by topical application of chemical carcinogens (DMBA-TPA); 2) human SCC cells (A431) implanted subcutaneously. To achieve a differentiated state of the tumors, pretreatment with a low concentration of methotrexate (MTX) or Vitamin D (Vit D) was administered for 72 h prior to exposure to ALA. Confocal images of histological sections were captured and digitally analyzed to determine relative PpIX levels. PpIX in the tumors was also monitored by real-time in vivo fluorescence dosimetry. In both models, a significant increase in levels of PpIX was observed following pretreatment with MTX or Vit D, as compared to no-pretreatment controls. This enhancing effect was observed at very low, non-cytotoxic concentrations, and was highly specific to cancer cells as compared to normal cells. These results suggest that use of differentiating agents such as MTX or Vit D, as a short-term combination therapy given prior to ALA-PDT, can increase the production of PpIX photosensitizer and enhance the therapeutic response of skin cancers.

  3. Shifting with the Paradigm: LJ's Picks & Pans for ALA in Disneyland

    ERIC Educational Resources Information Center

    Berry, John N., III

    2008-01-01

    The feelings of librarians planning for the American Library Association (ALA) conference at Disneyland (aka Anaheim, California, June 26-July 2) range from moderate pleasure to dread. Some remember the joys and difficulties of Orlando, especially the exorbitant cab fares and mediocre restaurants. Others quail at screaming kids and tourists in…

  4. Direct observation of a Γ -X energy spectrum transition in narrow AlAs quantum wells

    NASA Astrophysics Data System (ADS)

    Khisameeva, A. R.; Shchepetilnikov, A. V.; Muravev, V. M.; Gubarev, S. I.; Frolov, D. D.; Nefyodov, Yu. A.; Kukushkin, I. V.; Reichl, C.; Tiemann, L.; Dietsche, W.; Wegscheider, W.

    2018-03-01

    Spectra of magnetoplasma excitations have been investigated in two-dimensional electron systems in AlAs quantum wells (QWs) of different widths. The magnetoplasma spectrum has been found to change profoundly when the quantum well width becomes thinner than 5.5 nm, indicating a drastic change in the conduction electron energy spectrum. The transformation can be interpreted in terms of transition from the in-plane strongly anisotropic Xx-Xy valley occupation to the out-of-plane isotropic Xz valley in the QW plane. Strong enhancement of the cyclotron effective mass over the band value in narrow AlAs QWs is reported.

  5. Ana and the Internet: a review of pro-anorexia websites.

    PubMed

    Norris, Mark L; Boydell, Katherine M; Pinhas, Leora; Katzman, Debra K

    2006-09-01

    The purpose of this article is to describe the content of pro-anorexia websites, both qualitatively and quantitatively. An Internet search protocol was developed to identify pro-anorexia websites. A grounded theory approach was used to generate themes from Internet-based information. Basic descriptive analysis was employed to report on key website characteristics. Twenty pro-anorexia websites met inclusion criteria. Saturation of themes was achieved after review of 12 websites. Key website characteristics included purpose of website (75%), information about webmaster (67%), website disclaimers (58%), and information on "tips and tricks" (67%). Religious metaphors, lifestyle descriptions, and "thinspiration" (inspirational photo galleries and quotes that aim to serve as motivators for weight loss) were frequently present. A total of 10 themes were generated. The most prevalent themes included control, success, and perfection. Health-care providers and caregivers should be aware of pro-anorexia websites and their content, as these websites contain information that promote and support anorexia nervosa. Copyright (c) 2006 by Wiley Periodicals, Inc.

  6. ALA-PpIX variability quantitatively imaged in A431 epidermoid tumors using in vivo ultrasound fluorescence tomography and ex vivo assay

    NASA Astrophysics Data System (ADS)

    DSouza, Alisha V.; Flynn, Brendan P.; Gunn, Jason R.; Samkoe, Kimberley S.; Anand, Sanjay; Maytin, Edward V.; Hasan, Tayyaba; Pogue, Brian W.

    2014-03-01

    Treatment monitoring of Aminolevunilic-acid (ALA) - Photodynamic Therapy (PDT) of basal-cell carcinoma (BCC) calls for superficial and subsurface imaging techniques. While superficial imagers exist for this purpose, their ability to assess PpIX levels in thick lesions is poor; additionally few treatment centers have the capability to measure ALA-induced PpIX production. An area of active research is to improve treatments to deeper and nodular BCCs, because treatment is least effective in these. The goal of this work was to understand the logistics and technical capabilities to quantify PpIX at depths over 1mm, using a novel hybrid ultrasound-guided, fiber-based fluorescence molecular spectroscopictomography system. This system utilizes a 633nm excitation laser and detection using filtered spectrometers. Source and detection fibers are collinear so that their imaging plane matches that of ultrasound transducer. Validation with phantoms and tumor-simulating fluorescent inclusions in mice showed sensitivity to fluorophore concentrations as low as 0.025μg/ml at 4mm depth from surface, as presented in previous years. Image-guided quantification of ALA-induced PpIX production was completed in subcutaneous xenograft epidermoid cancer tumor model A431 in nude mice. A total of 32 animals were imaged in-vivo, using several time points, including pre-ALA, 4-hours post-ALA, and 24-hours post-ALA administration. On average, PpIX production in tumors increased by over 10-fold, 4-hours post-ALA. Statistical analysis of PpIX fluorescence showed significant difference among all groups; p<0.05. Results were validated by exvivo imaging of resected tumors. Details of imaging, analysis and results will be presented to illustrate variability and the potential for imaging these values at depth.

  7. Loss of the Arabidopsis thaliana P₄-ATPase ALA3 reduces adaptability to temperature stresses and impairs vegetative, pollen, and ovule development.

    PubMed

    McDowell, Stephen C; López-Marqués, Rosa L; Poulsen, Lisbeth R; Palmgren, Michael G; Harper, Jeffrey F

    2013-01-01

    Members of the P4 subfamily of P-type ATPases are thought to help create asymmetry in lipid bilayers by flipping specific lipids between the leaflets of a membrane. This asymmetry is believed to be central to the formation of vesicles in the secretory and endocytic pathways. In Arabidopsis thaliana, a P4-ATPase associated with the trans-Golgi network (ALA3) was previously reported to be important for vegetative growth and reproductive success. Here we show that multiple phenotypes for ala3 knockouts are sensitive to growth conditions. For example, ala3 rosette size was observed to be dependent upon both temperature and soil, and varied between 40% and 80% that of wild-type under different conditions. We also demonstrate that ala3 mutants have reduced fecundity resulting from a combination of decreased ovule production and pollen tube growth defects. In-vitro pollen tube growth assays showed that ala3 pollen germinated ∼2 h slower than wild-type and had approximately 2-fold reductions in both maximal growth rate and overall length. In genetic crosses under conditions of hot days and cold nights, pollen fitness was reduced by at least 90-fold; from ∼18% transmission efficiency (unstressed) to less than 0.2% (stressed). Together, these results support a model in which ALA3 functions to modify endomembranes in multiple cell types, enabling structural changes, or signaling functions that are critical in plants for normal development and adaptation to varied growth environments.

  8. Preventing pressure sores of the nasal ala after nasotracheal tube intubation: from animal model to clinical application.

    PubMed

    Huang, Tze-Ta; Tseng, Chih-En; Lee, Tsan-Mu; Yeh, Jen-Ying; Lai, Yu-Yung

    2009-03-01

    Nasal-ala pressure sores induced by nasotracheal intubation are common complications of oral and maxillofacial surgery, but are easily ignored. To determine whether such sores could be prevented, we studied the effects of a combination of cushioning material in an animal model, and then analyzed the efficacy of this combination clinically. Four pigs received nasotracheal intubation. Each pig received intubation for 4, 8, 12, or 16 hours. Outcomes from pigs undergoing 500-gram-weight compression on each nostril were compared: one nostril received an application of cushioning materials, and the contralateral nostril did not. After the required study period, clinical assessment and further evaluation were performed by measuring pressure-sore dimensions and performing incisional biopsies. Clinical applications of this protective technique were then undertaken. Eight patients who underwent intubation without Soft Liner (GC Co, Tokyo, Japan) and DuoDERM CGF (ConvaTec, Inc, Princeton, NJ) protection, and 10 patients with Soft Liner and DuoDERM protection, were evaluated. The protective efficacy of the cushioning materials was significant in the animal model as well as in clinical practice. Pressure sores were avoided on the protected side, with severe tissue necrosis documented on the control side. We found that the combined use of Soft Liner and DuoDERM reduced the size and severity of nasal-ala pressure sores attributable to nasotracheal intubation during oral and maxillofacial surgery.

  9. Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes.

    PubMed

    Black, Mary Helen; Wu, Jun; Takayanagi, Miwa; Wang, Nan; Taylor, Kent D; Haritunians, Talin; Trigo, Enrique; Lawrence, Jean M; Watanabe, Richard M; Buchanan, Thomas A; Xiang, Anny H

    2015-03-01

    Peroxisome proliferator-activated receptor gamma (PPARG) is a susceptibility locus for type 2 diabetes mellitus (T2DM). Although cross-sectional associations have been reported, primarily for Pro12Ala, few longitudinal studies in nondiabetic populations have been conducted. This study aimed to examine whether and to what extent variation in PPARG is associated with longitudinal changes in anthropometric and metabolic traits in Mexican Americans at risk for T2DM. Subjects were participants of BetaGene, a family-based study of obesity, insulin resistance, and β-cell function, who completed a baseline and follow-up study visit (n = 378; mean followup, 4.6 ± 1.5 y). Phenotypes included body fat assessed by dual-energy x-ray absorptiometry; insulin sensitivity (SI), acute insulin response, and β-cell function (disposition index; DI) were estimated from iv glucose tolerance tests with Minimal Model analysis. Eighteen tag single nucleotide polymorphisms (SNPs) capturing variation in a 156-kb region surrounding PPARG were tested for association with changes in longitudinal traits. P-values were Bonferroni-corrected for multiple testing. Six SNPs (rs2972164, rs11128598, rs17793951, rs1151996, rs1175541, rs3856806) were significantly associated with rate of change in SI after adjustment for age, sex, and body fat percentage, but not with changes in adiposity. rs17793951 also had a significant effect on change in DI over time. Association between rs1175541 and change in SI varied by changes in adiposity such that only carriers of the minor allele who reduced body fat over followup improved SI. rs1306470 (captured Pro12Ala, r(2) = 0.9) was not associated with rates of change in any traits and its effects were not modified by changes in adiposity. Variation in PPARG, but not Pro12Ala, contributes to declining SI and concomitant deterioration in β-cell function in Mexican Americans at risk for T2DM.

  10. Monitoring blood flow and photobleaching during topical ALA PDT treatment

    NASA Astrophysics Data System (ADS)

    Sands, Theresa L.; Sunar, Ulas; Foster, Thomas H.; Oseroff, Allan R.

    2009-02-01

    Photodynamic therapy (PDT) using topical aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular shutdown early in treatment must be identified and prevented. This is especially important for topical ALA PDT where vascular shutdown is only temporary and is not a primary method of cell death. Shutdown in vasculature would limit the delivery of oxygen which is necessary for effective PDT treatment. Diffuse correlation spectroscopy (DCS) was used to monitor relative blood flow changes in Balb/C mice undergoing PDT at fluence rates of 10mW/cm2 and 75mW/cm2 for colon-26 tumors implanted intradermally. DCS is a preferable method to monitor the blood flow during PDT of lesions due to its ability to be used noninvasively throughout treatment, returning data from differing depths of tissue. Photobleaching of the photosensitizer was also monitored during treatment as an indirect manner of monitoring singlet oxygen production. In this paper, we show the conditions that cause vascular shutdown in our tumor model and its effects on the photobleaching rate.

  11. Meningiomas del foramen magno: Reporte de 12 casos y revisión de la literatura

    PubMed Central

    Campero, Álvaro; Ajler, Pablo; Roman, Guillermo; Rivadeneira, Conrado

    2017-01-01

    Resumen Objetivo: El propósito del presente trabajo es presentar los resultados de 12 pacientes con diagnóstico de meningiomas del foramen magno (MFM), de localización anterior o lateral, operados con técnicas microquirúrgicas. Método: Desde Junio de 2005 a Diciembre de 2016, 12 pacientes con diagnóstico de MFM fueron intervenidos quirúrgicamente. Se evaluó: edad, sexo, localización de la lesión (anterior o lateral), sintomatología, tipo de abordaje utilizado y resultados postoperatorios. Resultados: De los pacientes intervenidos, 8 fueron mujeres y 4 varones. La edad promedio fue de 47 años. La localización fue anterior en 8 casos y lateral en 4 casos. La sintomatología más frecuente fue dolor occipito-cervical (8 casos), seguido de tetraparesia (3 casos). En los pacientes con MFM de localización anterior se realizó un abordaje extremo-lateral transcondilar (ELTC), mientras que en los tumores laterales el abordaje fue extremo-lateral retrocondilar (ELRC). En 10 casos la resección fue completa. En dos pacientes fue necesario dejar una pequeña lámina de meningioma sobre la arteria vertebral y a nivel del foramen yugular. Como complicaciones postoperatorias, 3 pacientes presentaron una paresia del XII nervio craneano y 2 pacientes paresia del XI nervio craneano; además, 1 paciente presentó una fístula de LCR. Conclusión: La cirugía de los MFM de localización anterior y lateral puede ser realizada de forma segura y efectiva. Es necesario: a) buen conocimiento anatómico de la región; b) disecar los músculos de la nuca en 2 planos, exponiendo el triángulo suboccipital y la arteria vertebral (AV); 3) realizar un abordaje ELRC en los tumores laterales, y ELTC en los tumores anteriores; y 4) buena técnica microquirúrgica. PMID:29142778

  12. "LJ" Report "Anaheim, ALA 2008": Amid the Fantasy, Doses of Reality

    ERIC Educational Resources Information Center

    Blumenstein, Lynn; Berry, John; Fialkoff, Francine; Fox, Bette-Lee; Hadro, Josh; Horrocks, Norman; Oder, Norman; Roncevic, Mirela

    2008-01-01

    If the resort city of Anaheim, California, home of Disneyland and its "imagineers," marked a departure from the urban reality of the typical American Library Association (ALA) annual conference, it was impossible, at this 2008 meeting, to avoid urgent library issues. How do libraries maintain their value and cultural presence as users…

  13. Exploring the Core: An Examination of Required Courses in ALA-Accredited

    ERIC Educational Resources Information Center

    Hall, Russell A.

    2009-01-01

    This paper examines the required courses of ALA-accredited Library and Information Science programs as published on their websites. The study expands on previous research in this area. Findings show that the typical core curriculum has grown to include both research and information technology in addition to the more traditional subjects. The…

  14. A retrospective review of pain control by a two-step irradiance schedule during topical ALA-photodynamic therapy of non-melanoma skin cancer.

    PubMed

    Zeitouni, Nathalie C; Paquette, Anne D; Housel, Joseph P; Shi, Yi; Wilding, Gregory E; Foster, Thomas H; Henderson, Barbara W

    2013-02-01

    Photodynamic therapy (PDT) with topical δ-aminolevulinic acid (ALA) of non-melanoma skin cancers is often associated with treatment-limiting pain. A previous study on basal cell carcinomas (BCCs) at Roswell Park Cancer Institute evaluated a two-step irradiance scheme as a means of minimizing pain, preserving outcomes, and limiting treatment time. We used an initial low irradiance until 90% of the protoporphyrin IX was photobleached, followed by a high irradiance interval until the prescribed fluence was delivered. Success of this pilot investigation motivated integration of the protocol into routine practice. Here, we present a retrospective review of recent clinical experience in a broad patient population. This was a retrospective review of an existing dermatology database. Fourteen caucasion patients-nine men and five women, ages 18-80, with a total of 51 superficial and 73 nodular BCCs, and three Bowen's disease lesions-were included. ALA was applied to each lesion for approximately 4 hours. Lesions received an initial irradiance of 30-50 mW/cm(2) for 20 J/cm(2) , followed by 150 mW/cm(2) for a total fluence of 200-300 J/cm(2) . Pain was assessed using a visual analog scale (VAS). Clinical outcome was determined at 6-12 months. Median VAS scores were 1.0 for both irradiances. Five of 127 lesions required pain control with 1% xylocaine. Pain was strongly influenced by lesion location but not by lesion type, number, or size. Complete responses were achieved in 84.1% of BCCs, which compares favorably with reported results for single ALA-PDT treatments. Two of three Bowen's disease lesions showed a complete response. Complete responses for nodular BCCs were 37%, which are also within the range of reported outcomes. A two-step irradiance protocol in ALA-PDT effectively minimizes pain, maintains excellent clinical outcomes in superficial lesions, and adds minimal treatment time. Copyright © 2013 Wiley Periodicals, Inc.

  15. A Retrospective Review of Pain Control by a Two-Step Irradiance Schedule During Topical ALA-Photodynamic Therapy of Non-melanoma Skin Cancer

    PubMed Central

    Zeitouni, Nathalie C.; Paquette, Anne D.; Housel, Joseph P.; Shi, Yi; Wilding, Gregory; Foster, Thomas H.; Henderson, Barbara W.

    2013-01-01

    Background and Objective Photodynamic therapy (PDT) with topical δ-aminolevulinic acid (ALA) of non-melanoma skin cancers is often associated with treatment-limiting pain. A previous study on basal cell carcinomas (BCCs) at Roswell Park Cancer Institute evaluated a two-step irradiance scheme as a means of minimizing pain, preserving outcomes, and limiting treatment time. We used an initial low irradiance until 90% of the protoporphyrin IX was photobleached, followed by a high irradiance interval until the prescribed fluence was delivered. Success of this pilot investigation motivated integration of the protocol into routine practice. Here we present a retrospective review of recent clinical experience in a broad patient population. Study Design/Materials and Methods This was a retrospective review of an existing dermatology data base. Fourteen caucasion patients - 9 men and 5 women, ages 18 to 80, with a total of 51 superficial and 73 nodular BCCs, and three Bowen's disease lesions – were included. ALA was applied to each lesion for approximately 4h. Lesions received an initial irradiance of 30 - 50 mW/cm2 for 20 J/cm2, followed by 150 mW/cm2 for a total fluence of 200-300 J/cm2. Pain was assessed using a visual analog scale (VAS). Clinical outcome was determined at 6-12 months. Results Median VAS scores were 1.0 for both irradiances. Five of 127 lesions required pain control with 1% xylocaine. Pain was strongly influenced by lesion location but not by lesion type, number, or size. Complete responses were achieved in 84.1% of BCCs, which compares favorably with reported results for single ALA-PDT treatments. Two of three Bowen's disease lesions showed a complete response. Complete responses for nodular BCCs were 37%, which are also within the range of reported outcomes. Conclusions A two-step irradiance protocol in ALA-PDT effectively minimizes pain, maintains excellent clinical outcomes in superficial lesions, and adds minimal treatment time. PMID:23390058

  16. Bioavailability of Pb and Zn from mine tailings as indicated by erythrocyte aminolevulinic acid dehydratase (ALA-D) activity in suckers (Pisces: catostomidae)

    USGS Publications Warehouse

    Schmitt, Christopher J.; Dwyer, F. James; Finger, Susan E.

    1984-01-01

    The activity of the erythrocyte enzyme δ-aminolevulinic acid dehydratase (ALA-D) was measured in 35 catostomids (black redhorse, Moxostoma duquesnei; golden redhorse, M. erythrurum; northern hogsucker, Hypentelium nigricans) collected from three sites on a stream contaminated with Pb-, Cd-, and Zn-rich mine tailings and from an uncontaminated site upstream. Enzyme activity was expressed in terms of hemoglobin (Hb), DNA, and protein concentrations; these variables can be determined in the laboratory on once-frozen blood samples. Concentrations of Pb and Zn in blood and of Pb in edible tissues were significantly higher, and ALA-D activity was significantly lower, at all three contaminated sites than upstream. At the most contaminated site, ALA-D activity was 62–67% lower than upstream. Lead concentrations in the edible tissues and in blood were positively correlated (r = 0.80), whereas ALA-D activity was negatively correlated with Pb in blood (r = −0.70) and in edible tissues (r = −0.59). Five statistically significant relations between Pb and Zn in blood and ALA-D activity were determined. The two models that explained the highest percentage (> 74%) of the total variance also included factors related to Hb concentration. All five significant models included negative coefficients for variables that represented Pb in blood and positive coefficients for Zn in blood. The ALA-D assay with results standardized to Hb concentration represents an expedient alternative to the more traditional hematocrit standardization, and the measurement of ALA-D activity by this method can be used to document exposure of fish to environmental Pb.

  17. Biofortification of safflower: an oil seed crop engineered for ALA-targeting better sustainability and plant based omega-3 fatty acids.

    PubMed

    Rani, Arti; Panwar, Asha; Sathe, Manjary; Chandrashekhara, Karunakara Alageri; Kush, Anil

    2018-05-11

    Alpha-linolenic acid (ALA) deficiency and a skewed n6:n3 fatty acid ratio in the diet is a major explanation for the prevalence of cardiovascular diseases and inflammatory/autoimmune diseases. There is mounting evidence of the health benefits associated with omega-3 long chain polyunsaturated fatty acids (LC PUFA's). Although present in abundance in fish, a number of factors limit our consumption of fish based omega-3 PUFA's. To name a few, overexploitation of wild fish stocks has reduced their sustainability due to increased demand of aquaculture for fish oil and meal; the pollution of marine food webs has raised concerns over the ingestion of toxic substances such as heavy metals and dioxins; vegetarians do not consider fish-based sources for supplemental nutrition. Thus alternative sources are being sought and one approach to the sustainable supply of LC-PUFAs is the metabolic engineering of transgenic plants with the capacity to synthesize n3 LC-PUFAs. The present investigation was carried out with the goal of developing transgenic safflower capable of producing pharmaceutically important alpha-linolenic acid (ALA, C18:3, n3). This crop was selected as the seeds accumulate ~ 78% of the total fatty acids as linoleic acid (LA, C18:2, n6), the immediate precursor of ALA. In the present work, ALA production was achieved successfully in safflower seeds by transforming safflower hypocotyls with Arabidopsis specific delta 15 desaturase (FAD3) driven by truncated seed specific promoter. Transgenic safflower fortified with ALA is not only potentially valuable nutritional superior novel oil but also has reduced ratio of LA to ALA which is required for good health.

  18. The influence of photodynamic therapy (PDT) with δ-aminolevulinic acid (ALA) on J-774A.1 macrophage cell line

    NASA Astrophysics Data System (ADS)

    Kawczyk-Krupka, Aleksandra; Czuba, Zenon; Ledwon, Aleksandra; Latos, Wojciech; Sliszka, Ewelina; Mianowska, Marta; Krol, Wojciech; Sieron, Aleksander

    2008-02-01

    Introduction. The whole mechanism of the cellular level of tumor destruction by photodynamic therapy (PDT) is still unknown. Despite necrotic and apoptotic ways of cell death, there is a variety of events leading to and magnifying the inactivation of tumor cells. Material and methods. J-774A.1 were incubated with δ-aminolevulinic acid (ALA) at different concentrations (125, 250, 500, 1000 μM) and then irradiated with VIS (400 - 750 nm) at the dose of 5,10 and 30 J/cm2 delivered from the incoherent light source. The effects of the application of ALA-PDT were evaluated on the basis of cell viability, nitric oxide (NO), tumor necrosis factor α- (TNF-α) and interleukin-1β (IL-1β) produced by the J-774A.1 cells. Results. The cell viability (assessed using MTT test) was comparable with control group at 5,10 and 30 J/cm2. At these doses of energy using different concentrations of ALA we have observed that at the higher energy doses, the greater increase of TNF-α release, lowering of the level of IL-1β production and decrease of NO release were observed. There was also observed the dependence of the secretional activity of the cells on the ALA concentrations. Conclusion. The cell viability and production of cytokines depended on ALA concentrations and energy doses of the light. The higher some cytokines' release after PDT could be an additional factor for the complete eradication of tumor.

  19. Impact of an AlAs window layer upon the optical properties of Al x Ga1-x As photodiodes

    NASA Astrophysics Data System (ADS)

    Kang, T.; Chen, X. J.; Johnson, E. B.; Christian, J. F.; Lee, K.; Hammig, M. D.

    2016-05-01

    Recently developed advanced scintillators, which have the ability to distinguish gamma-ray interaction events from those that accompany neutron impact, require improved quantum efficiency in the blue to near UV region of the spectrum. We utilize GaAs/Al0.8Ga0.2As photodiode elements as components in a wide band-gap solid-state photomultiplier as a lower-cost, lower logistical burden, and higher quantum efficiency replacement for the photomultiplier tube. An AlAs window layer is employed as a means to increase the diode’s optical performance. Relative to structures absent the window layer, simulations and measurements demonstrate that the AlAs layer produces a spatial coincidence between regions of large drift fields with regions of high photon absorption. In addition to the AlAs layer, secondary ion mass spectrometry measurements show that an unexpected high degree of inter-diffusion of GaAs and AlAs quenches the photon-detection efficiency, a decrease that can be avoided by its post-growth removal. With the AlAs layer, the peak external quantum efficiency of 49% is achieved at 450 nm with 10 V reverse bias, which does not fully deplete the device. Simulations show that full depletion can result in efficiencies exceeding 90%. In order to enhance the optical response, a simple anti-reflective coating layer is designed using the existing passivation layer components that successfully minimizes the reflection at the wavelength range of interest (300 nm-500 nm).

  20. Pro-Gastrin Releasing Peptide: A New Serum Marker for Endometrioid Adenocarcinoma.

    PubMed

    Kiseli, Mine; Caglar, Gamze Sinem; Yarci Gursoy, Asli; Tasci, Tolga; Candar, Tuba; Akincioglu, Egemen; Pabuccu, Emre Goksan; Boran, Nurettin; Tulunay, Gokhan; Umudum, Haldun

    2018-06-13

    Gastrin-releasing peptide (GRP) is thought to play a role in the metastatic process of various malignancies. The more stable precursor of GRP, pro-GRP (ProGRP), has been shown to be secreted by neuroendocrine tumors. This study was designed to assess the validity of ProGRP as a diagnostic marker in endometrioid adenocarcinomas (EAs) of the endometrium. Thirty-seven patients with a diagnosis of EA, 23 patients with endometrial hyperplasia, and 32 age-matched controls with normal endometrial histology were recruited for this study. Serum ProGRP and cancer antigen 125 (CA125) values were compared between groups. Median serum ProGRP levels were significantly higher in the cancer group compared to corresponding levels in both the hyperplasia and control groups (p = 0.008 and p < 0.001 respectively; endometrial cancer: 27.5 pg/mL; hyperplasia: 16.1 pg/mL; controls: 12.9 pg/mL). Age and endometrial thickness were positively correlated with ProGRP levels (r = 0.322, p = 0.006 and r = 0.269, p = 0.023, respectively). Receiver Operating Characteristic curve analyses for EA revealed a threshold of 20.81 pg/mL, with a sensitivity of 60.7% and specificity of 81.4%, positive predictive value of 68% and negative predictive value of 76.1%. Significantly higher ProGRP levels were observed in patients with EA than in controls. Serum ProGRP has good diagnostic sensitivity and specificity for EA. © 2018 S. Karger AG, Basel.

  1. The Simplified Aircraft-Based Paired Approach With the ALAS Alerting Algorithm

    NASA Technical Reports Server (NTRS)

    Perry, Raleigh B.; Madden, Michael M.; Torres-Pomales, Wilfredo; Butler, Ricky W.

    2013-01-01

    This paper presents the results of an investigation of a proposed concept for closely spaced parallel runways called the Simplified Aircraft-based Paired Approach (SAPA). This procedure depends upon a new alerting algorithm called the Adjacent Landing Alerting System (ALAS). This study used both low fidelity and high fidelity simulations to validate the SAPA procedure and test the performance of the new alerting algorithm. The low fidelity simulation enabled a determination of minimum approach distance for the worst case over millions of scenarios. The high fidelity simulation enabled an accurate determination of timings and minimum approach distance in the presence of realistic trajectories, communication latencies, and total system error for 108 test cases. The SAPA procedure and the ALAS alerting algorithm were applied to the 750-ft parallel spacing (e.g., SFO 28L/28R) approach problem. With the SAPA procedure as defined in this paper, this study concludes that a 750-ft application does not appear to be feasible, but preliminary results for 1000-ft parallel runways look promising.

  2. 5-ALA/PpIX fluorescence detection of gastrointestinal neoplasia

    NASA Astrophysics Data System (ADS)

    Borisova, Ekaterina G.; Vladimirov, Borislav; Terziev, Ivan; Ivanova, Radina; Avramov, Latchezar

    2009-07-01

    In the recent study delta-ALA/PpIX is used as fluorescent marker for dysplasia and tumor detection in esophagus, stomach and colon. ALA is administered per os six to eight (depending on the lesion location) hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built for the LED to use the light guide of standard video-endoscopic system. Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer. The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Spectral features observed during endoscopic investigations could be distinct as the next regions: 450-630 nm region, where tissue autofluorescence is observed; 630-710 nm region, where fluorescence of PpIX is clearly pronounced; 530-580 nm region, where minima in the autofluorescence signal are observed, related to re-absorption of oxy-hemoglobin in this spectral area. Endogenous and exogenous fluorescence spectra are used to develop simple but effective algorithm, based on dimensionless ratio of the signals at 560 and 635 nm, for differentiation of normal/abnormal gastrointestinal tissues. Very good correlation between fluorescence signals and histology examination of the lesions investigated is achieved.

  3. Feasibility of Raman spectroscopy in vitro after 5-ALA-based fluorescence diagnosis in the bladder

    NASA Astrophysics Data System (ADS)

    Grimbergen, M. C. M.; van Swol, C. F. P.; van Moorselaar, R. J. A.; Mahadevan-Jansen, A.,; Stone, N.

    2006-02-01

    Photodynamic diagnosis (PDD) has become popular in bladder cancer detection. Several studies have however shown an increased false positive biopsies rate under PDD guidance compared to conventional cystoscopy. Raman spectroscopy is an optical technique that utilizes molecular specific, inelastic scattering of light photons to interrogate biological tissues, which can successfully differentiate epithelial neoplasia from normal tissue and inflammations in vitro. This investigation was performed to show the feasibility of NIR Raman spectroscopy in vitro on biopsies obtained under guidance of 5-ALA induced PPIX fluorescence imaging. Raman spectra of a PPIX solution was measured to obtain a characteristic signature for the photosensitzer without contributions from tissue constituents. Biopsies were obtained from patients with known bladder cancer instilled with 50ml, 5mg 5-ALA two hours prior to trans-urethral resection of tumor (TURT). Additional biopsies were obtained at a fluorescent and non-fluorescent area, snap-frozen in liquid nitrogen and stored at -80 °C. Each biopsy was thawed before measurements (10sec integration time) with a confocal Raman system (Renishaw Gloucestershire, UK). The 830 nm excitation (300mW) source is focused on the tissue by a 20X ultra-long-working-distance objective. Differences in fluorescence background between the two groups were removed by means of a special developed fluorescence subtraction algorithm. Raman spectra from ALA biopsies showed different fluorescence background which can be effectively removed by a fluorescence subtraction algorithm. This investigation shows that the interaction of the ALA induced PPIX with Raman spectroscopy in bladder samples. Combination of these techniques in-vivo may lead to a viable method of optical biopsies in bladder cancer detection.

  4. Assessment of the anticonvulsant potency of various benzylamide derivatives in the mouse maximal electroshock-induced seizure threshold model.

    PubMed

    Świąder, Mariusz J; Paruszewski, Ryszard; Łuszczki, Jarogniew J

    2016-04-01

    The aim of this study was to assess the anticonvulsant potency of 6 various benzylamide derivatives [i.e., nicotinic acid benzylamide (Nic-BZA), picolinic acid 2-fluoro-benzylamide (2F-Pic-BZA), picolinic acid benzylamide (Pic-BZA), (RS)-methyl-alanine-benzylamide (Me-Ala-BZA), isonicotinic acid benzylamide (Iso-Nic-BZA), and (R)-N-methyl-proline-benzylamide (Me-Pro-BZA)] in the threshold for maximal electroshock (MEST)-induced seizures in mice. Electroconvulsions (seizure activity) were produced in mice by means of a current (sine-wave, 50Hz, 500V, strength from 4 to 18mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA administered systemically (ip) in a dose-dependent manner increase the threshold for maximal electroconvulsions in mice. Linear regression analysis of Nic-BZA, 2F-Pic-BZA, Pic-BZA, MeAla-BZA, IsoNic-BZA, and Me-Pro-BZA doses and their corresponding threshold increases allowed determining threshold increasing doses by 20% (TID20 values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID20 values in the MEST test for Nic-BZA, 2F-Pic-BZA, Pic-BZA, Me-Ala-BZA, Iso-Nic-BZA, and Me-Pro-BZA were 7.45mg/kg, 7.72mg/kg, 8.74mg/kg, 15.11mg/kg, 21.95mg/kg and 28.06mg/kg, respectively. The studied benzylamide derivatives can be arranged with respect to their anticonvulsant potency in the MEST test as follows: Nic-BZA>2F-Pic-BZA>Pic-BZA>Me-Ala-BZA>Iso-Nic-BZA>Me-Pro-BZA. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  5. Identification of food-grade subtilisins as gluten-degrading enzymes to treat celiac disease

    PubMed Central

    Wei, Guoxian; Tian, Na; Siezen, Roland; Schuppan, Detlef

    2016-01-01

    Gluten are proline- and glutamine-rich proteins present in wheat, barley, and rye and contain the immunogenic sequences that drive celiac disease (CD). Rothia mucilaginosa, an oral microbial colonizer, can cleave these gluten epitopes. The aim was to isolate and identify the enzymes and evaluate their potential as novel enzyme therapeutics for CD. The membrane-associated R. mucilaginosa proteins were extracted and separated by DEAE chromatography. Enzyme activities were monitored with paranitroanilide-derivatized and fluorescence resonance energy transfer (FRET) peptide substrates, and by gliadin zymography. Epitope elimination was determined in R5 and G12 ELISAs. The gliadin-degrading Rothia enzymes were identified by LC-ESI-MS/MS as hypothetical proteins ROTMU0001_0241 (C6R5V9_9MICC), ROTMU0001_0243 (C6R5W1_9MICC), and ROTMU0001_240 (C6R5V8_9MICC). A search with the Basic Local Alignment Search Tool revealed that these are subtilisin-like serine proteases belonging to the peptidase S8 family. Alignment of the major Rothia subtilisins indicated that all contain the catalytic triad with Asp (D), His (H), and Ser (S) in the D-H-S order. They cleaved succinyl-Ala-Ala-Pro-Phe-paranitroanilide, a substrate for subtilisin with Pro in the P2 position, as in Tyr-Pro-Gln and Leu-Pro-Tyr in gluten, which are also cleaved. Consistently, FRET substrates of gliadin immunogenic epitopes comprising Xaa-Pro-Xaa motives were rapidly hydrolyzed. The Rothia subtilisins and two subtilisins from Bacillus licheniformis, subtilisin A and the food-grade Nattokinase, efficiently degraded the immunogenic gliadin-derived 33-mer peptide and the immunodominant epitopes recognized by the R5 and G12 antibodies. This study identified Rothia and food-grade Bacillus subtilisins as promising new candidates for enzyme therapeutics in CD. PMID:27469368

  6. Geroprotective effect of ala-glu-asp-gly peptide in male rats exposed to different illumination regimens.

    PubMed

    Vinogradova, I A; Bukalev, A V; Zabezhinski, M A; Semenchenko, A V; Khavinson, V Kh; Anisimov, V N

    2008-04-01

    Exposure of male rats to permanent or natural illumination of North-Western Russia accelerated their death in comparison with animals exposed to standard (12 h) light. Permanent illumination promoted the development of spontaneous tumors in comparison with the standard photoregimen. Injection of epithalone (synthetic Ala-Glu-Asp-Gly peptide; subcutaneously 0.1 microg/rat 5 times a week from the age of 4 months until natural death) virtually did not change the mean lifespan of male rats, but was associated with a significant (p<0.05) normalization of population aging rate and hence, time of mortality rate doubling in groups exposed to natural or constant illumination. Epithalone injected to rats exposed to any photoregimen significantly inhibited the development of spontaneous tumors, primarily testicular leydigomas and leukemias.

  7. Idiopathic elastosis perforans serpiginosa with satisfactory response after 5-ALA photodynamic therapy.

    PubMed

    Alique-García, S; Company-Quiroga, J; Horcajada-Reales, C; Echeverría-García, B; Tardío-Dovao, J C; Borbujo, J

    2018-03-01

    Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light, and oxygen for the treatment of malignant or benign diseases. Topical photosensitizers employed in dermatology are 5-aminolevulinic acid (5 ALA) and methyl aminolevulinate, classically used for the treatment of superficial non-melanoma skin cancer and their precursors. Recently the efficacy of PDT has been introduced in other benign diseases. Elastosis perforans serpiginosa (EPS) is a rare skin disorder characterized by transepidermal elimination of abnormal elastic fibers. Management of this condition is complicated, various methods have been used but with limited success. We report a case of EPS in a 30-yeard-old woman treated with 5 ALA-PDT. After 4 sessions the lesions have almost completely disappeared with no residual side effects. Therefore we present an effective and safe alternative for the treatment of EPS. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Aronia melanocarpa Concentrate Ameliorates Pro-Inflammatory Responses in HaCaT Keratinocytes and 12-O-Tetradecanoylphorbol-13-Acetate-Induced Ear Edema in Mice.

    PubMed

    Goh, Ah Ra; Youn, Gi Soo; Yoo, Ki-Yeon; Won, Moo Ho; Han, Sang-Zin; Lim, Soon Sung; Lee, Keun Wook; Choi, Soo Young; Park, Jinseu

    2016-07-01

    Abnormal expression of pro-inflammatory mediators such as cell adhesion molecules and cytokines has been implicated in various inflammatory skin diseases, including atopic dermatitis. In this study, we investigated the anti-inflammatory activity of Aronia melanocarpa concentrate (AC) and its action mechanisms using in vivo and in vitro skin inflammation models. Topical application of AC on mouse ears significantly suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema formation, as judged by measuring ear thickness and weight, and histological analysis. Topical administration of AC also reduced the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in TPA-stimulated mouse ears. Pretreatment with AC suppressed TNF-α-induced ICAM-I expression and subsequent monocyte adhesiveness in human keratinocyte cell line HaCaT. In addition, AC significantly decreased intracellular reactive oxygen species (ROS) generation as well as mitogen-activated protein kinase (MAPK) activation in TNF-α-stimulated HaCaT cells. AC and its constituent cyanidin 3-glucoside also attenuated TNF-α-induced IKK activation, IκB degradation, p65 phosphorylation/nuclear translocation, and p65 DNA binding activity in HaCaT cells. Overall, our results indicate that AC exerts anti-inflammatory activities by inhibiting expression of pro-inflammatory mediators in vitro and in vivo possibly through suppression of ROS-MAPK-NF-κB signaling pathways. Therefore, AC may be developed as a therapeutic agent to treat various inflammatory skin diseases.

  9. Loss of the Arabidopsis thaliana P4-ATPase ALA3 Reduces Adaptability to Temperature Stresses and Impairs Vegetative, Pollen, and Ovule Development

    PubMed Central

    McDowell, Stephen C.; López-Marqués, Rosa L.; Poulsen, Lisbeth R.; Palmgren, Michael G.; Harper, Jeffrey F.

    2013-01-01

    Members of the P4 subfamily of P-type ATPases are thought to help create asymmetry in lipid bilayers by flipping specific lipids between the leaflets of a membrane. This asymmetry is believed to be central to the formation of vesicles in the secretory and endocytic pathways. In Arabidopsis thaliana, a P4-ATPase associated with the trans-Golgi network (ALA3) was previously reported to be important for vegetative growth and reproductive success. Here we show that multiple phenotypes for ala3 knockouts are sensitive to growth conditions. For example, ala3 rosette size was observed to be dependent upon both temperature and soil, and varied between 40% and 80% that of wild-type under different conditions. We also demonstrate that ala3 mutants have reduced fecundity resulting from a combination of decreased ovule production and pollen tube growth defects. In-vitro pollen tube growth assays showed that ala3 pollen germinated ∼2 h slower than wild-type and had approximately 2-fold reductions in both maximal growth rate and overall length. In genetic crosses under conditions of hot days and cold nights, pollen fitness was reduced by at least 90-fold; from ∼18% transmission efficiency (unstressed) to less than 0.2% (stressed). Together, these results support a model in which ALA3 functions to modify endomembranes in multiple cell types, enabling structural changes, or signaling functions that are critical in plants for normal development and adaptation to varied growth environments. PMID:23667493

  10. Photodynamic diagnosis following intravesical instillation of aminolevulinic acid (ALA): first clinical experiences in urology

    NASA Astrophysics Data System (ADS)

    Baumgartner, Reinhold; Kriegmair, M.; Stepp, Herbert G.; Lumper, W.; Heil, Peter; Riesenberg, Rainer; Stocker, Susanne; Hofstetter, Alfons G.

    1993-06-01

    Delta Aminolevulinic acid (ALA), a precursor of Protoporphyrin IX (PP IX) in hem biosynthesis has been topically applied in urinary bladders in order to study its potential as fluorescent tumor marker. Preclinical experiments have been performed on chemically induced tumors in rats, revealing a ratio of PP IX-fluorescence intensity up to 20:1 in tumors as compared to healthy urothelium. Synthesis of PP IX has been stimulated in 56 patients by intravesical instillation of a pH-neutral ALA-solution. After an incubation time of two to four hours strong red fluorescence was endoscopically observed even in tiny superficial tumors. Brightness and contrast allows visualization of early stage urothelial diseases with naked eyes and without the necessity suppressing background fluorescence or violet excitation light.

  11. A TATA binding protein mutant with increased affinity for DNA directs transcription from a reversed TATA sequence in vivo.

    PubMed

    Spencer, J Vaughn; Arndt, Karen M

    2002-12-01

    The TATA-binding protein (TBP) nucleates the assembly and determines the position of the preinitiation complex at RNA polymerase II-transcribed genes. We investigated the importance of two conserved residues on the DNA binding surface of Saccharomyces cerevisiae TBP to DNA binding and sequence discrimination. Because they define a significant break in the twofold symmetry of the TBP-TATA interface, Ala100 and Pro191 have been proposed to be key determinants of TBP binding orientation and transcription directionality. In contrast to previous predictions, we found that substitution of an alanine for Pro191 did not allow recognition of a reversed TATA box in vivo; however, the reciprocal change, Ala100 to proline, resulted in efficient utilization of this and other variant TATA sequences. In vitro assays demonstrated that TBP mutants with the A100P and P191A substitutions have increased and decreased affinity for DNA, respectively. The TATA binding defect of TBP with the P191A mutation could be intragenically suppressed by the A100P substitution. Our results suggest that Ala100 and Pro191 are important for DNA binding and sequence recognition by TBP, that the naturally occurring asymmetry of Ala100 and Pro191 is not essential for function, and that a single amino acid change in TBP can lead to elevated DNA binding affinity and recognition of a reversed TATA sequence.

  12. Analysis of Manganese Superoxide Dismutase and Glutathione Peroxidase 1 Gene Polymorphisms in Vitiligo.

    PubMed

    Seçkin, Havva Yıldız; Kalkan, Göknur; Bütün, İlknur; Akbaş, Ali; Baş, Yalçın; Karakuş, Nevin; Benli, İsmail

    2016-08-01

    Vitiligo is a hereditary/acquired progressive pigmentation disorder characterized by discoloration of skin as a result of melanocyte dysfunction. Recent studies have proposed that oxidant/antioxidant status plays an important role in vitiligo pathogenesis because of the toxic effects on melanocytes. In this study, we aimed to investigate possible associations of MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms with vitiligo with in Turkish population. The study group consists of 57 patients with vitiligo and 69 healthy controls. Genotyping is performed to identify MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms. The method used for genotyping was based on the PCR amplification and detection of polymorphisms by hybridization probes labeled with fluorescent dyes. Both the genotype and allele frequencies of MnSOD Ala-9Val (p = 0.817 and p = 0.553, respectively) and GPx1 Pro198Leu polymorphisms (p = 0.422 and p = 0.673, respectively) were not significantly different between vitiligo patients and the control group. Although no significant difference was found, this is the first report investigating the possible associations between the MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms in Turkish population. Further studies with large populations will be able to clarify the association better.

  13. Increasing NT-proBNP Precedes The Development of Arterial Hypertension: The Multi-Ethnic Study Of Atherosclerosis

    PubMed Central

    Sanchez, Otto A.; Jacobs, David R.; Bahrami, Hossein; Peralta, Carmen A.; Daniels, Lori B.; Lima, João A.; Maisel, Alan; Duprez, Daniel A.

    2014-01-01

    Background Longitudinal associations between the aminoterminal pro B-type natriuretic peptide (NT-proBNP) and incident hypertension are lacking. Methods We tested associations between baseline NT-proBNP (bNT-proBNP) and also change in NT-proBNP (ΔNT-proBNP) (visit 3 NT-proBNP – bNT-proBNP; 3.2 years apart) with incident hypertension (systolic blood pressure ≥140 and/or diastolic BP ≥90 mmHg or taking anti-hypertensive medications). Incident hypertension was evaluated in 5596 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) without hypertension at baseline (53% females, age range 45 – 84 years without overt cardiovascular disease) and followup for 9.5 years and in a subgroup (1550) who had bNT-proBNP <100 pg/mL and no hypertension at visit 3. Incident hypertension was regressed (proportional hazards) on quintiles of bNT-proBNP (range) 1) reference <19.2, 2) 19.3 – 40.8, 3) 40.9 – 70.9, 4) 71 – 135.2 and 5) >135.5 and also on ΔNT-proBNP categories (reference < −10, −10 — 10, >10 — 50 and >50 pg/mL). Hazard ratios (HRs) were adjusted for age, race, sex, education, diabetes, obesity, LV mass/height, SBP and DBP, IL-6, salt intake, estimated glomerular filtration rate and exercise. Results Compared to the reference category, HRs (95% CI) for incident hypertension compared to the first quintile of bNT-proBNP were 1.47 (1.13–1.93), 1.57 (1.18–2.09), 1.52 (1.12–2.06) and 2.36 (1.62–3.41). HRs for incident hypertension by categories of ΔNT-proBNP from 3.2 to 9.5 years followup were 0.98 (0.62 – 1.56), 1.13 (0.72 – 1.79) and 1.82 (1.07 – 3.12). Conclusion The development of hypertension tended to be preceded by elevated levels of bNT-proBNP or a substantial positive ΔNT-proBNP. PMID:25909698

  14. [Expression of proBNP and NT-proBNP in Sudden Death of Coronary Heart Disease].

    PubMed

    Zeng, Q; Sun, R F; Li, Z; Zhai, L Q; Liu, M Z; Guo, X J; Gao, C R

    2017-10-01

    To study the expression change of pro-brain natriuretic peptide (proBNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in sudden death of coronary atherosclerotic heart disease, and to explore its application in forensic diagnosis. Myocardial and blood samples were collected from normal control group, sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group (20 cases in each group). The expression of proBNP in myocardial samples were detected by immunohistochemical staining and Western blotting, and that of BNP mRNA were detected by reverse transcription PCR (RT-PCR). The content of NT-proBNP in plasma were detected by ELISA. Immunohistochemical staining showed positive expression of proBNP in both sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group. There was no positive expression in normal control group. For sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group, the relative expression of proBNP protein and BNP mRNA in myocardial tissue and the NT-proBNP content in plasma were higher than that of normal control group ( P <0.05). The NT-proBNP content in plasma of sudden death of coronary atherosclerotic heart disease group was higher than that of single coronary stenosis group ( P <0.05). In myocardial ischemia condition, the higher expression of proBNP in cardiac muscle cell shows that the detection of NT-proBNP in plasma can be useful to differentially diagnose the degree of coronary atherosclerotic heart disease and determine whether the sudden death due to coronary atherosclerotic heart disease. Copyright© by the Editorial Department of Journal of Forensic Medicine

  15. Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia.

    PubMed

    Sundaram, Meenakshi; Zhong, Shumei; Bou Khalil, Maroun; Zhou, Hu; Jiang, Zhenghui G; Zhao, Yang; Iqbal, Jahangir; Hussain, M Mahmood; Figeys, Daniel; Wang, Yuwei; Yao, Zemin

    2010-06-01

    We have shown that expression of apolipoprotein (apo) C-III promotes VLDL secretion from transfected McA-RH7777 cells under lipid-rich conditions. To determine structural elements within apoC-III that confer to this function, we contrasted wild-type apoC-III with a mutant Ala23Thr originally identified in hypotriglyceridemia subjects. Although synthesis of [(3)H]glycerol-labeled TAG was comparable between cells expressing wild-type apoC-III (C3wt cells) or Ala23Thr mutant (C3AT cells), secretion of [(3)H]TAG from C3AT cells was markedly decreased. The lowered [(3)H]TAG secretion was associated with an inability of C3AT cells to assemble VLDL(1). Moreover, [(3)H]TAG within the microsomal lumen in C3AT cells was 60% higher than that in C3wt cells, yet the activity of microsomal triglyceride-transfer protein in C3AT cells was not elevated. The accumulated [(3)H]TAG in C3AT microsomal lumen was mainly associated with lumenal IDL/LDL-like lipoproteins. Phenotypically, this [(3)H]TAG fractionation profiling resembled what was observed in cells treated with brefeldin A, which at low dose specifically blocked the second-step VLDL(1) maturation. Furthermore, lumenal [(35)S]Ala23Thr protein accumulated in IDL/LDL fractions and was absent in VLDL fractions in C3AT cells. These results suggest that the presence of Ala23Thr protein in lumenal IDL/LDL particles might prevent effective fusion between lipid droplets and VLDL precursors. Thus, the current study reveals an important structural element residing within the N-terminal region of apoC-III that governs the second step VLDL(1) maturation.

  16. Studying Online: Student Motivations and Experiences in ALA-Accredited LIS Programs

    ERIC Educational Resources Information Center

    Oguz, Fatih; Chu, Clara M.; Chow, Anthony S.

    2015-01-01

    This paper presents a large scale study of online MLIS students (n = 910), who completed at least one online course and were enrolled in 36 of the 58 ALA-accredited MLIS programs in Canada and the United States. The results indicate that the typical student is female, White, lives in an urban setting, and is in her mid-30s. Online students were…

  17. The Short Life and Ignominious Death of ALA Video and Special Projects.

    ERIC Educational Resources Information Center

    Handman, Gary

    1991-01-01

    Discussion of videocassettes in our culture and the function of video collections in libraries focuses on the creation and demise of a unit sponsored by the American Library Association, the ALA Video and Special Projects. The unit's role is discussed and funding decisions that led to its demise are explained. (LRW)

  18. The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

    PubMed

    Abbasi, Mehrnaz; Daneshpour, Maryam S; Hedayati, Mehdi; Mottaghi, Azadeh; Pourvali, Katayoun; Azizi, Fereidoun

    2018-01-01

    Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P  = 0.006). Median serum TAC in CKD group was 920 μmol/L and was significantly lower ( p  < 0.001) compared to the control group (1045 μmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

  19. Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity.

    PubMed

    Rathi, Sonika; Jalali, Subhadra; Musada, Ganeswara Rao; Patnaik, Satish; Balakrishnan, Divya; Hussain, Anjli; Kaur, Inderjeet

    2018-02-01

    Retinopathy of prematurity (ROP) is a vasoproliferative eye disease in preterm infants. Based on its phenotypic similarities with familial exudative vitreo retinopathy (FEVR), the present study was conducted to screen the Norrin signalling pathway genes (already been implicated in FEVR) for understanding their involvement among Indian patients with ROP. The study cohort consisted of patients with ROP (n=246) and controls (n=300) that included full term (n=110) and preterm babies devoid of ROP (n=190). Screening of the NDP, FZD4, TSPAN12 genes were accomplished by resequencing the entire coding and untranslated regions (UTR). The genotype data of the patients with ROP were analysed in the background of their clinical manifestations and further analysed in conjunction with other available data on these genes worldwide. Two novel variants in intron 1 (IVS1 +16A>G) and 3'UTR (c.5 22T>C) along with a previously reported change in the 5'UTR (c.395_409del14bp) were observed in the NDP gene in three patients with ROP. Screening of the FZD4 revealed four heterozygous variants, p.(Pro33Ser), p.(Pro168Ser), p.(Ile192Ile) and p.(Ile360Val), a compound heterozygous (p.(Pro33Ser)/p.(Pro168Ser)) and a 3'UTR (c*G>T) variants in the study cohort. Variants p.(Pro33Ser) and p.(Pro168Ser) were found to be significantly associated with ROP. A heterozygous variant p.(Leu119Arg) in TSPAN12 gene was observed in a patient with threshold ROP. However, a formal genotype-phenotype correlation could not be established due to the low frequencies of the variant alleles in these genes. This is a first study that revealed association of few variants in Norrin signalling genes among Indian patients with ROP that warrants further detailed investigation worldwide. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  20. Patients’ Perspectives of Enrollment in Research Without Consent- The Patients’ Experiences in Emergency Research- ProTECT Study (PEER-ProTECT)

    PubMed Central

    Dickert, Neal W; Scicluna, Victoria M; Baren, Jill M; Biros, Michelle H; Fleischman, Ross J; Govindarajan, Prasanthi R; Jones, Elizabeth B; Pancioli, Arthur M; Wright, David W; Pentz, Rebecca D

    2016-01-01

    Objective Research in acute illness often requires an exception from informed consent (EFIC). Few studies have assessed the views of patients enrolled in EFIC trials. This study was designed to assess the views of patients and their surrogates of EFIC enrollment in a randomized, placebo-controlled trial of an investigational agent for traumatic brain injury. Design Interactive interview study. Setting Nested within the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III) trial, a Phase III randomized controlled trial in acute traumatic brain injury (TBI). Participants Patients and surrogates (for patients incapable of being interviewed) enrolled in ProTECT III under EFIC at 12 sites. Measurements Interviews focused on respondents’ acceptance of EFIC enrollment in ProTECT, use of placebo and randomization, understanding of major study elements, and views regarding regulatory protections. Descriptive statistical analysis was performed; textual data were analyzed thematically. Main Results 85 individuals were interviewed. 84% had positive attitudes toward ProTECT III inclusion. 78% found their inclusion under EFIC acceptable, and 72% found use of EFIC in ProTECT III acceptable in general. Only 2 respondents clearly disagreed with both personal and general EFIC enrollment. The most common concerns (26%) related to absence of consent. 80% and 92% were accepting of placebo use and randomization, respectively. Though there were few black respondents (n=11), they were less accepting of personal EFIC enrollment than white respondents (55% vs 83%, p= 0.0494). Conclusions Acceptance of EFIC in this placebo-controlled trial of an investigational agent was high and exceeded acceptance among community consultation participants. EFIC enrollment appears generally consistent with patients’ preferences. PMID:25574795

  1. Roles of Ala-149 in the catalytic activity of diadenosine tetraphosphate phosphorylase from Mycobacterium tuberculosis H37Rv.

    PubMed

    Mori, Shigetarou; Kim, Hyun; Rimbara, Emiko; Arakawa, Yoshichika; Shibayama, Keigo

    2015-01-01

    Diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap4A) phosphorylase from Mycobacterium tuberculosis H37Rv (MtAPA) belongs to the histidine triad motif (HIT) superfamily, but is the only member with an alanine residue at position 149 (Ala-149). Enzymatic analysis revealed that the Ala-149 deletion mutant displayed substrate specificity for diadenosine 5',5'''-P(1),P(5)-pentaphosphate and was inactive on Ap4A and other substrates that are utilized by the wild-type enzyme.

  2. Finite size effect on hydrogen bond cooperativity in (Ala)n polypeptides: A DFT study using numeric atom-centered orbitals

    NASA Astrophysics Data System (ADS)

    Blum, Volker; Ireta, Joel; Scheffler, Matthias

    2007-03-01

    An accurate representation of the energetic contribution Ehb of hydrogen bonds to structure formation is paramount to understand the secondary structure stability of proteins, both qualitatively and quantitatively. However, Ehb depends strongly on its environment, and even on the surrounding peptide conformation itself. For instance, a short α-helical polypeptide (Ala)4 can not be stabilized by its single hydrogen bond, whereas an infinite α-helical chain (Ala)∞ is clearly energetically stable over a fully extended conformation. We here use all-electron density functional calculations in the PBE generalized gradient approximation by a recently developed, computationally efficient numeric atom-centered orbital based code^1 to investigate this H-bond cooperativity that is intrinsic to Alanine-based polypeptides (Ala)n (n=1-20,∞). We compare finite and infinite prototypical helical conformations (α, π, 310) on equal footing, with both neutral and ionic termination for finite (Ala)n peptides. Moderately sized NAO basis sets allow to capture Ehb with meV accuracy, revealing a clear jump in Ehb (cooperativity) when two H-bonds first appear in line, followed by slower and more continuous increase of Ehb towards n->∞. ^1 V. Blum, R. Gehrke, P. Havu, V. Havu, M. Scheffler, The FHI Ab Initio Molecular Simulations (aims) Project, Fritz-Haber-Institut, Berlin (2006).

  3. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

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

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observedmore » link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.« less

  4. #Proana: Pro-Eating Disorder Socialization on Twitter.

    PubMed

    Arseniev-Koehler, Alina; Lee, Hedwig; McCormick, Tyler; Moreno, Megan A

    2016-06-01

    Pro-eating disorder (ED) online movements support engagement with ED lifestyles and are associated with negative health consequences for adolescents with EDs. Twitter is a popular social media site among adolescents that provides a unique setting for Pro-ED content to be publicly exchanged. The purpose of this study was to investigate Pro-ED Twitter profiles' references to EDs and how their social connections (followers) reference EDs. A purposeful sample of 45 Pro-ED profiles was selected from Twitter. Profile information, all tweets, and a random sample of 100 of their followers' profile information were collected for content analysis using the Twitter Application Programming Interface. A codebook based on ED screening guidelines was applied to evaluate ED references. For each Pro-ED profile, proportion of tweets with ED references and proportion of followers with ED references in their own profile were evaluated. In total, our 45 Pro-ED profiles generated 4,245 tweets for analysis. A median of 36.4% of profiles' tweets contained ED references. Pro-ED profiles had a median of 173 followers, and a median of 44.5% of followers had ED references. Pro-ED profiles with more tweets with ED references also tended to have more followers with ED references (β = .37, p < .01). Findings suggest that profiles which self-identify as Pro-ED express disordered eating patterns through tweets and have an audience of followers, many of whom also reference ED in their own profiles. ED socialization on Twitter might provide social support, but in the Pro-ED context this activity might also reinforce an ED identity. Copyright © 2016 The Society for Adolescent Health and Medicine. All rights reserved.

  5. Reactivity of Ala-Gly dipeptide with β-turn secondary structure

    NASA Astrophysics Data System (ADS)

    Yu, Craig P.; Gerlei, Klára Z.; Rágyanszki, Anita; Jensen, Svend J. Knak; Viskolcz, Béla; Csizmadia, Imre G.

    2018-01-01

    The conformational space of β-turns of Ala-Gly dipeptide is analyzed theoretically using quantum mechanical methods. A number of potential minima are obtained and characterized. The potential energy surface suggests that β-turn conformers are susceptible to rapid radical formation, which leads to potential L and D epimerization. The calculated thermodynamics show that the radical mediated epimerization is possible and that the estimated barrier height for hydrogen abstraction on the Cα is the lowest for the Gly residue.

  6. 75 FR 12254 - Official Trail Marker for the Ala Kahakai National Historic Trail

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-15

    ... DEPARTMENT OF THE INTERIOR National Park Service Official Trail Marker for the Ala Kahakai National Historic Trail AGENCY: National Park Service, Interior. ACTION: Official Insignia, Designation. Authority: National Trails System Act, 16 U.S.C. 1241(a) and l246(c) and Protection of Official Badges...

  7. Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors-γ2 with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status in Emirati Population

    PubMed Central

    Al-Safar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Afandi, Bachar; Rais, Naushad

    2015-01-01

    Background. Transcription factor 7-like 2 gene (TCF7L2) and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2) have a profound effect on the incidence of type 2 diabetes mellitus (T2DM) and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282) of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. Methods. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2) and rs1801282 (PPAR-γ2 P12A) variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. Results. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127–3.461], P = 0.017), but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96) was similar in the groups tested and more than 90% population was homozygous for this allele. Conclusions. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population. PMID:26273662

  8. Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors- γ 2 with Type 2 Diabetes Mellitus and is Interaction with Obesity Status in Emirati Population.

    PubMed

    Al-Safar, Habiba; Hassoun, Ahmed; Almazrouei, Shaikha; Kamal, Wala; Afandi, Bachar; Rais, Naushad

    2015-01-01

    Transcription factor 7-like 2 gene (TCF7L2) and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2) have a profound effect on the incidence of type 2 diabetes mellitus (T2DM) and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282) of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2) and rs1801282 (PPAR-γ2 P12A) variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127-3.461], P = 0.017), but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96) was similar in the groups tested and more than 90% population was homozygous for this allele. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population.

  9. Total plasma proANP increases with atrial dilatation in horses.

    PubMed

    Van Der Vekens, N; Hunter, I; Timm, A; Decloedt, A; De Clercq, D; Deprez, P; Goetze, J P; van Loon, G

    2015-12-19

    Equine atrial natriuretic peptide (ANP) plasma concentrations are correlated with left atrial size. However, species-specific assays are lacking and the results from human assays are poorly reproducible. A new methodology called processing independent analysis (PIA) that measures the total proANP product in plasma has proven to be successful in human medicine, but has never been used in horses. The aims were to establish an equine proANP reference interval by measurement of the total proANP product using PIA and to examine the proANP concentrations in horses with atrial dilatation. Sample stability was studied by comparison of storage at -80°C and -20°C. Plasma samples were obtained from 23 healthy horses, 12 horses with moderate or severe valvular regurgitation without atrial dilatation and 42 horses with valvular regurgitation and atrial dilatation. The proANP concentration was significantly (P<0.001) higher in horses with atrial dilatation (761.4 (442.1-1859.1) pmol/l) than in healthy horses (491.6 (429.5-765.9) pmol/l; P<0.001) or horses with cardiac disease but without atrial dilatation (544.4 (457.0-677.6) pmol/l). A cut-off value (573.8 pmol/l) for detection of atrial dilatation was calculated. Sample storage at -80°C did not differ from sample storage at -20°C. The measurement of total proANP in plasma detects atrial dilatation in horses and may be useful for clinical evaluation in equine medicine. British Veterinary Association.

  10. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

    PubMed

    Bloch, Yehudi; Bouchareychas, Laura; Merceron, Romain; Składanowska, Katarzyna; Van den Bossche, Lien; Detry, Sammy; Govindarajan, Srinath; Elewaut, Dirk; Haerynck, Filomeen; Dullaers, Melissa; Adamopoulos, Iannis E; Savvides, Savvas N

    2018-01-16

    Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Prosomatostatin-I is processed to somatostatin-26 and somatostatin-14 in the pancreas of the bowfin, Amia calva.

    PubMed

    Wang, Y; Youson, J H; Conlon, J M

    1993-08-13

    With the exception of the Agnatha (lampreys and hagfishes), somatostatin-14 is the predominant molecular form of somatostatin in the pancreas of species from all classes of vertebrates yet studied. The pancreas of the holostean fish, Amia calva (bowfin; order Amiiformes) contained somatostatin-like immunoreactivity that was resolved by reversed phase HPLC in two components. The primary structure of the more abundant peptide (somatostatin-26) was established as: Ser-Ala-Asn-Pro-Ala5-Leu-Ala-Pro-Arg-Glu10-Arg-Lys-Ala-Gly-+ ++Cys15-Lys-Asn-Phe- Phe-Trp20-Lys-Thr-Phe-Thr-Ser25-Cys. This amino acid sequence shows one substitution (Leu for Met at position 6) and two deletions compared with mammalian somatostatin-28. The minor component was identical to somatostatin-14. The data show that the pathway of post-translational processing of prosomatostatin-I in the bowfin pancreas is appreciably different from the corresponding pathway in teleost fish and higher vertebrates.

  12. Retardation of ice crystallization by short peptides

    NASA Astrophysics Data System (ADS)

    Kim, Jun Soo; Yethiraj, Arun

    2009-03-01

    The effect of short peptides on the growth of ice crystals is studied using molecular dynamics simulations. The simulations focus on two sequences (Gly-Pro-Ala-Gly and Gly-Gly-Ala-Gly) that are found in collagen hydrolysate, a substance that is known to retard crystal growth. In the absence of peptides, the growth of ice crystal in the solution with the ice/water interface is observed in at a rate comparable to the experimental data. When peptides are present in the liquid phase, the crystal growth is retarded to a significant extent compared to the pure water. It is found that Gly-Pro-Ala-Gly is more effective (crystallization is up to 5 times slower than in its absence) than Gly-Gly-Ala-Gly (up to 3 times slower) implying that the role of the proline residue is important. The mechanism can be understood in the nature of binding of the peptides to the growing crystal.

  13. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

    PubMed

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

    2015-02-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. © 2014 American Heart Association, Inc.

  14. Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

    PubMed Central

    Li, Wencheng; Sullivan, Michelle N.; Zhang, Sheng; Worker, Caleb J.; Xiong, Zhenggang; Speth, Robert C.; Feng, Yumei

    2016-01-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT1 receptor–dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. PMID:25421983

  15. Isolation and structural elucidation of antioxidant peptides from oyster (Saccostrea cucullata) protein hydrolysate.

    PubMed

    Umayaparvathi, S; Meenakshi, S; Vimalraj, V; Arumugam, M; Balasubramanian, T

    2014-01-01

    Protein derived from the oyster (Saccostrea cucullata) was hydrolyzed using protease from Bacillus cereus SU12 for isolation of antioxidant peptides. The oyster hydrolysate exhibited a strong antioxidant potential in DPPH (85.7±0.37%) followed by Hydrogen peroxide radical scavenging activity (81.6±0.3%), Hydroxyl radical-scavenging activity (79.32±0.6%), Reducing power assay (2.63±0.2 OD at 700nm). Due to the high antioxidant potential, hydrolysate was fractionated in Sephadex G-25 gel filtration chromatography. The active peptide fraction was further purified by UPLC-MS. Totally 7 antioxidant peptides were collected. Among 7 peptides (SCAP 1-7), 3 peptides (SCAP 1, 3 and 7) had highest scavenging ability on DPPH radicals. The amino acid sequence and molecular mass of purified antioxidant peptides (SCAP1, SCAP3 and SCAP7) were determined by Q-TOF ESI mass spectroscopy and structures of the peptides were Leu-Ala-Asn-Ala-Lys (MW=515.29Da), Pro-Ser-Leu-Val-Gly-Arg-Pro-Pro-Val-Gly-Lys-Leu-Thr-Leu (MW=1432.89Da) and Val-Lys-Val-Leu-Leu-Glu-His-Pro-Val-Leu (MW=1145.75Da), respectively. The unique amino acid composition and sequence in the peptides might play an important role in expression of their antioxidant activity. The results of this study suggest that oyster protein hydrolysate is good source of natural antioxidants.

  16. ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-β1 pathway.

    PubMed

    Jiang, Mingxia; Zhang, Haifen; Zhai, Lijie; Ye, Bianliang; Cheng, Yin; Zhai, Chengkai

    2017-11-16

    Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-β1 and the possible mechanisms mediating the effects. The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor β 1 (TGF-β 1 ) signal pathway were measured by real-time RT-PCR and western blot. The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-β 1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-β 1 in HK-2 cells.

  17. ALA16VAL-MnSOD gene polymorphism and stroke: Association with dyslipidemia and glucose levels.

    PubMed

    Flores, Ariane Ethur; Pascotini, Eduardo Tanuri; Kegler, Aline; Gabbi, Patricia; Bochi, Guilherme Vargas; Barbisan, Fernanda; Duarte, Thiago; Prado, Ana Lucia Cervi; Duarte, Marta M M F; da Cruz, Ivana B M; Moresco, Rafael Noal; Santos, Adair Roberto Soares; Bresciani, Guilherme; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

    2017-09-05

    Stroke risk has been associated to the progression of carotid plaques due to high glucose levels and lipid accumulation, which are greatly associated to cerebral injury, brain oxidative stress, and apoptosis. The ALA16VAL-MnSOD gene single nucleotide polymorphism (SNP) has shown to modulate risk factors of several metabolic and vascular diseases, such as blood glucose (GLU) and lipid levels. However, the association of these factors in stroke patients has not been studied to date. Thus, we evaluated the influence of the Ala16Val-MnSOD SNP on lipid profile, GLU levels, oxidative and DNA damage of 44 patients in a late phase of stroke (>6months). The statistical analysis showed a greater proportion of VV carries in stroke patients. The results also indicated that stroke patients had higher cholesterol (CHO) and GLU levels when compared to healthy counterparts. Interestingly, V allele carriers with stroke showed higher levels of CHO and GLU when compared to AA stroke and healthy counterparts. Our findings suggest that oxidative stress markers are still increased even after 6 months of cerebral injury. Furthermore, we propose that the Ala16Val-MnSOD SNPs may contribute to hypercholesterolemia and higher GLU levels, increasing the risk to neurovascular events that may lead to stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Real-time analysis of endogenous protoporphyrin IX fluorescence from δ-aminolevulinic acid and its derivatives reveals distinct time- and dose-dependent characteristics in vitro

    NASA Astrophysics Data System (ADS)

    Kiesslich, Tobias; Helander, Linda; Illig, Romana; Oberdanner, Christian; Wagner, Andrej; Lettner, Herbert; Jakab, Martin; Plaetzer, Kristjan

    2014-08-01

    Photodynamic therapy (PDT) and photodiagnosis based on the intracellular production of the photosensitizer protoporphyrin IX (PPIX) by administration of its metabolic precursor δ-aminolevulinic acid (ALA) achieved their breakthrough upon the clinical approval of MAL (ALA methyl ester) and HAL (ALA hexyl ester). For newly developed ALA derivatives or application in new tumor types, in vitro determination of PPIX formation involves multiparametric experiments covering variable pro-drug concentrations, medium composition, time points of analysis, and cell type(s). This study uses a fluorescence microplate reader with a built-in temperature and atmosphere control to investigate the high-resolution long-term kinetics (72 h) of cellular PPIX fueled by administration of either ALA, MAL, or HAL for each 10 different concentrations. For simultaneous proliferation correction, A431 cells were stably transfected with green fluorescent protein. The results indicate that the peak PPIX level is a function of both, incubation concentration and period: maximal PPIX is generated with 1 to 2-mM ALA/MAL or 0.125-mM HAL; also, the PPIX peak shifts to longer incubation periods with increasing pro-drug concentrations. The results underline the need for detailed temporal analysis of PPIX formation to optimize ALA (derivative)-based PDT or photodiagnosis and highlight the value of environment-controlled microplate readers for automated in vitro analysis.

  19. Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications

    PubMed Central

    Pourvali, Katayoun; Abbasi, Mehrnaz; Mottaghi, Azadeh

    2016-01-01

    Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear. PMID:27141263

  20. A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.

    PubMed

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

    2017-01-26

    The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

  1. GaAs, AlAs, and AlxGa1-xAs: Material parameters for use in research and device applications

    NASA Astrophysics Data System (ADS)

    Adachi, Sadao

    1985-08-01

    The AlxGa1-xAs/GaAs heterostructure system is potentially useful material for high-speed digital, high-frequency microwave, and electro-optic device applications. Even though the basic AlxGa1-xAs/GaAs heterostructure concepts are understood at this time, some practical device parameters in this system have been hampered by a lack of definite knowledge of many material parameters. Recently, Blakemore has presented numerical and graphical information about many of the physical and electronic properties of GaAs [J. S. Blakemore, J. Appl. Phys. 53, R123 (1982)]. The purpose of this review is (i) to obtain and clarify all the various material parameters of AlxGa1-xAs alloy from a systematic point of view, and (ii) to present key properties of the material parameters for a variety of research works and device applications. A complete set of material parameters are considered in this review for GaAs, AlAs, and AlxGa1-xAs alloys. The model used is based on an interpolation scheme and, therefore, necessitates known values of the parameters for the related binaries (GaAs and AlAs). The material parameters and properties considered in the present review can be classified into sixteen groups: (1) lattice constant and crystal density, (2) melting point, (3) thermal expansion coefficient, (4) lattice dynamic properties, (5) lattice thermal properties, (6) electronic-band structure, (7) external perturbation effects on the band-gap energy, (8) effective mass, (9) deformation potential, (10) static and high-frequency dielectric constants, (11) magnetic susceptibility, (12) piezoelectric constant, (13) Fröhlich coupling parameter, (14) electron transport properties, (15) optical properties, and (16) photoelastic properties. Of particular interest is the deviation of material parameters from linearity with respect to the AlAs mole fraction x. Some material parameters, such as lattice constant, crystal density, thermal expansion coefficient, dielectric constant, and elastic constant

  2. Mixed pro and antisaccade performance in children and adults.

    PubMed

    Irving, Elizabeth L; Tajik-Parvinchi, Diana J; Lillakas, Linda; González, Esther G; Steinbach, Martin J

    2009-02-19

    Pro and antisaccades are usually presented in blocks of similar type but they can also be presented such that prosaccade and antisaccade eye movements are mixed and a cue, usually the shape/colour of the fixation target or the peripheral target, determines which type of eye movement is required in a particular trial. A mixed-saccade task theoretically equalizes the inhibitory requirements for pro and antisaccades. Using a mixed-saccade task paradigm the aims of the study were to: 1) compare pro and antisaccades of children, 2) compare performance of children and adults and 3) explore the effect of increased working memory load in adults. The eye movements of 22 children (5-12 years) and 22 adults (20-51 years) were examined using a video-based eye tracking system (El-Mar Series 2020 Eye Tracker, Toronto, Canada). The task was a mixed-saccade task of pro and antisaccades and the colour of the peripheral target was the cue for whether the required saccade was to be a pro or an antisaccade. The children performed the mixed-saccade task and 11 adults performed the same mixed-saccade task alone and in a dual-task paradigm (together with mental subtraction or number repetition). A second group of 11 adults performed the mixed-saccade task alone. Children made mainly antisaccade errors. The adults' error rates increased in the mental subtraction dual-task condition but both antisaccade and prosaccade errors were made. It was concluded that the increased error rates of these two groups are reflective of different processing dynamics.

  3. Assay for identification of heterozygous single-nucleotide polymorphism (Ala67Thr) in human poliovirus receptor gene.

    PubMed

    Nandi, Shyam Sundar; Sharma, Deepa Kailash; Deshpande, Jagadish M

    2016-07-01

    It is important to understand the role of cell surface receptors in susceptibility to infectious diseases. CD155 a member of the immunoglobulin super family, serves as the poliovirus receptor (PVR). Heterozygous (Ala67Thr) polymorphism in CD155 has been suggested as a risk factor for paralytic outcome of poliovirus infection. The present study pertains to the development of a screening test to detect the single nucleotide (SNP) polymorphism in the CD155 gene. New primers were designed for PCR, sequencing and SNP analysis of Exon2 of CD155 gene. DNAs extracted from either whole blood (n=75) or cells from oral cavity (n=75) were used for standardization and validation of the SNP assay. DNA sequencing was used as the gold standard method. A new SNP assay for detection of heterozygous Ala67Thr genotype was developed and validated by testing 150 DNA samples. Heterozygous CD155 was detected in 27.33 per cent (41/150) of DNA samples tested by both SNP detection assay and sequencing. The SNP detection assay was successfully developed for identification of Ala67Thr polymorphism in human PVR/CD155 gene. The SNP assay will be useful for large scale screening of DNA samples.

  4. Cephalometrically assessing the validity of superior, middle and inferior tragus points on ala-tragus line while establishing the occlusal plane in edentulous patient

    PubMed Central

    Thombare, Ram

    2013-01-01

    PURPOSE The purpose of this study was to decide the most appropriate point on tragus to be used as a reference point at time of marking ala tragus line while establishing occlusal plane. MATERIALS AND METHODS The data was collected in two groups of subjects: 1) Dentulous 2) Edentulous group having sample size of 30 for each group with equal gender distribution (15 males, 15 females each). Downs analysis was used for base value. Lateral cephalographs were taken for all selected subjects. Three points were marked on tragus as Superior (S), Middle (M), and Inferior (I) and were joined with ala (A) of the nose to form ala-tragus lines. The angle formed by each line (SA plane, MA plane, IA plane) with Frankfort Horizontal (FH) plane was measured by using custom made device and modified protractor in all dentulous and edentulous subjects. Also, in dentulous subjects angle between Frankfort Horizontal plane and natural occlusal plane was measured. The measurements obtained were subjected to the following statistical tests; descriptive analysis, Student's unpaired t-test and Pearson's correlation coefficient. RESULTS The results demonstrated, the mean angle COO (cant of occlusal plane) as 9.76°, inferior point on tragus had given the mean angular value of IFH [Angle between IA plane (plane formed by joining inferior point-I on tragus and ala of nose- A) and FH plane) as 10.40° and 10.56° in dentulous and edentulous subjects respectively which was the closest value to the angle COO and was comparable with the values of angle COO value in Downs analysis. Angulations of ala-tragus line marked from inferior point with occlusal plane in dentulous subject had given the smallest value 2.46° which showed that this ala-tragus line was nearly parallel to occlusal plane. CONCLUSION The inferior point marked on tragus is the most appropriate point for marking ala-tragus line. PMID:23508068

  5. ALA Office for Intellectual Freedom: Who We Are and How We Help Librarians

    ERIC Educational Resources Information Center

    Pekoll, Kristin

    2015-01-01

    The American Library Association's (ALA's) Office for Intellectual Freedom (OIF) strives to educate librarians and the public about the nature and importance of intellectual freedom in libraries, and it will celebrate its fiftieth anniversary in 2017. Libraries are a forum for information and ideas (under the First Amendment), and librarians are…

  6. Ala67Thr mutation in the poliovirus receptor CD155 is a potential risk factor for vaccine and wild-type paralytic poliomyelitis.

    PubMed

    Kindberg, Elin; Ax, Cecilia; Fiore, Lucia; Svensson, Lennart

    2009-05-01

    Poliovirus infections can be asymptomatic or cause severe paralysis. Why some individuals develop paralytic poliomyelitis is unknown, but a role for host genetic factors has been suggested. To investigate if a polymorphism, Ala67Thr, in the poliovirus receptor, which has been found to facilitate increased resistance against poliovirus-induced cell lysis and apoptosis, is associated with increased risk of paralytic poliomyelitis, poliovirus receptor genotyping was undertaken among Italian subjects with vaccine-associated (n = 9), or with wild-type paralytic poliomyelitis (n = 6), and control subjects (n = 71), using RFLP-PCR and pyrosequencing. Heterozygous poliovirus receptor Ala67Thr genotype was found in 13.3% of the patients with paresis and in 8.5% of the controls (Odds Ratio = 1.667). The frequency of Ala67Thr among the controls is in agreement with earlier published data. It is concluded that the Ala67Thr mutation in the poliovirus receptor is a possible risk factor for the development of vaccine-associated or paralytic poliomyelitis associated with wild-type virus. Copyright 2009 Wiley-Liss, Inc.

  7. PVR/CD155 Ala67Thr Mutation and Cleft Lip/Palate.

    PubMed

    Vieira, Alexandre R; Letra, Ariadne; Silva, Renato M; Granjeiro, Jose M; Shimizu, Takehiko; Poletta, Fernando A; Mereb, Juan C; Castilla, Eduardo E; Orioli, Iêda M

    2018-03-01

    The 19q13 locus has been linked to cleft lip and palate by our group and independently by others. Here we fine mapped the region in an attempt to identify an etiological variant that can explain cleft lip and palate occurrence. A total of 2739 individuals born with cleft lip and palate, related to individuals born with cleft lip and palate, and unrelated were studied. We used linkage and association approaches to fine map the interval between D19S714 and D19S433 and genotypes were defined by the use of TaqMan chemistry. We confirmed our previous findings that markers in PVR/CD155 are associated with cleft lip and palate. We studied the mutation Ala67Thr further and calculated its penetrance. We also attempted to detect PVR/CD155 expression in human whole saliva. Our results showed that markers in PVR/CD155 are associated with cleft lip and palate and the penetrance of the Ala67Thr is very low (between 1% and 5%). We could not detect PVR/CD155 expression in adult human whole saliva and PVR/CD155 possibly interacts with maternal infection to predispose children to cleft lip only.

  8. [Study on association of FABP2 gene Ala54Thr polymorphism with risk of obesity, body fat mass and physical activity].

    PubMed

    Nasibulina, É S; Borisova, A V; Akhmetov, I I

    2013-01-01

    Obesity is a multifactorial disease which depends on the interaction between genome and environment. Fatty acid-binding protein 2 (FABP2) regulates lipid transport, intestinal absorption and metabolism. The aim of the study was to investigate the interrelation between the FABP2 gene Ala54Thr polymorphism, body mass index and body fat mass and to study distribution of genotypes and alleles frequencies of FABP2 gene in athletes and individuals who are not involved in sports. 315 athletes of different sport disciplines and levels and 612 controls (predominantly students) participated in the study. Genotyping for the FABP2 gene Ala54Thr polymorphism was performed by PCR. Body composition was analyzed by bioimpedance method. The study did not confirm the association of FABP2 gene Ala54Thr polymorphism with the risk of obesity and body fat mass. However, the frequency of the Thr54 allele was significantly higher in elite stayers (50.0%, p = 0.025) and combat athletes (46.2%, p = 0.013) in comparison with controls (32.2%). Thus, FABP2 gene Ala54Thr polymorphism is associated with the predisposition to endurance athletic performance.

  9. Differential processing of pro-neurotensin/neuromedin N and relationship to pro-hormone convertases.

    PubMed

    Kitabgi, Patrick

    2006-10-01

    Neurotensin (NT) is synthesized as part of a larger precursor that also contains neuromedin N (NN), a six amino acid neurotensin-like peptide. NT and NN are located in the C-terminal region of the precursor (pro-NT/NN) where they are flanked and separated by three Lys-Arg sequences. A fourth dibasic sequence is present in the middle of the precursor. Dibasics are the consensus sites recognized and cleaved by endoproteases that belong to the recently identified family of pro-protein convertases (PCs). In tissues that express pro-NT/NN, the three C-terminal Lys-Arg sites are differentially processed, whereas the middle dibasic is poorly cleaved. Pro-NT/NN processing gives rise mainly to NT and NN in the brain, to NT and a large peptide ending with the NN sequence at its C-terminus (large NN) in the gut and to NT, large NN and a large peptide ending with the NT sequence (large NT) in the adrenals. Recent evidence indicates that PC1, PC2 and PC5-A are the pro-hormone convertases responsible for the processing patterns observed in the gut, brain and adrenals, respectively. As NT, NN, large NT and large NN are all endowed with biological activity, the evidence reviewed here supports the idea that post-translational processing of pro-NT/NN in tissues may generate biological diversity.

  10. ScreenPro FH: from the Czech MedPed to international collaboration. ScreenPro FH is a participating project of the EAS-FHCS.

    PubMed

    Ceska, R; Freiberger, T; Vaclova, M; Aleksicova, T; Votavova, L; Vrablik, M

    2017-04-05

    This article describes the evolution of our understanding of familial hypercholesterolemia (FH) in the Central, Eastern, and Southern Europe (CESE) region, and the dissemination of this understanding to other countries. Using the ScreenPro FH project as an example, we would like to illustrate the progression from national objectives, to regional networking and, finally, to international collaboration via the Familial Hypercholesterolemia Studies Collaboration (FHSC) project under the leadership of the European Atherosclerosis Society (EAS). It is essential to improve our ability to diagnose FH. In this regard, the EAS and its FHSC project must be commended for their educational and organizational activities which, above all, are dedicated to the creation of a global FH patient registry. In the CESE region, FH diagnostics and treatment situation are markedly different than in Western Europe or North America. Since the Czech MedPed project (Make Early Diagnoses to Prevent Early Deaths in Medical Pedigrees) has been so successful (with results not only comparable to, but, for some parameters, even surpassing the results of many Western countries) we decided to apply the Czech experience to the CESE region. Thus, the ScreenPro FH project was created. The aim of ScreenPro FH is to create a specialist network in the CESE region. The primary objective of the ScreenPro FH project was to dramatically reduce the number of premature deaths due to clinical complications of atherosclerosis in FH patients. At present, ScreenPro FH comprises 18 member countries with a total population of 500,000,000; which, in terms of the FH population, represents 1-2 million patients.

  11. On the Split Personality of Penultimate Proline

    PubMed Central

    Glover, Matthew S.; Shi, Liuqing; Fuller, Daniel R.; Arnold, Randy J.; Radivojac, Predrag; Clemmer, David E.

    2014-01-01

    The influence of the position of the amino acid proline in polypeptide sequences is examined by a combination of ion mobility spectrometry-mass spectrometry (IMS-MS), amino acid substitutions, and molecular modeling. The results suggest that when proline exists as the second residue from the N-terminus (i.e., penultimate proline), two families of conformers are formed. We demonstrate the existence of these families by a study of a series of truncated and mutated peptides derived from the 11-residue peptide Ser1-Pro2-Glu3-Leu4-Pro5-Ser6-Pro7-Gln8-Ala9-Glu10-Lys11. We find that every peptide from this sequence with a penultimate proline residue has multiple conformations. Substitution of Ala for Pro residues indicates that multiple conformers arise from the cis- trans isomerization of Xaa1–Pro2 peptide bonds as Xaa–Ala peptide bonds are unlikely to adopt the cis isomer, and examination of spectra from a library of 58 peptides indicates that ~80% of sequences show this effect. A simple mechanism suggesting that the barrier between the cis-and trans-proline forms is lowered because of low steric impedance is proposed. This observation may have interesting biological implications as well, and we note that a number of biologically active peptides have penultimate proline residues. PMID:25503299

  12. Fluorescence imaging and spectroscopy of ALA-induced protoporphyrin IX preferentially accumulated in tumor tissue

    NASA Astrophysics Data System (ADS)

    Stepp, Herbert G.; Baumgartner, Reinhold; Beyer, Wolfgang; Knuechel, Ruth; Koerner, T. O.; Kriegmair, M.; Rick, Kai; Steinbach, Pia; Hofstetter, Alfons G.

    1995-12-01

    In a clinical pilot study performed on 104 patients suffering from bladder cancer it could be shown that intravesical instillation of a solution of 5-aminolevulinic acid (5-ALA) induces a tumorselective accumulation of Protoporphyrin IX (PPIX). Malignant lesions could be detected with a sensitivity of 97% and a specificity of 67%. The Kr+-laser as excitation light source could successfully be replaced by a filtered short arc Xe-lamp. Its emission wavelength band (375 nm - 440 nm) leads to an efficiency of 58% for PPIX- excitation compared to the laser. Two-hundred-sixty mW of output power at the distal end of a slightly modified cystoscope could be obtained. This is sufficient for recording fluorescence images with a target integrating color CCD-camera. Red fluorescence and blue remitted light are displayed simultaneously. Standard white light observation is possible with the same instrumentation. Pharmacokinetic measurements were performed on 18 patients after different routes of 5-ALA application (oral, inhalation and intravesical instillation). PPIX-fluorescence measurements were made on the skin and on the blood plasma. Pharmacokinetic of 5-ALA could be performed on blood plasma. Endoscopical florescence spectroscopy showed the high fluorescence contrast between tumor and normal tissue with a mean value of 10.7. Forthcoming clinical multicenter studies require an objective measure of the fluorescence intensity. Monte Carlo computer simulations showed that artifacts due to observation geometry and varying absorption can largely be reduced by ratioing fluorescence (red channel of camera) to remission (blue channel). Real time image ratioing provides false color images with a reliable fluorescence information.

  13. Cyclo(His-Pro) promotes cytoprotection by activating Nrf2-mediated up-regulation of antioxidant defence

    PubMed Central

    Minelli, Alba; Conte, Carmela; Grottelli, Silvia; Bellezza, Maria; Cacciatore, Ivana; Bolaños, Juan P

    2009-01-01

    Hystidyl-proline [cyclo(His-Pro)] is an endogenous cyclic dipeptide produced by the cleavage of thyrotropin releasing hormone. Previous studies have shown that cyclo(His-Pro) protects against oxidative stress, although the underlying mechanism has remained elusive. Here, we addressed this issue and found that cyclo(His-Pro) triggered nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that up-regulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes, in PC12 cells. Cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion caused by glutamate, rotenone, paraquat and β-amyloid treatment. Moreover, real-time PCR analyses revealed that cyclo(His-Pro) induced the expression of a number of ARE-related genes and protected cells against hydrogen peroxide-mediated apoptotic death. Furthermore, these effects were abolished by RNA interference-mediated Nrf2 knockdown. Finally, pharmacological inhibition of p-38 MAPK partially prevented both cyclo(His-Pro)-mediated Nrf2 activation and cellular protection. These results suggest that the signalling mechanism responsible for the cytoprotective actions of cyclo(His-Pro) would involve p-38 MAPK activation leading to Nrf2-mediated up-regulation of antioxidant cellular defence. PMID:18373731

  14. TGFbeta1 (Leu10Pro), p53 (Arg72Pro) can predict for increased risk for breast cancer in south Indian women and TGFbeta1 Pro (Leu10Pro) allele predicts response to neo-adjuvant chemo-radiotherapy.

    PubMed

    Rajkumar, Thangarajan; Samson, Mani; Rama, Ranganathan; Sridevi, Veluswami; Mahji, Urmila; Swaminathan, Rajaraman; Nancy, Nirmala K

    2008-11-01

    The breast cancer incidence has been increasing in the south Indian women. A case (n=250)-control (n=500) study was undertaken to investigate the role of Single Nucleotide Polymorphisms (SNP's) in GSTM1 (Present/Null); GSTP1 (Ile105Val), p53 (Arg72Pro), TGFbeta1 (Leu10Pro), c-erbB2 (Ile655Val), and GSTT1 (Null/Present) in breast cancer. In addition, the value of the SNP's in predicting primary tumor's pathologic response following neo-adjuvant chemo-radiotherapy was assessed. Genotyping was done using PCR (GSTM1, GSTT1), Taqman Allelic discrimination assay (GSTP1, c-erbB2) and PCR-CTPP (p53 and TGFbeta1). None of the gene SNP's studied were associated with a statistically significant increased risk for the breast cancer. However, combined analysis of the SNP's showed that p53 (Arg/Arg and Arg/Pro) with TGFbeta1 (Pro/Pro and Leu/Pro) were associated with greater than 2 fold increased risk for breast cancer in Univariate (P=0.01) and Multivariate (P=0.003) analysis. There was no statistically significant association for the GST family members with the breast cancer risk. TGFbeta1 (Pro/Pro) allele was found to predict complete pathologic response in the primary tumour following neo-adjuvant chemo-radiotherapy (OR=6.53 and 10.53 in Univariate and Multivariate analysis respectively) (P=0.004) and was independent of stage. This study suggests that SNP's can help predict breast cancer risk in south Indian women and that TGFbeta1 (Pro/Pro) allele is associated with a better pCR in the primary tumour.

  15. Cellular pH and PI3K signaling as determinants of Protoporphyrin IX conversion and ALA PDT response

    NASA Astrophysics Data System (ADS)

    Anderson, Michael; El-Hamidi, Hamid; Celli, Jonathan

    2018-02-01

    ALA PDT is a FDA approved cancer treatment. The general model is that excess exogenous ALA is eventually converted to the active photosensitizer, PpIX, and accumulates PpIX to concentrations well above baseline. This accumulation, however, varies considerable from person to person and even intra-tumorally due to a high number of factors that are involved. Due to this there is an increasing desire to pair ALA PDT with other treatments to enhance the efficacy of PDT. This idea itself isn't new as the labs of Bin Chen and Edward Maytin have a long history of using biology to enhance PpIX accumulation. The PI3K pathway is a long-studied cancer treatment target due to it being one of the most ubiquitous over expressed pathways in cancer and that many treatments have demonstrated enhanced efficacy upon PI3K inhibition. In this paper we show that the PI3K pathway inhibitor, LY294002, alters PpIX accumulation in cells (decreased for A431 and increases for Panc-1 and Panc-1 OR) and significantly increases the efficacy of ALA PDT in every case for both monolayer and spheroid cultures. Additionally, we show that PDT treatments using the nonendogenous photosensitizer, verteporfin, also have enhanced efficacy upon PI3K inhibition. Beyond the treatment synergy of PI3K inhibition and PDT, this work presents a cell pairing model that is perfect to study the previously, to our knowledge, undocumented connection between the PI3K pathway and PpIX accumulation.

  16. P5CDH affects the pathways contributing to Pro synthesis after ProDH activation by biotic and abiotic stress conditions

    PubMed Central

    Rizzi, Yanina S.; Monteoliva, Mariela I.; Fabro, Georgina; Grosso, Carola L.; Laróvere, Laura E.; Alvarez, María E.

    2015-01-01

    Plants facing adverse conditions usually alter proline (Pro) metabolism, generating changes that help restore the cellular homeostasis. These organisms synthesize Pro from glutamate (Glu) or ornithine (Orn) by two-step reactions that share Δ1 pyrroline-5-carboxylate (P5C) as intermediate. In the catabolic process, Pro is converted back to Glu using a different pathway that involves Pro dehydrogenase (ProDH), P5C dehydrogenase (P5CDH), and P5C as intermediate. Little is known about the coordination of the catabolic and biosynthetic routes under stress. To address this issue, we analyzed how P5CDH affects the activation of Pro synthesis, in Arabidopsis tissues that increase ProDH activity by transient exposure to exogenous Pro, or infection with Pseudomonas syringae pv. tomato. Wild-type (Col-0) and p5cdh mutant plants subjected to these treatments were used to monitor the Pro, Glu, and Orn levels, as well as the expression of genes from Pro metabolism. Col-0 and p5cdh tissues consecutively activated ProDH and Pro biosynthetic genes under both conditions. However, they manifested a different coordination between these routes. When external Pro supply was interrupted, wild-type leaves degraded Pro to basal levels at which point Pro synthesis, mainly via Glu, became activated. Under the same condition, p5cdh leaves sustained ProDH induction without reducing the Pro content but rather increasing it, apparently by stimulating the Orn pathway. In response to pathogen infection, both genotypes showed similar trends. While Col-0 plants seemed to induce both Pro biosynthetic routes, p5cdh mutant plants may primarily activate the Orn route. Our study contributes to the functional characterization of P5CDH in biotic and abiotic stress conditions, by revealing its capacity to modulate the fate of P5C, and prevalence of Orn or Glu as Pro precursors in tissues that initially consumed Pro. PMID:26284090

  17. Corner Office: ProQuest's Marty Kahn

    ERIC Educational Resources Information Center

    Fialkoff, Francine; Oder, Norman

    2009-01-01

    In a scant three years at ProQuest, Marty Kahn, CEO, has moved a company coming out of a financial morass back onto solid ground. He came on board after the purchase of ProQuest Information and Learning by the (mostly) privately owned Cambridge Information Group in late 2006 and the merger of ProQuest and CSA to form ProQuest CSA. (It's now just…

  18. Ala42S100A8 Ameliorates Psychological-Stress Impaired Cutaneous Wound Healing

    PubMed Central

    Sroussi, Herve Y.; Williams, Richard L.; Zhang, Qing. L.; Villines, Dana.; Marucha, Phillip. T.

    2009-01-01

    Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation sensitive repellent of human neutrophils in-vitro. Ala42S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild type and ala42S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala42S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing. PMID:19336252

  19. Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

    PubMed

    Sroussi, Herve Y; Williams, Richard L; Zhang, Qing L; Villines, Dana; Marucha, Phillip T

    2009-08-01

    Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological-stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. About 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation-sensitive repellent of human neutrophils in-vitro. Ala(42)S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild-type and ala(42)S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala(42)S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild-type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.

  20. Comparison of the crystal structure and function to wild-type and His25Ala mutant human heme oxygenase-1.

    PubMed

    Zhou, Wen-Pu; Zhong, Wen-Wei; Zhang, Xue-Hong; Ding, Jian-Ping; Zhang, Zi-Li; Xia, Zhen-Wei

    2009-03-01

    Human heme oxygenase-1 (hHO-1) is a rate-limiting enzyme in heme metabolism. It regulates serum bilirubin level. Site-directed mutagenesis studies indicate that the proximal residue histidine 25 (His25) plays a key role in hHO-1 activity. A highly purified hHO-1 His25Ala mutant was generated and crystallized with a new expression system. The crystal structure of the mutant was determined by X-ray diffraction technology and molecular replacement at the resolution of 2.8 A, and the model of hHO-1 His25Ala mutant was refined. The final crystallographic and free R factors were 0.245 and 0.283, respectively. The standard bond length deviation was 0.007 A, and the standard bond angle deviation was 1.3 degrees . The mutation of His25 to Ala led to an empty pocket underneath the ferric ion in the heme, leading to loss of binding iron ligand. Although this did not cause an overall structural change, the enzymatic activity of the mutant hHO-1 was reduced by 90%. By supplementing imidazole, the HO-1 activity was restored approximately 90% to its normal level. These data suggest that Ala25 remains unchanged in the structure compared to His25, but the important catalytic function of hHO-1 is lost. Thus, it appears that His25 is a crucial residue for proper hHO-1 catalysis.

  1. Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction.

    PubMed

    Milev, Miroslav P; Grout, Megan E; Saint-Dic, Djenann; Cheng, Yong-Han Hank; Glass, Ian A; Hale, Christopher J; Hanna, David S; Dorschner, Michael O; Prematilake, Keshika; Shaag, Avraham; Elpeleg, Orly; Sacher, Michael; Doherty, Dan; Edvardson, Simon

    2017-08-03

    Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs ∗ 14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs ∗ 7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Spontaneous abortion and functional polymorphism (Val16Ala) in the manganese SOD gene.

    PubMed

    Eskafi Sabet, E; Salehi, Z; Khodayari, S; Sabouhi Zarafshan, S; Zahiri, Z

    2015-02-01

    Spontaneous abortion is the most common complication of early pregnancy. Genetic factors have been hypothesised to play a role in spontaneous abortion. Since it is possible that the balance of oxidants and antioxidants can be affected by different genetic variants, gene polymorphisms have been proposed as a susceptibility factor that increases the chance of miscarriage. Manganese superoxide dismutase is an important antioxidant enzyme encoded by manganese superoxide dismutase (MnSOD) gene. The aim of this experiment was to assess whether Val16Ala polymorphism of MnSOD gene is associated with miscarriage in northern Iran. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Statistical analyses were conducted using the χ(2)-test. The genetic distributions did not differ significantly between cases and controls, however slightly more Val/Val genotypes were found among the patients compared with control subjects (p = 0.059). No correlation was observed between susceptibility to abortion and MnSOD Val16Ala polymorphism. Larger population-based studies are needed for clarifying the relationship between abortion and MnSOD genotypes.

  3. The Role of Limited Proteolysis of Thyrotropin-Releasing Hormone in Thermoregulation.

    DTIC Science & Technology

    1982-01-01

    exogenously. The limited proteolysis of TRH by pyroglutamate aminopeptidase from CNS results into formation of a new cyclic dipeptide, cyclo (His-Pro...amino acids (L-histidine and L-proline), and two analogues of cyclo (His-Pro), cyclo (Pro-Gly) and cyclo . (Ala-Gly). Cyclo (His-Pro) cross-reacted only...cyclo (His-Pro). Figure 3 shows the chromato- graphic profile obtained when a neutralized perchloric acid extract of rat brain was passed through DEAE

  4. Energy consumption of ProTaper Next X1 after glide path with PathFiles and ProGlider.

    PubMed

    Berutti, Elio; Alovisi, Mario; Pastorelli, Michele Angelo; Chiandussi, Giorgio; Scotti, Nicola; Pasqualini, Damiano

    2014-12-01

    Instrument failure caused by excessive torsional stress can be controlled by creating a manual or mechanical glide path. The ProGlider single-file system (Dentsply Maillefer, Ballaigues, Switzerland) was recently introduced to perform a mechanical glide path. This study was designed to compare the effect of a glide path performed with PathFiles (Dentsply Maillefer) and ProGlider on torque, time, and pecking motion required for ProTaper Next X1 (Dentsply Maillefer) to reach the full working length in simulated root canals. Forty Endo Training Blocks (Dentsply Maillefer) were used. Twenty were prepared with a mechanical glide path using PathFiles 1 and 2 (the PathFile group), and 20 were prepared with a mechanical glide path using a ProGlider single file (the ProGlider group). All samples were shaped with ProTaper Next X1 driven by an endodontic motor connected to a digital wattmeter. The required torque for root canal instrumentation was analyzed by evaluating the electrical power consumption of the endodontic engine. Electric power consumption (mW/h), elapsed time (seconds), and number of pecking motions required to reach the full working length with ProTaper Next X1 were calculated. Differences among groups were analyzed with the parametric Student t test for independent data (P < .05). Elapsed time and electric power consumption were significantly different between groups (P = .0001 for both). ProGlider appears to perform more efficiently than PathFiles in decreasing electric power consumption of ProTaper Next X1 to reach the full working length. This study confirmed the ability of ProGlider to reduce stress in ProTaper Next X1 during shaping through a glide path and preliminary middle and coronal preflaring. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  5. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia.

    PubMed

    Ghodsian, Nooshin; Ismail, Patimah; Ahmadloo, Salma; Heidari, Farzad; Haghvirdizadeh, Polin; Ataollahi Eshkoor, Sima; Etemad, Ali

    2016-01-01

    With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (p < 0.05). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences (p < 0.05) between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder.

  6. Genetic polymorphisms in extracellular superoxide dismutase Leu53Leu, Arg213Gly, and Ala40Thr and susceptibility to type 2 diabetes mellitus.

    PubMed

    Yang, Y M; Xie, X R; Jin, A L

    2016-12-02

    The most common type of endocrine disease is type 2 diabetes mellitus (T2DM); genetic factors contribute to the development to T2DM. In this study, we investigated the role of the Leu53Leu, Arg213Gly, and Ala40Thr polymorphisms in extracellular superoxide dismutase (EC-SOD) gene in the development of T2DM in a Chinese population. DNA was extracted from peripheral blood samples obtained from 256 T2DM patients and 324 control subjects recruited from our hospital between January 2013 and March 2015. DNA was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The obtained data was then statistically analyzed. The chi-square test revealed a statistically significant difference in the genotype frequencies of EC-SOD Ala40Thr (χ 2 = 13.26, P = 0.001) between the patients and controls. Unconditional regression analysis indicated that the GA and AA genotypes of EC-SOD Ala40Thr were associated with an increased risk of T2DM compared to the GG genotype {adjusted odds ratio (OR) [95% confidence interval (CI)] = 1.46 (1.01-2.11) and 2.67 (1.48-4.85), respectively}. In the dominant model, the GA+AA genotype of EC-SOD Ala40Thr was correlated with a higher risk of T2DM, in comparison with the GG genotype (OR = 1.64, 95%CI = 1.16-2.33). In the recessive model, AA of EC-SOD Ala40Thr showed a 2.19-fold higher risk of developing T2DM than the GG+GA genotype. In conclusion, people with the Ala40Thr polymorphism in EC-SOD are at a higher risk of developing T2DM; therefore, this may be utilized as a biomarker for early screening of T2DM in a Chinese population.

  7. Cloning and characterization of the novel D-aspartyl endopeptidase, paenidase, from Paenibacillus sp. B38.

    PubMed

    Nirasawa, Satoru; Nakahara, Kazuhiko; Takahashi, Saori

    2018-02-27

    Paenidase is the first microorganism-derived D-aspartyl endopeptidase that specifically recognizes an internal D-Asp residue to cleave [D-Asp]-X peptide bonds. Using peptide sequences obtained from the protein, we performed PCR with degenerate primers to amplify the paenidase I-encoding gene. Nucleotide sequencing revealed that mature paenidase I consists of 322 amino acid residues and that the protein is encoded as a pro-protein with a 197-amino-acid N-terminal extension compared to the mature protein. Paenidase I exhibits amino acid sequence similarity to several penicillin-binding proteins. In addition, paenidase I was classified into peptidase family S12 based on a MEROPS database search. Family S12 contains serine-type D-Ala-D-Ala carboxypeptidases that have three active site residues (Ser, Lys, and Tyr) in the conserved motifs Ser-Xaa-Thr-Lys and Tyr-Xaa-Asn. These motifs were conserved in the primary structure of paenidase I, and the role of these residues was confirmed by site-directed mutagenesis.

  8. Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

    PubMed

    Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

    2016-12-01

    Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Modeling of phase velocity and frequency spectrum of guided Lamb waves in piezoelectric-semiconductor multilayered structures made of AlAs and GaAs

    NASA Astrophysics Data System (ADS)

    Othmani, Cherif; Takali, Farid; Njeh, Anouar

    2017-11-01

    Modeling of guided Lamb waves propagation in piezoelectric-semiconductor multilayered structures made of AlAs and GaAs is evaluated in this paper. Here, the Legendre polynomial method is used to calculate dispersion curves, frequency spectrum and field distributions of guided Lamb waves propagation modes in AlAs, GaAs, AlAs/GaAs and AlAs/GaAs/AlAs-1/2/1 structures. In fact, formulations are given for open-circuit surface. Consequently, the polynomial method is numerically stable according to the total number of layers and the frequency range. This analysis is meaningful for the applications of the piezoelectric-semiconductor multilayered structures made of AlAs and GaAs such as in novel acoustic devices.

  10. A patient with scirrhous stomach cancer treated with combination of hyperthermotherapy and 5-aminolevulinic acid (ALA).

    PubMed

    Saito, Masashi; Yano, Kazuhito; Kamigaki, Takashi; Goto, Shigenori

    2013-07-01

    A 35-year-old female with scirrhous stomach cancer (stage IV) was treated with a combination of 5-aminolevulinic acid (ALA), sodium dichloroacetate (DCA), hyperthermotherapy, and immunotherapy as terminal care. The patient survived for one year and seven months, during which her quality of life was markedly improved and she returned to work. The patient was diagnosed with poorly-differentiated adenocarcinoma and progressive signet-ring cell carcinoma, accompanied by left ovarian metastasis, peritoneal dissemination, and right hydronephrosis stage IV, and treated with combination chemotherapy with tegafur-gimeracil-oteracil potassium (TS-1) and docetaxel. Oral ALA and DCA were concomitantly administered at 50 mg each three times a day (150 mg/day, respectively). In addition, hyperthermotherapy using thermotron was concomitantly performed at 2- to 3-week intervals. Cellular immunotherapy with αβ T- and immature dendritic cells was also performed. The disease did not progress for 11 months, her quality of life was markedly improved, and she was able to return to work. However, the signs of enlargement of the ovarian metastatic lesion were noted later, for which chemotherapy with four cycles of second-line paclitaxel and a half dose of irinotecan and cisplatin as third-line treatment were performed. Combination of ALA/DCA, hyperthermotherapy, and cellular immunotherapy may be a low-invasive palliative therapy superior in maintaining quality of life of tumor-bearing terminally ill individuals.

  11. EPA and DHA, but not ALA, have antidepressant effects with 17β-estradiol injection via regulation of a neurobiological system in ovariectomized rats.

    PubMed

    Choi, Jeong-Eun; Park, Yongsoon

    2017-11-01

    Our previous studies found that n-3 polyunsaturated fatty acids (PUFAs) and estrogen had synergistic antidepressant-like effects. The purpose of the present study was to investigate the hypothesis that three major n-3 PUFAs, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), individually had antidepressant effects combined with 17β-estradiol-3-benzoate (E) through a neurobiological pathway in ovariectomized rats. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFAs and 1% ALA, EPA and DHA relative to total energy intake for 12 weeks and were injected with corn oil or E every 4 days during the last 3 weeks. Supplementation of EPA, DHA and E increased serum concentrations of serotonin and climbing behavior, and decreased immobility during a forced swimming test. Supplementation with EPA, DHA and E also decreased hippocampal expressions of interleukin-6 and tumor necrosis factor-α, and increased cAMP response element binding protein, brain-derived neurotrophic factor (BDNF) and estrogen receptor-α. Immunofluorescence staining consistently showed elevated expressions of BDNF. Magnetic resonance spectroscopy showed that E increased glucose and decreased glutamate, glutamine and myo-inositol concentrations regardless of n-3 PUFA supplementation. In addition, supplementation with EPA, DHA and E decreased levels of nitrite and nitrate. However, ALA had no antidepressant effect. The present study suggested that the antidepressant-like effects of EPA and DHA supplementation and E injection could be due to the regulation of serotonergic neurotransmission and inflammatory cytokines rather than due to the antioxidative system. Supplementation with n-3 PUFA and E had the additional function of modulating neurometabolites in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Energetics and Structure Prediction of the Network of Homo- and Hetero-Oligomers Formed by the Transmembrane Domains of the ErbB Receptor Family of Proteins

    DTIC Science & Technology

    2005-06-01

    acid residue motif, Small-x-x-Large-G/A, consist- complexes is critical to understanding the signal ing of a small residue (Gly, Ala , Ser, Thr, or Pro...in transduction process. Recent structures of the the zero position, a large aliphatic residue ( Ala , Val, ligand-binding domains of the erbB...receptors Leu, or Ile) in position 3, followed by Gly or Ala in have begun to provide insight into the mechanisms position four.’ This motif was identified

  13. Selective Production of 9R-Hydroxy-10E,12Z,15Z-Octadecatrienoic Acid from α-Linolenic Acid in Perilla Seed Oil Hydrolyzate by a Lipoxygenase from Nostoc Sp. SAG 25.82.

    PubMed

    Kim, Kyoung-Rok; An, Jung-Ung; Lee, Seon-Hwa; Oh, Deok-Kun

    2015-01-01

    Hydroxy fatty acids (HFAs) derived from omega-3 polyunsaturated fatty acids have been known as versatile bioactive molecules. However, its practical production from omega-3 or omega-3 rich oil has not been well established. In the present study, the stereo-selective enzymatic production of 9R-hydroxy-10E,12Z,15Z-octadecatrienoic acid (9R-HOTE) from α-linolenic acid (ALA) in perilla seed oil (PO) hydrolyzate was achieved using purified recombinant 9R-lipoxygenase (9R-LOX) from Nostoc sp. SAG 25.82. The specific activity of the enzyme followed the order linoleic acid (LA) > ALA > γ-linolenic acid (GLA). A total of 75% fatty acids (ALA and LA) were used as a substrate for 9R-LOX from commercial PO by hydrolysis of Candida rugosa lipase. The optimal reaction conditions for the production of 9R-HOTE from ALA using 9R-LOX were pH 8.5, 15°C, 5% (v/v) acetone, 0.2% (w/v) Tween 80, 40 g/L ALA, and 1 g/L enzyme. Under these conditions, 9R-LOX produced 37.6 g/L 9R-HOTE from 40 g/L ALA for 1 h, with a conversion yield of 94% and a productivity of 37.6 g/L/h; and the enzyme produced 34 g/L 9R-HOTE from 40 g/L ALA in PO hydrolyzate for 1 h, with a conversion yields of 85% and a productivity of 34 g/L/h. The enzyme also converted 9R-hydroxy-10E,12Z-octadecadienoic acid (9R-HODE) from 40 g/L LA for 1.0 h, with a conversion yield of 95% and a productivity of 38.4 g/L. This is the highest productivity of HFA from both ALA and ALA-rich vegetable oil using LOX ever reported. Therefore, our result suggests an efficient method for the production of 9R-HFAs from LA and ALA in vegetable oil using recombinant LOX in biotechnology.

  14. Selective Production of 9R-Hydroxy-10E,12Z,15Z-Octadecatrienoic Acid from α-Linolenic Acid in Perilla Seed Oil Hydrolyzate by a Lipoxygenase from Nostoc Sp. SAG 25.82

    PubMed Central

    Kim, Kyoung-Rok; An, Jung-Ung; Lee, Seon-Hwa; Oh, Deok-Kun

    2015-01-01

    Hydroxy fatty acids (HFAs) derived from omega-3 polyunsaturated fatty acids have been known as versatile bioactive molecules. However, its practical production from omega-3 or omega-3 rich oil has not been well established. In the present study, the stereo-selective enzymatic production of 9R-hydroxy-10E,12Z,15Z-octadecatrienoic acid (9R-HOTE) from α-linolenic acid (ALA) in perilla seed oil (PO) hydrolyzate was achieved using purified recombinant 9R-lipoxygenase (9R-LOX) from Nostoc sp. SAG 25.82. The specific activity of the enzyme followed the order linoleic acid (LA) > ALA > γ-linolenic acid (GLA). A total of 75% fatty acids (ALA and LA) were used as a substrate for 9R-LOX from commercial PO by hydrolysis of Candida rugosa lipase. The optimal reaction conditions for the production of 9R-HOTE from ALA using 9R-LOX were pH 8.5, 15°C, 5% (v/v) acetone, 0.2% (w/v) Tween 80, 40 g/L ALA, and 1 g/L enzyme. Under these conditions, 9R-LOX produced 37.6 g/L 9R-HOTE from 40 g/L ALA for 1 h, with a conversion yield of 94% and a productivity of 37.6 g/L/h; and the enzyme produced 34 g/L 9R-HOTE from 40 g/L ALA in PO hydrolyzate for 1 h, with a conversion yields of 85% and a productivity of 34 g/L/h. The enzyme also converted 9R-hydroxy-10E,12Z-octadecadienoic acid (9R-HODE) from 40 g/L LA for 1.0 h, with a conversion yield of 95% and a productivity of 38.4 g/L. This is the highest productivity of HFA from both ALA and ALA-rich vegetable oil using LOX ever reported. Therefore, our result suggests an efficient method for the production of 9R-HFAs from LA and ALA in vegetable oil using recombinant LOX in biotechnology. PMID:26379279

  15. [In Process Citation].

    PubMed

    Fófano do Lago, Márcia; Chaia Kaippert, Vanessa; Lopes Souto, Débora; Lopes Rosado, Eliane

    2016-03-25

    Introducción: el tipo de ácido graso de la dieta presenta diferentes efectos sobre la obesidad y sus complicaciones, pero estos efectos pueden verse influenciados por los genes y sus polimorfismos, tales como los receptores activados por el proliferador de los peroxisomas isoforma γ2 (PPARγ2). Además, no está claro si el grado de insaturación de los lípidos posee diferentes efectos en el metabolismo de los lípidos y de la glucosa y, particularmente, en la pérdida de peso. Objetivos: evaluar la influencia de dietas ricas en ácidos grasos poliinsaturados (AGPI) y monoinsaturados (AGMI) en las variables antropométricas y bioquímicas en el peso corporal y el perfil glucémico y lipémico en mujeres obesas con el genotipo Pro12Pro en el gen PPARγ2. Métodos: dieciocho mujeres obesas con genotipo Pro12Pro fueron distribuidas aleatoriamente para una de las dietas, rica en AGPI (n = 8) o AGMI (n = 10). Las variables antropométricas (índice de masa corporal [IMC] y circunferencia de la cintura) y bioquímicas (glucosa, insulina, HOMA-IR, colesterol total, LDL-colesterol, HDL colesterol y triglicéridos) fueron evaluadas antes y después de un periodo de 45 días. Resultados: las variables antropométricas y bioquímicas fueron similares entre los grupos antes y después de la intervención (p > 0,05). El IMC disminuyó después de la ingesta de AGPI (p = 0,01), probablemente debido al menor contenido de lípidos. El AGMI redujo la glucosa (p = 0,03), insulina (p = 0,03) y HOMA-IR (p = 0,02). Conclusión: los AGMI fueron más eficientes para reducir la resistencia a la insulina en mujeres obesas con el genotipo Pro12Pro en el gen PPARγ2, aunque las mujeres presentaran una elevada ingesta de lípidos totales y ácidos grasos saturados.

  16. Evaluating the role of the FSH receptor gene Thr307-Ala and Asn680-Ser polymorphisms in male infertility and their association with semen quality and reproductive hormones.

    PubMed

    Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Saba

    2011-07-01

    To determine whether Thr(307)-Asn(680) and Ala(307)-Ser(680) polymorphisms of the follicle-stimulating hormone receptor (FSH-R) gene are associated with male infertility, semen quality, and reproductive hormones. The FSH-R polymorphisms at codons 680 and 307 were analysed by restriction-fragment-length polymorphism (RFLP) in 172 infertile men and in an equal number of age-matched healthy fertile men. Genotyping of the FSH-R gene was performed using the polymerase chain reaction RFLP technique. All of the participants underwent semen analysis, and reproductive hormones were also measured. Allelic frequencies were 29.7% serine (Ser) and 70.3% asparagine (Asn) for fertile men (the control group), and 33.1% Ser and 66.9% Asn for infertile men (P > 0.05). The FSH-R genotype at position 680 was 49.4% (Asn/Asn), 41.9% (Asn/Ser), and 8.7% (Ser/Ser) in the control group and 40.1% (Asn/Asn), 46.5% (Asn/Ser), and 13.4% (Ser/Ser) in infertile men, respectively (P > 0.05, chi-squared test). Allelic frequencies were 33.1% alanine (Ala) and 66.9% threonine (Thr) for the control group, and 37.8% Ala and 62.2% Thr for the infertile men. The frequencies of genotypes at position 307 were 45.5% Thr/Thr, 43% Thr/Ala, and 11.6% Ala/Ala for the control group and 36.1% Thr/Thr, 52.3% Thr/Ala, and 11.6% Ala/Ala for infertile men. No significant association between codon 680 and codon 307 genotypes and infertility was observed (P = 0.076 and P = 0.073, respectively). The odds ratio (OR) values indicated that individuals with the Thr/Thr + Asn/Ser combined genotypes had a > 50% decreased risk for developing infertility (OR = 0.44; 95% confidence interval [CI]: 0.22-0.77; P = 0.006). The patients with heterozygous Thr/Ala + Asn/Ser combined genotype were 2.65 times more susceptible to infertility than the control group (OR = 2.65; 95% CI: 1.74-3.82; P = 0.0053). The FSH-R codon 680 and codon 307 genotypes did not result in different serum FSH levels either in men with normal spermatogenesis

  17. Influence of ALA54THR polymorphism of fatty acid binding protein 2 on lifestyle modification response in obese subjects.

    PubMed

    de Luis, D A; Aller, R; Izaola, O; Sagrado, M Gonzalez; Conde, R

    2006-01-01

    It has been found that the expression of fatty acid binding protein 2 (FABP2) mRNA is under dietary control. A G-to-A transition at codon 54 of FABP2 results in an amino acid substitution (from Ala 54 to Thr 54). This polymorphism was associated with high insulin resistance and high fasting insulin concentrations. The aim of our study was to investigate the influence of Thr54 polymorphism in the FABP2 protein on the response to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. A population of 69 obese (body mass index > 30) nondiabetic outpatients was analyzed in a prospective way. Before and after 3 months of the lifestyle modification program, indirect calorimetry, tetrapolar electrical bioimpedance measurement, blood pressure recording, serial assessment of the nutritional intake (3 days of written food records), and biochemical analysis were performed. The lifestyle modification program consisted of a hypocaloric diet (1,520 kcal; 52% carbohydrates, 25% lipids, and 23% proteins). The exercise program consisted of aerobic exercise for at least three times/week (60 min each). Statistical analysis was performed for combined Ala54/Thr54 and Thr54/Thr54 as a mutant group and wild-type Ala54/Ala54 as second group. The mean age was 45.5 +/- 16.7 years, the mean body mass index was 34.1 +/- 5.1, and there were 14 males (20.3%) and 55 females (79.7%) with a weight loss of 3.17 +/- 3.5 kg (3.5%). Thirty-seven patients (53.6%) had the genotype Ala54/Ala54 (wild-type group) and 32 (46.4%) patients either the genotype Ala54/Thr54 (26 patients, 30.2%) or the genotype Thr54/Thr54 (6 patients, 16.2%). The percentage of responders (weight loss) was similar in both groups (89.2 vs. 90.6%). In the wild-type group, body mass index, weight, fat mass, low-density lipoprotein cholesterol level, and waist circumference decreased, whereas the VO2 (oxygen consumption) increased. In the mutant group, glucose, body mass index, weight, waist

  18. The cytotoxic constituents from marine-derived streptomyces 3320#

    NASA Astrophysics Data System (ADS)

    Ren, Hong; Gu, Qianqun; Cui, Chengbin; Zhu, Weiming

    2006-01-01

    The present work studies the chemical constituents from marine-derived streptomyces 3320# and their antitumor activities. The n-BuOH extract of the ferment broth of 3320# was chromatographed on silica gel, Sephadex LH-20, ODS columns and HPLC to separate the compounds with antitoumor activities. Their structures were identified using IR, UV, NMR, MS spectroscopic techniques and compared with published data. The antitumor activities of the isolates were assayed using SRB method and flow cytometry assay, accompanied with the morphological observation of the cells under light microscope against mammalian tsFT210 cells. Ten compounds, cyclo-(Ala-Leu) 1, cyclo-(Ala-Ile) 2, cyclo-(Ala-Val) 3, cyclo-(Phe- Pro) 4, cyclo-(Phe-Gly) 5, cyclo-(Leu-Pro) 6, 1-methyl-1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid 7, N-(4-hydroxyphenethyl) acetamide 8, 4-methyoxy-1-(2-hydroxy) ethylbenzene 9 and uridine 10, were isolated from the ferment broth of streptomyces 3320#. Among them, compounds 6, 7, 8 and 10 showed potent cytotoxicity against the tsFT210 cell with the IC50 values of 3.6, 7.2, 5.2 and 1.6 mmol L-1, respectively. Compounds 8, 10 also exhibited apoptosis inducing activity under 2.0 mmol L-1. Compounds 6, 7, 8 and 10 are the principle bioactive constituents responsible for the antitumor activities of marine streptomyces 3320#. Compound 7 was isolated from this species for the first time.

  19. The Use of Protein Hydrolysates for Weed Control

    NASA Astrophysics Data System (ADS)

    Christians, Nick; Liu, Dianna; Unruh, Jay Bryan

    Corn gluten meal, the protein fraction of corn (Zea mays L.) grain, is commercially used as a natural weed control agent and nitrogen source in horticultural crops and in the turf and ornamental markets. Corn gluten hydrolysate, a water soluble form of gluten meal, has also been proposed for the same purpose, although it could be sprayed on the soil rather than applied in the granular form. Five depeptides, glutaminyl-glutamine (Gln-Gln), glycinyl-alanine (Gly-Ala), alanyl-­glutamine (Ala-Glu), alanyl-asparagine (Ala-Asp), and alaninyl-alanine (Ala-Ala) and a pentapeptide leucine-serine-proline-alanine-glutamine (Leu-Ser-Pro-Ala-Gln) were identified as the active components of the hydrolysate. Microscopic analysis revealed that Ala-Ala acted on some metabolic process rather than directly on the mitotic apparatus. Similar to the chloracetamides and sulfonyl-urea hebicides, Ala-Ala inhibits cell division rather than disrupting of cell division processes. Cellular ultrastructure changes caused by exposure to Ala-Ala implicate Ala-Ala as having membrane-disrupting characteristics similar to several synthetic herbicides. The potential use of the hydrolysate and the peptides as weed controls is discussed.

  20. Multidirectional testing of one- and two-level ProDisc-L versus simulated fusions.

    PubMed

    Panjabi, Manohar; Henderson, Gweneth; Abjornson, Celeste; Yue, James

    2007-05-20

    An in vitro human cadaveric biomechanical study. To evaluate intervertebral rotation changes due to lumbar ProDisc-L compared with simulated fusion, using follower load and multidirectional testing. Artificial discs, as opposed to the fusions, are thought to decrease the long-term accelerated degeneration at adjacent levels. A biomechanical assessment can be helpful, as the long-term clinical evaluation is impractical. Six fresh human cadaveric lumbar specimens (T12-S1) underwent multidirectional testing in flexion-extension, bilateral lateral bending, and bilateral torsion using the Hybrid test method. First, intact specimen total range of rotation (T12-S1) was determined. Second, using pure moments again, this range of rotation was achieved in each of the 5 constructs: A) ProDisc-L at L5-S1; B) fusion at L5-S1; C) ProDisc-L at L4-L5 and fusion at L5-S1; D) ProDisc-L at L4-L5 and L5-S1; and E) 2-level fusion at L4-L5 to L5-S1. Significant changes in the intervertebral rotations due to each construct were determined at the operated and nonoperated levels using repeated measures single factor ANOVA and Bonferroni statistical tests (P < 0.05). Adjacent-level effects (ALEs) were defined as the percentage changes in intervertebral rotations at the nonoperated levels due to the constructs. One- and 2-level ProDisc-L constructs showed only small ALE in any of the 3 rotations. In contrast, 1- and 2-level fusions showed increased ALE in all 3 directions (average, 7.8% and 35.3%, respectively, for 1 and 2 levels). In the disc plus fusion combination (construct C), the ALEs were similar to the 1-level fusion alone. In general, ProDisc-L preserved physiologic motions at all spinal levels, while the fusion simulations resulted in significant ALE.

  1. The Effects of Super-Flux (High Performance) Dialyzer on Plasma Glycosylated Pro-B-Type Natriuretic Peptide (proBNP) and Glycosylated N-Terminal proBNP in End-Stage Renal Disease Patients on Dialysis

    PubMed Central

    Nakagawa, Yasuaki; Nishikimi, Toshio; Kuwahara, Koichiro; Yasuno, Shinji; Kinoshita, Hideyuki; Kuwabara, Yoshihiro; Nakao, Kazuhiro; Minami, Takeya; Yamada, Chinatsu; Ueshima, Kenji; Ikeda, Yoshihiro; Okamoto, Hiroyuki; Horii, Kazukiyo; Nagata, Kiyoshi; Kangawa, Kenji; Minamino, Naoto; Nakao, Kazuwa

    2014-01-01

    Background Plasma BNP levels are predictive of prognosis in hemodialysis patients. However, recent studies showed that the current BNP immunoassay cross-reacts with glycosylated proBNP, and the NT-proBNP assay underestimates glycosylated NT-proBNP. In addition, the recently developed high performance dialyzer removes medium-sized molecular solutes such as β2-microgloburin. We therefore investigated the effects of high performance dialysis on measured levels of glycosylated proBNP, glycosylated NT-proBNP and other BNP-related peptides in end-stage renal disease (ESRD) patients on hemodialysis. Method The relationships between clinical parameters and BNP-related molecule were also investigated. We used our newly developed immunoassay to measure plasma total BNP and proBNP in 105 normal subjects and 36 ESRD patients before and after hemodialysis. Plasma NT-proBNP was measured using Elecsys II after treatment with or without deglycosylating enzymes. We also measured plasma ANP and cGMP using radioimmunoassays. Results All the measured BNP-related peptides were significantly higher in ESRD patients than healthy subjects. Total BNP (−38.9%), proBNP (−29.7%), glycoNT-proBNP (−45.5%), nonglycoNT-proBNP (−53.4%), ANP (−50.4%) and cGMP (−72.1%) were all significantly reduced after hemodialysis, and the magnitude of the reduction appeared molecular weight- dependent. Both the proBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios were increased after hemodialysis. The former correlated positively with hemodialysis vintage and negatively with systolic blood pressure, while the latter correlated positively with parathyroid hormone levels. Conclusion These results suggest that hemodialysis using super-flux dialyzer removes BNP-related peptides in a nearly molecular weight-dependent manner. The ProBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios appear to be influenced by hemodialysis-related parameters in ESRD patients on hemodialysis. PMID:24667631

  2. Local anaesthetic 5-aminolaeuvulinic acid photodynamic therapy in the treatment of superficial bladder cancer

    NASA Astrophysics Data System (ADS)

    Shackley, David C.

    The aim of this thesis was to study aspects of the treatment of superficial bladder carcinoma using photodynamic therapy by combining the delivery of laser light energy with the photosensitiser 5-aminolaeuvulinic acid (ALA). ALA is a novel pro-drug, which can be absorbed intravesically where it is converted in diseased urothelium and tumour to the active photosensitiser, PpK. Following whole bladder light irradiation there is release of toxic radicals, which are scavenged by oxygen causing selective necrosis (PDT). Preliminary studies on animals suggest that ALA is superior to earlier bladder PDT sensitisers in that generalised photosensitivity and bladder contracture are avoided. These problems in conjunction with the complexity of PDT whereby a general anaesthetic with rigid cystoscopy under continuous irrigation are required, have previously limited the development of this modality as a practical therapy. (Abstract shortened by ProQuest.).

  3. Patient-Reported Outcome (PRO) Consortium translation process: consensus development of updated best practices.

    PubMed

    Eremenco, Sonya; Pease, Sheryl; Mann, Sarah; Berry, Pamela

    2017-01-01

    This paper describes the rationale and goals of the Patient-Reported Outcome (PRO) Consortium's instrument translation process. The PRO Consortium has developed a number of novel PRO measures which are in the process of qualification by the U.S. Food and Drug Administration (FDA) for use in clinical trials where endpoints based on these measures would support product labeling claims. Given the importance of FDA qualification of these measures, the PRO Consortium's Process Subcommittee determined that a detailed linguistic validation (LV) process was necessary to ensure that all translations of Consortium-developed PRO measures are performed using a standardized approach with the rigor required to meet regulatory and pharmaceutical industry expectations, as well as having a clearly defined instrument translation process that the translation industry can support. The consensus process involved gathering information about current best practices from 13 translation companies with expertise in LV, consolidating the findings to generate a proposed process, and obtaining iterative feedback from the translation companies and PRO Consortium member firms on the proposed process in two rounds of review in order to update existing principles of good practice in LV and to provide sufficient detail for the translation process to ensure consistency across PRO Consortium measures, sponsors, and translation companies. The consensus development resulted in a 12-step process that outlines universal and country-specific new translation approaches, as well as country-specific adaptations of existing translations. The PRO Consortium translation process will play an important role in maintaining the validity of the data generated through these measures by ensuring that they are translated by qualified linguists following a standardized and rigorous process that reflects best practice.

  4. Synthesis and anti-cancer efficacy of rapid hydrolysed water-soluble paclitaxel pro-drugs.

    PubMed

    Ryu, Beom-Young; Sohn, Jeong-Sun; Hess, Michael; Choi, Soo-Kyung; Choi, Jae-Kon; Jo, Byung-Wook

    2008-01-01

    A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.

  5. A cephalometric study to establish the relationship of the occlusal plane to the three different ala-tragal lines and the Frankfort horizontal plane in different head forms.

    PubMed

    Subhas, S; Rupesh, P L; Devanna, R; Kumar, D R V; Paliwal, A; Solanki, P

    2017-04-01

    The aim of the study is to compare the relationship of the occlusal plane to 3 different ala-tragal lines, namely the superior, middle and inferior lines, in individuals having different head forms and its relation to the Frankfort horizontal plane. A total of 75 lateral cephalometric radiographs of subjects with natural dentition, having full complement of teeth, between the age group of 18-25 were screened and selected. Lateral cephalogram were made for each subjects in an open mouth position. Prior to making the lateral cephalogram, radiopaque markers were placed on the superior, middle and inferior tragus points and on the inferior border of the ala of the nose. Cephalometric tracing was done over each cephalogram. In mesiocephalic head form the middle ala-tragal line was most parallel to the occlusal plane having a mean angle of (1.96°). In dolichocephalic headform, the superior ala-tragal line was most parallel to the occlusal plane having a mean angle of (0.48°). In brachycephalic head form, the middle ala-tragal line was most parallel to the occlusal plane having a mean angle of (2.08°). The mean angulations of occlusal plane to FH plane is 11.04°, 10.16° and 10.60° in mesiocephalic, dolichocephalic and brachycephalic head forms, respectively. The study concludes that the middle ala-tragal line can be used as a reference for the mesiocephalic head form and the superior ala-tragal line for the dolichocephalic and brachycephalic head form as a reference to establish the occlusal plane. Copyright © 2016. Published by Elsevier Masson SAS.

  6. Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: a strategy for the design of peptidase inhibitors.

    PubMed

    Ganellin, C R; Bishop, P B; Bambal, R B; Chan, S M; Law, J K; Marabout, B; Luthra, P M; Moore, A N; Peschard, O; Bourgeat, P; Rose, C; Vargas, F; Schwartz, J C

    2000-02-24

    The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH(2). In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 microM) and Ala-Pro-Ala-OH (K(i) = 3 microM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 microM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 microM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.

  7. Importance of tetrahedral intermediate formation in the catalytic mechanism of the serine proteases chymotrypsin and subtilisin.

    PubMed

    Petrillo, Teodolinda; O'Donohoe, Catrina A; Howe, Nicole; Malthouse, J Paul G

    2012-08-07

    Two new inhibitors in which the terminal α-carboxyl groups of Z-Ala-Ala-Phe-COOH and Z-Ala-Pro-Phe-COOH have been replaced with a proton to give Z-Ala-Ala-Phe-H and Z-Ala-Pro-Phe-H, respectively, have been synthesized. Using these inhibitors, we estimate that for α-chymotrypsin and subtilisin Carlsberg the terminal carboxylate group decreases the level of inhibitor binding 3-4-fold while a glyoxal group increases the level of binding by 500-2000-fold. We show that at pH 7.2 the effective molarities of the catalytic hydroxyl group of the active site serine are 41000-229000 and 101000-159000 for α-chymotrypsin and subtilisin Carlsberg, respectively. It is estimated that oxyanion stabilization and the increased effective molarity of the catalytic serine hydroxyl group can account for the catalytic efficiency of the reaction. We argue that substrate binding induces the formation of a strong hydrogen bond or low-barrier hydrogen bond between histidine-57 and aspartate-102 that increases the pK(a) of the active site histidine, allowing it to be an effective general base catalyst for the formation of the tetrahedral intermediate and increasing the effective molarity of the catalytic hydroxyl group of serine-195. A catalytic mechanism for acyl intermediate formation in the serine proteases is proposed.

  8. Role of 5-ALA in improving extent of tumour resection in patients with Glioblastoma Multiforme.

    PubMed

    Waqas, Muhammad; Khan, Inamullah; Shamim, Muhammad Shahzad

    2017-10-01

    Goal of surgery for patients with Glioblastoma Multiforme (GBM) is gross total resection with no new neurological deficits. Surgical resection is often restricted due the difficulty in differentiating the tumour from surrounding normal brain using either naked eye, or standard intra-operative white light microscopy. GBM uptakes orally administered 5-ALA becomes fluorescent when viewed by a special light, and this property has been used to improve intra-operative tumour identification. This technique should therefore allow better extent of tumour resection. The hypothesis has been tested through several studies and even though most studies are of low quality, they strongly favour the use of 5- ALA in improving the extent of resection when compared to white light microscopy. A systematic review on the topic had a similar conclusion. Few studies have also hinted on a high false negative rate with the use of this technique..

  9. A low insertion loss GaAs pHEMT switch utilizing dual n +-doping AlAs etching stop layers design

    NASA Astrophysics Data System (ADS)

    Chien, Feng-Tso; Lin, Da-Wei; Yang, Chih-Wei; Fu, Jeffrey S.; Chiu, Hsien-Chin

    2010-03-01

    A low insertion loss single-pole-single-throw (SPST) pseudomorphic high electron mobility transistor (pHEMT) switch utilizing the n +-type doping in AlAs etching stop layer was fabricated and investigated. This novel design reduces device sheet resistance resulting in an improvement of dc and rf power performance. In addition, the gate recess selectivity for GaAs/AlAs interface was not sacrificed after highly n +-type doping in AlAs etching stop layer. The pHEMT with n +-AlAs etching stop layer, also named Modified pHEMT (M-pHEMT), demonstrated a lower sheet resistance ( Rsh) of 65.9 Ω/γ, a higher maximum drain-to-source current ( Idmax) of 317.8 mA/mm and a higher peak transconductance ( gm) of 259.3 mS/mm which are superior to standard pHEMT performance with values of 71.9 Ω/γ, 290.3 mA/mm and 252.1 mS/mm, respectively. Due to a significant sheet resistance improvement from this novel epitaxial design, an SPST pHEMT switch was realized to manifest its industrial application potential. The results achieved an on-state insertion loss of 1.42 dB, an off-state isolation of 13.02 dB at 0.9 GHz, which were superior to traditional pHEMT switch under same condition of operation with values of 1.68 dB and 11.42 dB, respectively. It is proved that dual n +-doping AlAs etching stop layers scheme is beneficial for low loss microwave switches applications.

  10. Effects of a 12-week high-α-linolenic acid intervention on EPA and DHA concentrations in red blood cells and plasma oxylipin pattern in subjects with a low EPA and DHA status.

    PubMed

    Greupner, Theresa; Kutzner, Laura; Nolte, Fabian; Strangmann, Alena; Kohrs, Heike; Hahn, Andreas; Schebb, Nils Helge; Schuchardt, Jan Philipp

    2018-03-01

    The essential omega-3 fatty acid alpha-linolenic acid (ALA, 18:3n3) can be converted into EPA and DHA. The aim of the present study was to determine the effect of a high-ALA diet on EPA and DHA levels in red blood cells (RBCs) and their oxylipins in the plasma of subjects with a low EPA and DHA status. Fatty acid concentrations [μg mL -1 ] and relative amounts [% of total fatty acids] in the RBCs of 19 healthy men (mean age 26.4 ± 4.6 years) were analyzed by means of GC-FID. Free plasma oxylipin concentrations were determined by LC-MS based targeted metabolomics. Samples were collected and analyzed at baseline (week 0) and after 1 (week 1), 3 (week 3), 6 (week 6), and 12 (week 12) weeks of high dietary ALA intake (14.0 ± 0.45 g day -1 ). ALA concentrations significantly (p < 0.001) increased from 1.44 ± 0.10 (week 0) to 4.65 ± 0.22 (week 1), 5.47 ± 0.23 (week 3), 6.25 ± 0.24 (week 6), and 5.80 ± 0.28 (week 12) μg mL -1 . EPA concentrations increased from 6.13 ± 0.51 (week 0) to 7.33 ± 0.33 (week 1), 8.38 ± 0.42 (p = 0.021, week 3), 10.9 ± 0.67 (p < 0.001, week 6), and 11.0 ± 0.64 (p < 0.001, week 12) μg mL -1 . DHA concentrations unexpectedly decreased from 41.0 ± 1.93 (week 0) to 37.0 ± 1.32 (week 1), 36.1 ± 1.37 (week 3), 35.1 ± 1.06 (p = 0.010, week 6), and 30.4 ± 1.09 (p < 0.001, week 12) μg mL -1 . Relative ΣEPA + DHA amounts were unchanged during the intervention (week 0: 4.63 ± 0.19, week 1: 4.67 ± 0.16, week 3: 4.61 ± 0.13, week 6: 4.73 ± 0.15, week 12: 4.52 ± 0.11). ALA- and EPA-derived hydroxy- and dihydroxy-PUFA increased similarly to their PUFA precursors, although in the case of ALA-derived oxylipins, the concentrations increased less rapidly and to a lesser extent compared to the concentrations of their precursor FA. LA-derived oxylipins remained unchanged and arachidonic acid and DHA oxylipin concentrations were not significantly changed. Our results confirm that the intake of ALA is not a sufficient source for the increase

  11. Serum levels of NT- pro ANP, BNP, NT-pro BNP and function of the left atrium in patients with heart failure and preserved ejection fraction after myocardial infarction

    NASA Astrophysics Data System (ADS)

    Shurupov, V.; Suslova, T.; Ryabov, V.

    2015-11-01

    The objective of our study was to evaluate the levels of natriuretic peptides in patients (pts) with heart failure with preserved ejection fraction (HFpEF) in 12 month after ST elevation myocardial infarction (STEMI) with a focus on the function of left atrium (LA) and left ventricular (LV) filling pressure. 55 pts were included in the study. 6-minute walk test was performed. Echo exam was performed by the diagnostic system VIVID 7. BNP in whole blood was determined using the Triage ® Meter BNP test. The serum levels of NT-pro BNP, NT-pro ANP («Biomedica», Austria) were determined in blood samples by enzyme-linked immune-sorbent assay (ELISA). LA volume index were differences (16.03±3.39 ml/m2; 25.36±8.26 ml/m2; 29.41±9.46 ml/m2 accordingly I, II, III class) depending on severity of HF. Well as E/E' ratio were differences (7.5±1.4; 9.8±5.1; 13.5±7.6 accordingly I, II, III class) depending on severity of HF. The LA volume index correlated with levels of NT-pro ANP (R=0.29; p=0.04), levels of NT-pro BNP (R=0.37; p=0.01), levels of BNP (R=0.51; p=0.0001). The LV filling pressure correlated with levels of NT-pro ANP (R=0.45; p=0.002), levels of NT-pro BNP (R=0.49; p=0.001), levels of BNP (R=0.37; p=0.01).

  12. Long-term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS.

    PubMed

    Goutman, Stephen A; Brown, Morton B; Glass, Jonathan D; Boulis, Nicholas M; Johe, Karl; Hazel, Tom; Cudkowicz, Merit; Atassi, Nazem; Borges, Lawrence; Patil, Parag G; Sakowski, Stacey A; Feldman, Eva L

    2018-06-01

    Intraspinal human spinal cord-derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb-onset ALS participants in Phase 1 and 2 (Ph1/2) open-label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. Survival, ALSFRS-R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS-R) functional status were assessed for matched participant subsets: PRO-ACT n  = 1108, Ph1/2 n  = 21 and ceftriaxone n  = 177, Ph1/2 n  = 20. Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO-ACT 2.3 years (1.9, 2.5), P  = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P  = 0.88. Mean ALSFRS-R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO-ACT 24.0 ± 10.2, P  = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P  = 0.0023). Using ALS/SURV, median PRO-ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS-Rs were 23 ( P  = 0.0038) and 19 ( P  = 0.14) in PRO-ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO-ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power

  13. Occurrence of the angiotensin-converting enzyme inhibiting tripeptides Val-Pro-Pro and Ile-Pro-Pro in different cheese varieties of Swiss origin.

    PubMed

    Bütikofer, U; Meyer, J; Sieber, R; Walther, B; Wechsler, D

    2008-01-01

    The contents of the 2 antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) were determined in 101 samples from 10 different Swiss cheese varieties using HPLC with subsequent triple mass spectrometry. In the category of extra hard and hard cheeses, the Protected Denomination of Origin cheeses Berner Alpkäse and Berner Hobelkäse, L'Etivaz à rebibes, Le Gruyère, Sbrinz, Emmentaler (organic and conventional) and in the category of semihard cheeses, the varieties Tilsiter, Appenzeller 1/4 fat and full fat, Tête de Moine, and Vacherin fribourgeois were screened in the study. The average concentration of the sum of VPP and IPP in the screened cheese varieties varied to a large extent, and substantial variations were obtained for individual samples within the cheese varieties. The lowest average concentration of the 2 tri-petides was found in L'Etivaz à rebibes (n = 3) at 19.1 mg/kg, whereas Appenzeller 1/4 fat (n = 4) contained the greatest concentration at 182.2 mg/kg. In individual samples, the total concentration of VPP and IPP varied between 1.6 and 424.5 mg/kg. With the exception of a 10-yr-old cheese, VPP was always present at greater concentrations than IPP. Milk pretreatment, cultures, scalding conditions, and ripening time were identified as the key factors influencing the concentration of these 2 naturally occurring bioactive peptides in cheese. The results of the present study show that various traditional cheese varieties contain, on average, similar concentrations of the 2 antihypertensive peptides to the recently developed fermented milk products with blood pressure-lowering property. This may serve as a basis for the development of a functional cheese with blood pressure-lowering property.

  14. Comparison of apical transportation between ProFile and ProTaper NiTi rotary instruments.

    PubMed

    Iqbal, M K; Firic, S; Tulcan, J; Karabucak, B; Kim, S

    2004-06-01

    To use a newly developed radiographic technique to compare apical transportation and loss of working length (WL) between.06 taper ProFile Series 29 and ProTaper nickel-titanium (NiTi) rotary instruments in vitro. Mesio-buccal canals of 40 extracted mandibular molars were randomly divided into two groups. Group 1 was instrumented with ProFile and group 2 with ProTaper instruments according to the manufacturers' directions. A specially constructed radiographic jig with a Schick digital radiographic system (Schick Technologies Inc., Long Island City, NY, USA) was used to take pre- and postoperative radiographs of the samples at predetermined angulations. Using AutoCAD 2000 (Autodesk Inc., San Rafael, CA, USA), the central axes of initial and final instruments were radiographically superimposed to determine the loss of WL and degree of transportation at D(0), D(1), D(2) and D(4) from the WL. Data were analysed using repeated-measures anova. A statistically significant difference in apical transportation was found at the D(4) level between the two groups (P = 0.05). There was no statistical significance regarding postinstrumentation change in WL between groups. Spearman's Bivariate Correlation analysis indicated no statistically significant relationship between the radius of curvature and transportation. The results indicate that both ProTaper and ProFile instruments are comparable to each other in regards to their ability to optimally enlarge root canal with minimal transportation and loss of WL in vitro.

  15. H2O2 mediates ALA-induced glutathione and ascorbate accumulation in the perception and resistance to oxidative stress in Solanum lycopersicum at low temperatures.

    PubMed

    Liu, Tao; Hu, Xiaohui; Zhang, Jiao; Zhang, Junheng; Du, Qingjie; Li, Jianming

    2018-02-15

    Low temperature is a crucial factor influencing plant growth and development. The chlorophyll precursor, 5-aminolevulinic acid (ALA) is widely used to improve plant cold tolerance. However, the interaction between H 2 O 2 and cellular redox signaling involved in ALA-induced resistance to low temperature stress in plants remains largely unknown. Here, the roles of ALA in perceiving and regulating low temperature-induced oxidative stress in tomato plants, together with the roles of H 2 O 2 and cellular redox states, were characterized. Low concentrations (10-25 mg·L - 1 ) of ALA enhanced low temperature-induced oxidative stress tolerance of tomato seedlings. The most effective concentration was 25 mg·L - 1 , which markedly increased the ratio of reduced glutathione and ascorbate (GSH and AsA), and enhanced the activities of superoxide dismutase, catalase, ascorbate peroxidase, dehydroascorbate reductase, and glutathione reductase. Furthermore, gene expression of respiratory burst oxidase homolog1 and H 2 O 2 content were upregulated with ALA treatment under normal conditions. Treatment with exogenous H 2 O 2 , GSH, and AsA also induced plant tolerance to oxidative stress at low temperatures, while inhibition of GSH and AsA syntheses significantly decreased H 2 O 2 -induced oxidative stress tolerance. Meanwhile, scavenging or inhibition of H 2 O 2 production weakened, but did not eliminate, GSH- or AsA- induced tomato plant tolerance to oxidative stress at low temperatures. Appropriate concentrations of ALA alleviated the low temperature-induced oxidative stress in tomato plants via an antioxidant system. The most effective concentration was 25 mg·L - 1 . The results showed that H 2 O 2 induced by exogenous ALA under normal conditions is crucial and may be the initial step for perception and signaling transmission, which then improves the ratio of GSH and AsA. GSH and AsA may then interact with H 2 O 2 signaling, resulting in enhanced antioxidant capacity

  16. Synthetic peptide, Ala-Arg-Glu-Gly-Glu-Met, abolishes pro-proliferative and anti-apoptotic effects of high glucose in vascular smooth muscle cells

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

    Cao, Xiaozhou; Lyu, Yi; Collaborative Innovation Centre for Modern Grain Circulation and Safety, Nanjing University of Finance and Economics, Nanjing 210023

    Apoptosis plays a critical role in normal vascular development and atherosclerosis. However, high glucose has been reported to generate a certain level of ROS that can inhibit vascular smooth muscle cell (VSMC) apoptosis, with the underlying mechanism remaining unclear. In this study, a synthetic peptide AREGEM (Ala-Arg-Glu-Gly-Glu-Met) exhibited antioxidative effects and was used to investigate its function in VSMCs during hyperglycaemia. MTT assay results demonstrated that AREGEM significantly attenuated high glucose-induced VSMCs proliferation. Flow cytometry displayed that high glucose levels inhibited cell apoptosis, whereas this effect was attenuated by pre-incubation with AREGEM. In addition, the 2′,7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probemore » assay further demonstrated that AREGEM reduced intracellular ROS accumulation in VSMCs. Furthermore, this peptide was able to prevent the decrease of caspase-3 activity and the increase of the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose. These findings demonstrated that AREGEM is able to abolish the effects of high glucose in VSMCs; therefore, this peptide can be a potential candidate to develop a novel strategy for curing diabetic related diseases. - Highlights: • A peptide, AREGEM, can reduce intracellular ROS accumulation in vascular smooth muscle cells (VSMCs). • AREGEM significantly inhibits high glucose-induced proliferation of VSMCs. • AREGEM attenuates the inhibitory effect of high glucose on VSMC Apoptosis and caspase-3 activity. • AREGEM decreases the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose.« less

  17. PRO-140 (Progenics).

    PubMed

    Poli, G

    2001-09-01

    PRO-140, a monoclonal antibody against the HIV coreceptor CCR5, is under investigation by Progenics and the Aaron Diamond AIDS Research Center (ADARC) as a potential treatment for HIV infection [211441], [286246], [286247]. Phase I/II trials were expected to commence during 2001 [395621], [409142], despite being initially planned for 2000 [322637], [361819], [365216], [375598], [408483]. In January 1998, ADARC and Progenics reported that the HIV binding site on the CCR5 coreceptor is distinct from betachemokine binding domains, which they claimed may allow for the development of therapeutics with fewer side effects [273391], 421256]. In vitro studies have shown PRO-140 potently blocked all of 17 primary HIV isolates that use CCR5 as a fusion coreceptor [342173]. In October 2000, Progenics was awarded an SBIR grant to fund a 2-year project exploring the breadth, potency and durability of PRO-140 therapy in laboratory and animal models of HIV infection. This project was a collaboration between Progenics, Weill Medical College of Cornell University and the Scripps Research Institute [385982]. In May 1999, the company entered into an agreement with Protein Design Labs (PDL) for the humanization by PDL of PRO-140 [325445]. In November 1997, Progenics was awarded a 600,000 dollars grant from the NIAID for the examination of new approaches to HIV vaccine design based on CCR5 [268407].

  18. Quantifying the Persistence of Pro-Smoking Media Effects on College Students’ Smoking Risk

    PubMed Central

    Setodji, Claude M.; Martino, Steven C.; Scharf, Deborah M.; Shadel, William G.

    2013-01-01

    Purpose To quantify the persistence of pro-smoking media exposure effects on college students’ intentions to smoke and smoking refusal self-efficacy. Method A total of 134 college students (ages 18–24) were enrolled in an ecological momentary assessment study in which they carried handheld data collection devices for three weeks and reported their exposures to pro-smoking media as they occurred in the real world. Smoking intentions and smoking refusal self-efficacy were assessed after each exposure to pro-smoking media and at random prompts during each day of the three-week assessment period. A generalized additive model was used to determine how long the effect of an exposure to pro-smoking media persisted. Results The effect of pro-smoking media exposures persisted for 7 days. After exposure, smoking intentions immediately increased (0.56; 95% confidence interval [CI]: [0.26, 0.87]) and then steadily decreased (−0.12; 95% CI: [−0.19, −0.05]) each day for 7 days, while smoking refusal self-efficacy immediately decreased (−0.42; 95% CI: [−0.75, −0.10]) and then steadily increased (0.09; 95% CI: [0.02, 0.16]) each day for 7 days. Daily changes occurring after 7 days were not statistically significant, suggesting that smoking intentions and refusal self-efficacy had stabilized and were no longer affected by pro-smoking media exposure. Conclusions Exposures to pro-smoking media may have strong implications for emerging young adults smoking risk as the impact of an individual exposure appears to persist for at least a week. PMID:24268361

  19. Quantifying the persistence of pro-smoking media effects on college students' smoking risk.

    PubMed

    Setodji, Claude M; Martino, Steven C; Scharf, Deborah M; Shadel, William G

    2014-04-01

    To quantify the persistence of pro-smoking media exposure effects on college students' intentions to smoke and smoking refusal self-efficacy. A total of 134 college students (ages 18-24 years) were enrolled in an ecological momentary assessment study in which they carried handheld data collection devices for 3 weeks and reported their exposures to pro-smoking media as they occurred in the real world. Smoking intentions and smoking refusal self-efficacy were assessed after each exposure to pro-smoking media and at random prompts during each day of the 3-week assessment period. A generalized additive model was used to determine how long the effect of an exposure to pro-smoking media persisted. The effect of pro-smoking media exposures persisted for 7 days. After exposure, smoking intentions immediately increased (.56; 95% confidence interval [CI]: [.26, .87]) and then steadily decreased (-.12; 95% CI: [-.19, -.05]) each day for 7 days, while smoking refusal self-efficacy immediately decreased (-.42; 95% CI: [-.75, -.10]) and then steadily increased (.09; 95% CI: [.02, .16]) each day for 7 days. Daily changes occurring after 7 days were not statistically significant, suggesting that smoking intentions and refusal self-efficacy had stabilized and were no longer affected by pro-smoking media exposure. Exposures to pro-smoking media may have strong implications for emerging young adults smoking risk as the impact of an individual exposure appears to persist for at least a week. Copyright © 2014 Society for Adolescent Health and Medicine. All rights reserved.

  20. Energetics and Structure Prediction of the Network of Homo- and Hetero-Oligomers Formed by the Transmembrane Domains of the ErbReceptor Family of Proteins

    DTIC Science & Technology

    2006-06-01

    amino acid residue motif, Small-x-x-Large-G/A, consist- ing of a small residue (Gly, Ala , Ser, Thr, or Pro) in the zero position, a large aliphatic...residue ( Ala , Val, Leu, or Ile) in position 3, followed by Gly or Ala in position four.15 This motif was identified in a large number of receptor tyrosine...M. A., Codony-Servat, J., Albanell, J., Rojo, F., Arribas , J. & Baselga, J. (2001). Trastuzumab (her- ceptin), a humanized anti-Her2 receptor

  1. Conformational restriction through C alpha i <--> C alpha i cyclization: Ac12c, the largest cycloaliphatic C alpha,alpha- disubstituted glycine known.

    PubMed

    Saviano, M; Iacovino, R; Menchise, V; Benedetti, E; Bonora, G M; Gatos, M; Graci, L; Formaggio, F; Crisma, M; Toniolo, C

    2000-02-01

    Two complete series of N-protected, monodispersed oligopeptide esters to the pentamer level from 1-aminocyclododecane-1-carboxylic acid (Ac(12)c), an alpha-amino acid conformationally constrained through C(alpha)(i) <--> C(alpha)(i) cyclization, and either L-Ala or Aib residues, along with the N-protected Ac(12)c homopeptide alkylamide series from monomer to trimer, have been synthesized by solution methods and fully characterized. The solution-preferred conformations of these peptides have been assessed by Fourier transform ir absorption and (1)H-nmr techniques. Moreover, the molecular structures of one derivative (Z-Ac(12)c-OH) and three peptides [the tripeptide ester Z-L-Ala-Ac(12)c-L-Ala-OMe, the tripeptide alkylamide Z-(Ac(12)c)(3)-NHiPr, and the tetrapeptide ester Z-(Aib)(2)-Ac(12)c-Aib-OtBu (Aib, alpha-aminoisobutyric acid)] have been determined in the crystal state by x-ray diffraction. The results obtained point to the conclusion that beta-bends and 3(10)-helices are preferentially adopted by peptides based on Ac(12)c, the largest cycloaliphatic C-disubstituted glycine known. A comparison with the structural tendencies extracted from published works on peptides from Aib, the prototype of C-disubstituted glycines, and the other extensively studied members of the class of 1-aminocycloalkane-1-carboxylic acids (Ac(n) c, with n = 3-9), is made and the implications for the use of the Ac(12)c residue in the Ac(n) c scan approach of conformationally restricted analogues of bioactive peptides are briefly discussed. Copyright 2000 John Wiley & Sons, Inc.

  2. [Deformation evaluation of ProTaper nickel-titanium rotary instruments in curved canals instrumentation in vitro].

    PubMed

    Yan, Hong; Ren, Min; Yin, Xing-Zhe; Zhao, Shu-Yan; Zhang, Cheng-Fei

    2008-04-01

    To evaluate the deformation of ProTaper rotary instruments using in root canals of different curvature in vitro. Extracted first mandibular molars were divided into two experimental groups according to the curvature of mesial buccal canals: group A with moderate curvature and group B with severe curvature. Only the mesial buccal canals of all these teeth were prepared with 6 sets of new ProTaper rotary instruments individually. Additionally, the control group was established with a set of new ProTaper rotary instruments. After finishing each canal preparation, the instruments accompanied by control were examined under the stereomicroscope by an inspector without knowing the group. If distortion, unwinding, abrasion or fracture occurred within one set of instruments, then the whole set was disposed. The sets without problems were in use until 30 times. After 5, 10, 20 times canal preparation, S1, F1 files without deformation under stereomicroscope were examined under scanning electron microscope (SEM). Deformation of ProTaper rotary instruments happened after 12 times in group A and after 7 times in group B. In these two experimental groups, microcracks were found increasing with the times of use under SEM in the instruments without deformation under stereomicroscope. The microcracks on tip of instruments were deep in the early use and became smoother after 10 times. Similar changes happened on knife-edge of instruments, and the microcracks extended over the edge after 20 times use. Root canals with severe curvature tend to damage ProTaper rotary instruments more frequently than moderately curved canals. ProTaper rotary instruments are appropriate to treat less than 7 root canals with severe curvature or 12 root canals with moderate curvature. Stereomicroscope is recommended to detect early damages on Ni-Ti rotary instruments, for preventing instruments fracture in clinic.

  3. Pro-/antiinflammatory dysregulation in early psychosis: results from a 1-year follow-up study.

    PubMed

    García-Bueno, Borja; Bioque, Miquel; MacDowell, Karina S; Santabárbara, Javier; Martínez-Cengotitabengoa, Mónica; Moreno, Carmen; Sáiz, Pilar A; Berrocoso, Esther; Gassó, Patricia; Fe Barcones, M; González-Pinto, Ana; Parellada, Mara; Bobes, Julio; Micó, Juan A; Bernardo, Miguel; Leza, Juan C

    2014-10-31

    Previous studies indicated a systemic deregulation of the pro-/antiinflammatory balance in subjects after 6 months of a first psychotic episode. This disruption was reexamined 12 months after diagnosis to identify potential risk/protective factors and associations with symptom severity. Eighty-five subjects were followed during 12 months and the determination of the same pro-/antiinflammatory mediators was carried out in plasma and peripheral blood mononuclear cells. Multivariate logistic regression analyses were used to identify risk/protective factors. Multiple linear regression models were performed to detect the change of each biological marker during follow-up in relation to clinical characteristics and confounding factors. This study suggests a more severe systemic pro-/antiinflammatory deregulation than in earlier pathological stages in first psychotic episode, because not only were intracellular components of the inflammatory response increased but also the majority of soluble elements. Nitrite plasma levels and cyclooxygenase-2 expression in peripheral blood mononuclear cells are reliable potential risk factors and 15d-prostaglandin-J2 plasma levels a protection biomarker. An interesting relationship exists between antipsychotic dose and the levels of prostaglandin-E2 (inverse) and 15d-prostaglandin-J2 (direct). An inverse relationship between the Global Assessment of Functioning scale and lipid peroxidation is also present. Summing up, pro-/antiinflammatory mediators can be used as risk/protection biomarkers. The inverse association between oxidative/nitrosative damage and the Global Assessment of Functioning scale, and the possibility that one of the targets of antipsychotics could be the restoration of the pro-/antiinflammatory balance support the use of antiinflammatory drugs as coadjuvant to antipsychotics. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  4. Study of false positives in 5-ALA induced photodynamic diagnosis of bladder carcinoma

    NASA Astrophysics Data System (ADS)

    Draga, Ronald O. P.; Grimbergen, Matthijs C. M.; Kok, Esther T.; Jonges, Trudy G. N.; Bosch, J. L. H. R.

    2009-02-01

    Photodynamic diagnosis (PDD) is a technique that enhances the detection of tumors during cystoscopy using a photosensitizer which accumulates primarily in cancerous cells and will fluoresce when illuminated by violetblue light. A disadvantage of PDD is the relatively low specificity. In this retrospective study we aimed to identify predictors for false positive findings in PDD. Factors such as gender, age, recent transurethral resection of bladder tumors (TURBT), previous intravesical therapy (IVT) and urinary tract infections (UTIs) were examined for association with the false positive rates in a multivariate analysis. Data of 366 procedures and 200 patients were collected. Patients were instilled with 5-aminolevulinic acid (5-ALA) intravesically and 1253 biopsies were taken from tumors and suspicious lesions. Female gender and TURBT are independent predictors of false positives in PDD. However, previous intravesical therapy with Bacille Calmette-Guérin is also an important predictor of false positives. The false positive rate decreases during the first 9-12 weeks after the latest TURBT and the latest intravesical chemotherapy. Although shortly after IVT and TURBT false positives increase, PDD improves the diagnostic sensitivity and results in more adequate treatment strategies in a significant number of patients.

  5. Application of 1,2-diethyl-3-hydroxypyridin-4-one to enhance tissue selectivity for photodynamic therapy of the bladder

    NASA Astrophysics Data System (ADS)

    Chang, Shi-Chung; MacRobert, Alexander J.; Porter, John B.; Bown, Stephen G.

    1995-03-01

    Five-aminolaevulinic acid (ALA) induced protoporphyrin IX (PpIX) has proven to be a useful photosensitizer for photodynamic therapy (PDT). In living cells, the conversion of PpIX to photoinactive haem is catalyzed by ferrochelatase in the presence of tissue iron and inhibition of this final committed step results in increased accumulation of PpIX. The in vivo effect of a new iron chelator, 1,2-diethyl-3-hydroxypyridin-4-one (CP94), on the buildup of PpIX in different bladder layers was evaluated. In CP94 treated rats, 5 - 7 hours after intravesical instillation of ALA solution, the fluorescence intensity of PpIX in the urothelium was doubled whilst in the muscle layer it remained low at a similar level to those seen without the iron chelator. With CP94, further reduction of skin photosensitization is possible as a similar photodynamic effect on the bladder could be achieved at lower ALA concentration. The addition of CP94 seems an effective and convenient way to potentiate ALA induced PpIX tissue selectivity.

  6. Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics.

    PubMed

    Abhinand, P A; Shaikh, Faraz; Bhakat, Soumendranath; Radadiya, Ashish; Bhaskar, L V K S; Shah, Anamik; Ragunath, P K

    2016-01-01

    Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.

  7. Ribbon structure stabilized by C10 and C12 turns in αγ hybrid peptide.

    PubMed

    Wani, Naiem Ahmad; Kant, Rajni; Gupta, Vivek Kumar; Aravinda, Subrayashastry; Rai, Rajkishor

    2016-04-01

    The present study describes the synthesis and crystallographic analysis of αγ hybrid peptides, Boc-Gpn-L-Pro-NHMe (1), Boc-Aib-Gpn-L-Pro-NHMe (2), and Boc-L-Pro-Aib-Gpn-L-Pro-NHMe (3). Peptides 1 and 2 adopt expanded 12-membered (C12 ) helical turn over γα segment. Peptide 3 promotes the ribbon structure stabilized by type II β-turn (C10 ) followed by the expanded C12 helical γα turn. Both right-handed and left-handed helical conformations for Aib residue are observed in peptides 2 and 3, respectively. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  8. HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology.

    PubMed

    Gaub, Perrine; de Léon, Andrès; Gibon, Julien; Soubannier, Vincent; Dorval, Geneviève; Séguéla, Philippe; Barker, Philip A

    2016-01-01

    Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease.

  9. Skin peptide tyrosine-tyrosine, a member of the pancreatic polypeptide family: isolation, structure, synthesis, and endocrine activity.

    PubMed

    Mor, A; Chartrel, N; Vaudry, H; Nicolas, P

    1994-10-25

    Pancreatic polypeptide, peptide tyrosine-tyrosine (PYY), and neuropeptide tyrosine (NPY), three members of a family of structurally related peptides, are mainly expressed in the endocrine pancreas, in endocrine cells of the gut, and in the brain, respectively. In the present study, we have isolated a peptide of the pancreatic polypeptide family from the skin of the South American arboreal frog Phyllomedusa bicolor. The primary structure of the peptide was established as Tyr-Pro-Pro-Lys-Pro-Glu-Ser-Pro-Gly-Glu10-Asp-Ala-Ser-Pro-Glu-Glu- Met-Asn- Lys-Tyr20-Leu-Thr-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu30-Val-Thr- Arg-Gln-Arg-Tyr-NH2 . This unusual peptide, named skin peptide tyrosine-tyrosine (SPYY), exhibits 94% similarity with PYY from the frog Rana ridibunda. A synthetic replicate of SPYY inhibits melanotropin release from perifused frog neurointermediate lobes in very much the same way as NPY. These results demonstrate the occurrence of a PYY-like peptide in frog skin. Our data also suggest the existence of a pituitary-skin regulatory loop in amphibians.

  10. Skin peptide tyrosine-tyrosine, a member of the pancreatic polypeptide family: isolation, structure, synthesis, and endocrine activity.

    PubMed Central

    Mor, A; Chartrel, N; Vaudry, H; Nicolas, P

    1994-01-01

    Pancreatic polypeptide, peptide tyrosine-tyrosine (PYY), and neuropeptide tyrosine (NPY), three members of a family of structurally related peptides, are mainly expressed in the endocrine pancreas, in endocrine cells of the gut, and in the brain, respectively. In the present study, we have isolated a peptide of the pancreatic polypeptide family from the skin of the South American arboreal frog Phyllomedusa bicolor. The primary structure of the peptide was established as Tyr-Pro-Pro-Lys-Pro-Glu-Ser-Pro-Gly-Glu10-Asp-Ala-Ser-Pro-Glu-Glu- Met-Asn- Lys-Tyr20-Leu-Thr-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu30-Val-Thr- Arg-Gln-Arg-Tyr-NH2 . This unusual peptide, named skin peptide tyrosine-tyrosine (SPYY), exhibits 94% similarity with PYY from the frog Rana ridibunda. A synthetic replicate of SPYY inhibits melanotropin release from perifused frog neurointermediate lobes in very much the same way as NPY. These results demonstrate the occurrence of a PYY-like peptide in frog skin. Our data also suggest the existence of a pituitary-skin regulatory loop in amphibians. PMID:7937944

  11. NT-pro-BNP is an independent predictor of mortality in patients with end-stage renal disease.

    PubMed

    Svensson, M; Gorst-Rasmussen, A; Schmidt, E B; Jorgensen, K A; Christensen, J H

    2009-04-01

    Patients with end-stage renal disease (ESRD) have an increased mortality from cardiovascular disease (CVD). N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is an independent predictor of mortality in patients with ischemic heart disease and congestive heart failure. Previous data have shown markedly elevated levels of NT-pro-BNP in patients with ESRD, while the prognostic value of elevated levels of NT-pro-BNP in patients with ESRD is largely unknown. The aim of the present study was to examine if the level of NT-pro-BNP predicts mortality in patients with ERSD and CVD. We prospectively followed 206 patients with ESRD and documented CVD. Levels of NT-pro-BNP were measured at baseline, and patients were followed for 2 years or until they reached the predefined endpoint of all-cause mortality. During follow-up, the total mortality was 44% (90/206). Patients who died were followed for a median of 314 days (interquartile range 179 - 530). Using Cox regression analysis, age, female sex, systolic blood pressure, dialysis efficiency and plasma levels of NT-pro-BNP were independent prognostic risk factors of mortality. In receiver operating characteristic curve analysis a cut off value for NT-pro-BNP was determined. Patients with values of NT-pro-BNP above 12.200 pg/ml had a 3 times higher risk of death than patients below the cut-off value (HR 3.05 95% CI 1.96 - 4.77, p < 0.0001). In spite of generally elevated levels of NT-pro-BNP, NT-pro-BNP is still an independent predictor of mortality and might add prognostic information in patients with ESRD and documented CVD.

  12. Distinct effects of dietary ALA, EPA and DHA on rat adipose oxylipins vary by depot location and sex.

    PubMed

    Mendonça, Anne M; Cayer, Lucien G J; Pauls, Samantha D; Winter, Tanja; Leng, Shan; Taylor, Carla G; Zahradka, Peter; Aukema, Harold M

    2018-02-01

    Dietary EPA and DHA given together alter oxylipins in adipose tissue. To compare the separate effects of individual dietary n-3 PUFA on oxylipins in different adipose depots (gonadal, mesenteric, perirenal, subcutaneous) in males and females, rats were provided diets containing higher levels of α-linolenic acid (ALA), EPA or DHA. Each n-3 PUFA enhanced its respective oxylipins the most, while effects on other n-3 oxylipins varied. For example: in perirenal and subcutaneous depots, more DHA oxylipins were higher with dietary ALA than with EPA; dietary EPA uniquely decreased 14-hydroxy-docosahexaenoic acid, in contrast to increasing many other DHA oxylipins. The n-3 PUFAs also reduced oxylipins from n-6 PUFAs in order of effectiveness: DHA > EPA > ALA. Diet by sex interactions in all depots except the perirenal depot resulted in higher oxylipins in males given DHA, and higher oxylipins in females given the other diets. Diet and sex effects on oxylipins did not necessarily reflect effects on either their tissue phospholipid or neutral lipid PUFA precursors. These varying diet and sex effects on oxylipins in the different adipose sites indicate that they may have distinct effects on adipose function. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Spinal antinociceptive effects of [D-Ala2]deltorphin II, a novel and highly selective delta-opioid receptor agonist.

    PubMed

    Improta, G; Broccardo, M

    1992-01-01

    Pharmacological assays in isolated tissues and binding tests have recently shown that two peptides, with the sequence Tyr-D-Ala-Phe-Asp-(or Glu)- Val-Val-Gly-NH2, isolated from skin extracts of Phyllomedusa bicolor and named [D-Ala2]deltorphin I and II, respectively, possess a higher affinity and selectivity for delta-opioid receptors than any other known natural compound. Since much evidence supports the role of spinal delta-opioid sites in producing antinociceptive effects, we investigated whether analgesia might be detected by direct spinal cord administration of [D-Ala2]deltorphin II (DADELT II) in the rat. The thermal antinociceptive effects of intrathecal DADELT II and dermorphin, a potent mu-selective agonist, were compared at different postinjection times by means of the tail-flick test. The DADELT II produced a dose-related inhibition of the tail-flick response, which lasted 10-60 min depending on the dose and appeared to be of shorter duration than the analgesia produced in rats after intrathecal injection of dermorphin (20-120 min). The analgesic effect of infused or injected DADELT II was completely abolished by naltrindole, the highly selective delta antagonist. These results confirm the involvement of delta receptors in spinal analgesic activity in the rat.

  14. Hey, Small Spender: An Insider's Guide to Navigating ALA's Chicago Conference on the Cheap

    ERIC Educational Resources Information Center

    School Library Journal, 2009

    2009-01-01

    This article presents an insider's guide to navigating the American Library Association's (ALA) annual conference in Chicago on July 9-15. As for the extracurricular activities, Chicago has a lot to offer. This article provides tips from the arts and entertainment bible "Time Out Chicago" on where to go and what to do (on a limited…

  15. Structural and Functional Characterization of a New Double Variant Haemoglobin (HbG-Philadelphia/Duarte α(2)β(2)).

    PubMed

    Fais, Antonella; Casu, Mariano; Ruggerone, Paolo; Ceccarelli, Matteo; Porcu, Simona; Era, Benedetta; Anedda, Roberto; Sollaino, Maria Carla; Galanello, Renzo; Corda, Marcella

    2011-01-01

    WE REPORT THE FIRST CASE OF COSEGREGATION OF TWO HAEMOGLOBINS (HBS): HbG-Philadelphia [α68(E17)Asn → Lys] and HbDuarte [β62(E6)AlaPro]. The proband is a young patient heterozygous also for β°-thalassaemia. We detected exclusively two haemoglobin variants: HbDuarte and HbG-Philadelphia/Duarte. Functional study of the new double variant HbG-Philadelphia/Duarte exhibited an increase in oxygen affinity, with a slight decrease of cooperativity and Bohr effect. This functional behaviour is attributed to β62AlaPro instead of α68Asn → Lys substitution. Indeed, HbG-Philadelphia isolated in our laboratory from blood cells donor carrier for this variant is not affected by any functional modification, whereas purified Hb Duarte showed functional properties very similar to the double variant. NMR and MD simulation studies confirmed that the presence of Pro instead of Ala at the β62 position produces displacement of the E helix and modifications of the tertiary structure. The substitution α68(E17)Asn → Lys does not cause significant structural and dynamical modifications of the protein. A possible structure-based rational of substitution effects is suggested.

  16. Taste, umami-enhance effect and amino acid sequence of peptides separated from silkworm pupa hydrolysate.

    PubMed

    Yu, Zilin; Jiang, Hongrui; Guo, Rongcan; Yang, Bo; You, Gang; Zhao, Mouming; Liu, Xiaoling

    2018-06-01

    Four umami peptides were separated and purified by ultrafiltration, gel filtration chromatography and identified by ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS), the amino acid sequences of four peptides are Val-Pro-Tyr (VPY), Thr-Ala-Tyr (TAY), Ala-Ala-Pro-Tyr (AAPY) and Gly-Phe-Pro (GFP). The result illustrates that the umami amino acids are not the content of umami peptides, but bitter amino acids are included. The threshold of VPY, TAY, AAPY and GFP were 1.65 mmol/L, 1.76 mmol/L, 2.97 mmol/L and 6.26 mmol/L, respectively. The peptide TAY, VPY and AAPY had an umami-enhancement effect on the monosodium glutamate (MSG) + sodium chloride (NaCl) solution, their concentrations were 2.5 g/L, 5 g/L and 5 g/L, respectively, while GFP has no significant umami-enhancement effect in solution. In addition, the peptides have better taste than its composing amino acids, which indicates that the taste of peptide does not depend on its composing amino acids. Copyright © 2018. Published by Elsevier Ltd.

  17. [Effects of epithalon and cortagene on immunity and hemostasis in neonatally hypophysectomized chicken and old birds].

    PubMed

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

    2008-01-01

    It has been found that chicken hypophysectomized early in the neonatal period develop anemia, cellular and humoral immune deficiency, hypercoagulation and inhibited fibrinolysis by their 45th postnatal day. An analogous operation performed on old birds produces less significant changes in erythrocytes, immunity and hemostasis. Injections of epithalon tetrapeptide (Ala-Glu-Asp-Gly) administered to either hypophysectomized chicken or old birds during a period of 40 days completely eliminate the shifts registered in erythrocytes, immunity and hemostasis, while injections of cortagene (Ala-Glu-Asp-Pro) which is distinguished from epithalon by a different terminal aminoacid (with Gly being replaced by Pro) do not affect the parameters studied.

  18. Silica, Alumina and Clay Catalyzed Peptide Bond Formation: Enhanced Efficiency of Alumina Catalyst

    NASA Astrophysics Data System (ADS)

    Bujdák, Juraj; Rode, Bernd M.

    1999-10-01

    Catalytic efficiencies of clay (hectorite), silica and alumina were tested in peptide bond formation reactions of glycine (Gly), alanine (Ala), proline (Pro), valine (Val) and leucine (Leu). The reactions were performed as drying/wetting (hectorite) and temperature fluctuation (silica and alumina) experiments at 85 °C. The reactivity of amino acids decreased in order Gly > Ala > Pro ~ Val ~ Leu. The highest catalytic efficiency was observed for alumina, the only catalyst producing oligopeptides in all investigated reaction systems. The peptide bond formation on alumina is probably catalyzed by the same sites and via similar reaction mechanisms as some alumina-catalyzed dehydration reactions used in industrial chemistry.

  19. Synthesis, biological evaluation, and automated docking of constrained analogues of the opioid peptide H-Dmt-D-Ala-Phe-Gly-NH₂ using the 4- or 5-methyl substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold.

    PubMed

    De Wachter, Rien; de Graaf, Chris; Keresztes, Atilla; Vandormael, Bart; Ballet, Steven; Tóth, Géza; Rognan, Didier; Tourwé, Dirk

    2011-10-13

    The Phe(3) residue of the N-terminal tetrapeptide of dermorphin (H-Dmt-d-Ala-Phe-Gly-NH(2)) was conformationally constrained using 4- or 5-methyl-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) stereoisomeric scaffolds. Several of the synthesized peptides were determined to be high affinity agonists for the μ opioid receptor (OPRM) with selectivity over the δ opioid receptor (OPRD). Interesting effects of the Aba configuration on ligand binding affinity were observed. H-Dmt-d-Ala-erythro-(4S,5S)-5-Me-Aba-Gly-NH(2)9 and H-Dmt-threo-(4R,5S)-5-Me-Aba-Gly-NH(2)12 exhibited subnanomolar affinity for OPRM, while they possess an opposite absolute configuration at position 4 of the Aba ring. However, in the 4-methyl substituted analogues, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH(2)14 was significantly more potent than the (4S)-derivative 13. These unexpected results were rationalized using the binding poses predicted by molecular docking simulations. Interestingly, H-Dmt-d-Ala-(4R)-Me-Aba-Gly-NH(2)14 is proposed to bind in a different mode compared with the other analogues. Moreover, in contrast to Ac-4-Me-Aba-NH-Me, which adopts a β-turn in solution and in the crystal structure, the binding mode of this analogue suggests an alternative receptor-bound conformation.

  20. Healthy reduced-fat Bologna sausages enriched in ALA and DHA and stabilized with Melissa officinalis extract.

    PubMed

    Berasategi, Izaskun; Navarro-Blasco, Iñigo; Calvo, Maria Isabel; Cavero, Rita Yolanda; Astiasarán, Iciar; Ansorena, Diana

    2014-03-01

    Reduced-energy and reduced-fat Bologna products enriched with ω-3 polyunsaturated fatty acids were formulated by replacing the pork back-fat by an oil-in-water emulsion containing a mixture of linseed-algae oil stabilized with a lyophilized Melissa officinalis extract. Healthier composition and lipid profile was obtained: 85 kcal/100 g, 3.6% fat, 0.6 g ALA and 0.44 g DHA per 100 g of product and ω-6/ω-3 ratio of 0.4. Technological and sensory problems were not detected in the new formulations. Reformulation did not cause oxidation problems during 32 days of storage under refrigeration. The results suggest that it is possible to obtain reduced-fat Bologna-type sausages rich in ALA and DHA and stabilized with natural antioxidants, applying the appropriate technology without significant effects on the sensory quality, yielding interesting products from a nutritional point of view. © 2013.

  1. cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides.

    PubMed

    Richter, K; Egger, R; Negri, L; Corsi, R; Severini, C; Kreil, G

    1990-06-01

    We present the structure of four precursors for [D-Ala2]deltorphins I and II as deduced from cDNAs cloned from skin of the frog Phyllomedusa bicolor. These contain the genetic information for one copy of [D-Ala2]deltorphin II and zero, one, or three copies of [D-Ala2]deltorphin I. In each case, the D-alanine of the end product is encoded by a normal GCG codon for L-alanine. In addition, the existence of three peptides related to dermorphin was predicted from the amino acid sequence of the precursors. These peptides were synthesized with a D-alanine in position 2 and their pharmacological properties were tested. Two of them, [Lys7]dermorphin-OH and [Trp4,Asn7]dermorphin-OH, were found to have roughly the same affinity and selectivity for mu-type opioid receptors as dermorphin.

  2. Genetics of Type III Bartter Syndrome in Spain, Proposed Diagnostic Algorithm

    PubMed Central

    García Castaño, Alejandro; Pérez de Nanclares, Gustavo; Madariaga, Leire; Aguirre, Mireia; Madrid, Alvaro; Nadal, Inmaculada; Navarro, Mercedes; Lucas, Elena; Fijo, Julia; Espino, Mar; Espitaletta, Zilac; Castaño, Luis; Ariceta, Gema

    2013-01-01

    The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families. PMID:24058621

  3. Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm.

    PubMed

    García Castaño, Alejandro; Pérez de Nanclares, Gustavo; Madariaga, Leire; Aguirre, Mireia; Madrid, Alvaro; Nadal, Inmaculada; Navarro, Mercedes; Lucas, Elena; Fijo, Julia; Espino, Mar; Espitaletta, Zilac; Castaño, Luis; Ariceta, Gema

    2013-01-01

    The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.

  4. NT-proBNP and Heart Failure Risk Among Individuals With and Without Obesity: The ARIC Study

    PubMed Central

    Ndumele, Chiadi E.; Matsushita, Kunihiro; Sang, Yingying; Lazo, Mariana; Agarwal, Sunil K.; Nambi, Vijay; Deswal, Anita; Blumenthal, Roger S.; Ballantyne, Christie M.; Coresh, Josef; Selvin, Elizabeth

    2016-01-01

    Background Obesity is a risk factor for heart failure (HF), but is associated with lower N-terminal of pro-Brain Natriuretic Peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results We followed 12,230 ARIC participants free of prior HF at baseline (visit 2, 1990–1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1,861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r = −0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall and even among those with severe obesity (BMI ≥35 kg/m2; improvement in c-statistic +0.032 [95% CI 0.011–0.053]). However, given higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP 100 to < 200 pg/ml, the average 10-year HF risk was <5% among normal weight individuals but >10% if severely obese. Conclusions Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information regarding the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population. PMID:26746175

  5. Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates.

    PubMed

    Huang, Shih-Li; Jao, Chia-Ling; Ho, Kit-Pan; Hsu, Kuo-Chiang

    2012-05-01

    The in vitro DPP-IV inhibitory activity of isolated peptides from of tuna cooking juice hydrolyzed by Protease XXIII (PR) and orientase (OR) was determined. The results showed that the peptide fractions with the molecular weight over 1,422 Da possessed the greatest DPP-IV inhibitory activity. The amino acid sequences of the three peptides isolated from PR and OR hydrolysates were identified by MALDI-TOF/TOF MS/MS, and they were Pro-Gly-Val-Gly-Gly-Pro-Leu-Gly-Pro-Ile-Gly-Pro-Cys-Tyr-Glu (1412.7 Da), Cys-Ala-Tyr-Gln-Trp-Gln-Arg-Pro-Val-Asp-Arg-Ile-Arg (1690.8 Da) and Pro-Ala-Cys-Gly-Gly-Phe-Try-Ile-Ser-Gly-Arg-Pro-Gly (1304.6 Da), while they showed the dose-dependent inhibition effect of DPP-IV with IC(50) values of 116.1, 78.0 and 96.4 μM, respectively. In vitro simulated gastrointestinal digestion retained or even improved the DPP-IV inhibitory activities of the three peptides. The results suggest that tuna cooking juice would be a good precursor of DPP-IV inhibitor, and the DPP-IV inhibitory peptides can successfully passed through the digestive tract. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. The Experience of Bulimic College Students Who Use "Pro-Ana/Pro-Mia" Web Sites: A Two-Phase Mixed-Method Study

    ERIC Educational Resources Information Center

    Davis, Blair J.

    2010-01-01

    Eating disorders (EDs) are a serious problem in the U.S. due to their rise in prevalence during the 20th century and high morbidity and mortality rates. A relatively new, controversial phenomenon, "pro-Ana" (pro-anorexia) and "pro-Mia" (pro-bulimia) Web sites, came to the public's attention around 2000. These sites are created by and for people…

  7. Relation between iron metabolism and antioxidants enzymes and δ-ALA-D activity in rats experimentally infected by Fasciola hepatica.

    PubMed

    Bottari, Nathieli B; Mendes, Ricardo E; Baldissera, Matheus D; Bochi, Guilherme V; Moresco, Rafael N; Leal, Marta L R; Morsch, Vera M; Schetinger, Maria R C; Christ, Ricardo; Gheller, Larissa; Marques, Éder J; Da Silva, Aleksandro S

    2016-06-01

    The aim of this study was to evaluate the iron metabolism in serum, as well as antioxidant enzymes, in addition to the Delta-Aminolevulinic Acid Dehydratase (δ-ALA-D) activity in the liver of rats experimentally infected by Fasciola hepatica. Thirty male adult rats (Wistar) specific pathogen free were divided into four groups: two uninfected group (CTRL 1 and CTRL 2) with five animals each and two infected groups (INF 1 and INF 2) with 10 animals each. Infection was performed orally with 20 metacercariae at day 1. On day 15 (CTRL 1 and INF 1 groups) and 87 PI (CTRL 2 and INF 2 groups) blood and bone marrow were collected and the animals were subsequently euthanized for liver sampling. Blood was allocated in tubes without anticoagulant for serum acquisition to measure iron, transferrin and unsaturated iron binding capacity (UIBC). δ-ALA-D, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the liver. A decrease in iron, transferrin and UIBC levels was observed in all infected animals compared to control groups (P < 0.05). Furthermore, iron accumulation was observed in bone marrow of infected mice. Infected animals showed an increase in δ-ALA-D activity at 87 post-infection (PI) (INF 2) as well as in SOD activity at days 15 (INF 1) and 87 PI (INF 2). On the other hand, CAT activity was reduced in rats infected by F. hepatica during acute and chronic phase of fasciolosis (INF 1 and INF 2 groups), when moderate (acute) and severe necrosis in the liver histopathology were observed. These results may suggest that oxidative damage to tissues along with antioxidant mechanisms might have taken part in fasciolosis pathogenesis and are also involved in iron deficiency associated to changes in δ-ALA-D activity during chronic phase of disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. The Importance of Pro-Environmental Behavior in Adolescent

    NASA Astrophysics Data System (ADS)

    Palupi, Tyas; Sawitri, Dian R.

    2018-02-01

    Studies regarding pro-environmental behavior in adolescents are lacking. This study aimed to examine the importance of pro-environmental behavior in adolescents (high school and university students) by conducting literature review from previous studies on pro environmental behavior. Pro-environmental behavior is the behavior of individuals that contributes towards environmental preservation. Based on previous studies, measurement of pro-environmental behavior were investigated on several theories, namely theory of planned behavior (TPB) and value, belief, norms (VBN) by using aspects of pro environmental behavior. Young people with critical thinking, and good environmental education, are expected to behave more environmentally friendly for creating a sustainable future.

  9. ["Pro Ana": Psychodynamic References for Anorexia Nervosa].

    PubMed

    Siefert, Linda

    2017-02-01

    "Pro Ana": Psychodynamic References for Anorexia Nervosa The internet-based phenomenon "Pro Ana" refers to the eating disorder anorexia nervosa in a positive way. To understand what the phenomenon "Pro Ana" represents, the websites are used as a starting point of the current analysis. Based on these results, similarities and differences between "Pro Ana" and the eating disorder anorexia nervosa are discussed. Furthermore psychodynamic references for anorexia nervosa are derived and finally their importance for treatment motivation will be considered.

  10. Ambulant photodynamic therapy of superficial malignomas with 5-ALA in combination with folic acid and use of noncoherent light.

    PubMed

    Jindra, R H; Kubin, A; Kolbabek, H; Alth, G; Dobrowsky, W

    1999-01-01

    This study reports our first results of ambulant photodynamic treatment with 5-aminolevulinic acid (5-ALA) in combination with folic acid and subsequent illumination with a noncoherent light source. The compound was topically applied to avoid total body skin sensitivity which occurs in the case of systemic administration. If no therapeutic response could be proved, we added folic acid to 5-ALA for a further treatment attempt. Illumination was performed by broad band red thermic light to also excitate reaction products with absorption bands located near to that of the sensitizer. As a result, we observed a response in all cases, however, in some cases only after the addition of folic acid.

  11. NT-proBNP is superior to BNP for predicting first cardiovascular events in the general population: the Heinz Nixdorf Recall Study.

    PubMed

    Kara, Kaffer; Lehmann, Nils; Neumann, Till; Kälsch, Hagen; Möhlenkamp, Stefan; Dykun, Iryna; Broecker-Preuss, Martina; Pundt, Noreen; Moebus, Susanne; Jöckel, Karl-Heinz; Erbel, Raimund; Mahabadi, Amir A

    2015-03-15

    B-type natriuretic peptide (BNP) as well as N-terminal-proBNP (NT-proBNP) are associated with cardiac events in the general population. Yet, data from the general population comparing both peptides for their prognostic value is lacking. Participants from the population-based Heinz-Nixdorf-Recall-study without cardiovascular diseases were included. Associations of BNP and NT-proBNP with incident cardiovascular events (incident myocardial infarction, stroke, or cardiovascular death) were assessed using Cox regression; prognostic value was addressed using Harrell's c statistic. From overall 3589 subjects (mean age: 59.3 ± 7.7 yrs, 52.5% female), 235 subjects developed a cardiovascular event during 8.9 ± 2.2 yrs of follow-up. In regression analysis both natriuretic peptides were associated with incident cardiovascular events, independent of traditional risk factors (hazard ratio (HR) per unit increase on log-scale (95% CI): NT-proBNP: 1.60 (1.39; 1.84); BNP: 1.37 (1.19; 1.58), p<0.0001 respectively). Specifically looking at subjects <60 yrs only NT-proBNP, was linked with events (HR (95% CI): 1.59 (1.19; 2.13) for NT-proBNP, p=0.0019; HR: 1.25 (0.94; 1.65) for BNP, p=0.12, after adjustment for age and gender). Similar results were observed for females (HR (95% CI) 1.65 (1.28; 2.12), p=0.0001 for NT-proBNP, and 1.24 (0.96; 1.61), p=0.10 for BNP after adjustment for age). Adding NT-proBNP/BNP to traditional risk factors increased the prognostic value, with effects being stronger for NT-proBNP (Harrell's c, 0.724 to 0.741, p=0.034) as compared to BNP (0.724 to 0.732, p=0.20). Both, NT-proBNP and BNP are associated with future cardiovascular events in the general population. However, when both are available, NT-proBNP seems to be superior due to its higher prognostic value, especially in younger subjects and females. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Biofortified Cassava with Pro-Vitamin A Is Sensory and Culturally Acceptable for Consumption by Primary School Children in Kenya

    PubMed Central

    Talsma, Elise F.; Melse-Boonstra, Alida; de Kok, Brenda P. H.; Mbera, Gloria N. K.; Mwangi, Alice M.; Brouwer, Inge D.

    2013-01-01

    Background Biofortification of cassava with pro-vitamin A can potentially reduce vitamin A deficiency in low-income countries. However, little is known about consumer acceptance of this deep yellow variety of cassava compared to the commonly available white varieties. We aimed to determine the sensory and cultural acceptability of the consumption of pro-vitamin A rich cassava in order to identify key factors predicting the intention to consume pro-vitamin A rich cassava by families with school-aged children in Eastern Kenya. Methods Sensory acceptability was measured by replicated discrimination tests and paired preference tests among 30 children (7–12 yr) and 30 caretakers (18–45 yr) in three primary schools. Cultural acceptability was assessed with a questionnaire based on the combined model of The Theory of Planned Behavior and The Health Belief Model in one primary school among 140 caretakers of children aged 6 to 12 years. Correlations and multivariate analyses were used to determine associations between summed scores for model constructs. Results Caretakers and children perceived a significant difference in taste between white and pro-vitamin A rich cassava. Both preferred pro-vitamin A rich cassava over white cassava because of its soft texture, sweet taste and attractive color. Knowledge about pro-vitamin A rich cassava and it's relation to health (‘Knowledge’ ((β = 0.29, P = <.01)) was a strong predictor of ‘Health behavior identity’. Worries related to bitter taste and color (‘Perceived barriers 1’ (β = −0.21, P = .02)), the belief of the caretaker about having control to prepare cassava (‘Control beliefs’ (β = 0.18, P = .02)) and activities like information sessions about pro-vitamin A rich cassava and recommendations from health workers (‘Cues to action’(β = 0.51, P = <.01)) were the best predictors of intention to consume pro-vitamin A rich cassava. Conclusions Pro-vitamin A rich cassava is

  13. Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

    PubMed Central

    Valdés, Pablo A.; Leblond, Frederic; Kim, Anthony; Harris, Brent T.; Wilson, Brian C.; Fan, Xiaoyao; Tosteson, Tor D.; Hartov, Alex; Ji, Songbai; Erkmen, Kadir; Simmons, Nathan E.; Paulsen, Keith D.; Roberts, David W.

    2011-01-01

    Object Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. Methods The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. Results A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors. Conclusions These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of

  14. cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides.

    PubMed Central

    Richter, K; Egger, R; Negri, L; Corsi, R; Severini, C; Kreil, G

    1990-01-01

    We present the structure of four precursors for [D-Ala2]deltorphins I and II as deduced from cDNAs cloned from skin of the frog Phyllomedusa bicolor. These contain the genetic information for one copy of [D-Ala2]deltorphin II and zero, one, or three copies of [D-Ala2]deltorphin I. In each case, the D-alanine of the end product is encoded by a normal GCG codon for L-alanine. In addition, the existence of three peptides related to dermorphin was predicted from the amino acid sequence of the precursors. These peptides were synthesized with a D-alanine in position 2 and their pharmacological properties were tested. Two of them, [Lys7]dermorphin-OH and [Trp4,Asn7]dermorphin-OH, were found to have roughly the same affinity and selectivity for mu-type opioid receptors as dermorphin. PMID:2352951

  15. Novel mutations in the CHST6 gene associated with macular corneal dystrophy in southern India.

    PubMed

    Warren, John F; Aldave, Anthony J; Srinivasan, M; Thonar, Eugene J; Kumar, Abha B; Cevallos, Vicky; Whitcher, John P; Margolis, Todd P

    2003-11-01

    To further characterize the role of the carbohydrate sulfotransferase (CHST6) gene in macular corneal dystrophy (MCD) through identification of causative mutations in a cohort of affected patients from southern India. Genomic DNA was extracted from buccal epithelium of 75 patients (51 families) with MCD, 33 unaffected relatives, and 48 healthy volunteers. The coding region of the CHST6 gene was evaluated by means of polymerase chain reaction amplification and direct sequencing. Subtyping of MCD into types I and II was performed by measuring serum levels of antigenic keratan sulfate. Seventy patients were classified as having type I MCD, and 5 patients as having type II MCD. Analysis of the CHST6 coding region in patients with type I MCD identified 11 homozygous missense mutations (Leu22Arg, His42Tyr, Arg50Cys, Arg50Leu, Ser53Leu, Arg97Pro, Cys102Tyr, Arg127Cys, Arg205Gln, His249Pro, and Glu274Lys), 2 compound heterozygous missense mutations (Arg93His and Ala206Thr), 5 homozygous deletion mutations (delCG707-708, delC890, delA1237, del1748-1770, and delORF), and 2 homozygous replacement mutations (ACCTAC 1273 GGT, and GCG 1304 AT). One patient with type II MCD was heterozygous for the C890 deletion mutation, whereas 4 possessed no CHST6 coding region mutations. A variety of previously unreported mutations in the coding region of the CHST6 gene are associated with type I MCD in a cohort of patients in southern India. An improved understanding of the genetic basis of MCD allows for earlier, more accurate diagnosis of affected individuals, and may provide the foundation for the development of novel disease treatments.

  16. Impact of the green tea ingredient epigallocatechin gallate and a short pentapeptide (Ile-Ile-ala-Glu-Lys) on the structural organization of mixed micelles and the related uptake of cholesterol.

    PubMed

    Giangreco, Francesco; Höfinger, Siegfried; Bakalis, Evangelos; Zerbetto, Francesco

    2018-06-07

    High levels of blood cholesterol are conventionally linked to an increased risk of developing cardiovascular disease (Grundy, 1986). Here we examine the molecular mode of action of natural products with known cholesterol-lowering activity, such as for example the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys. Molecular Dynamics simulations are used to gain insight into the formation process of mixed micelles and, correspondingly, how active agents epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys could possibly interfere with it. Self-assembly of physiological micelles occurs on the order of 35-50 ns; most of the structural properties of mixed micelles are unaffected by epigallocatechin gallate or Ile-Ile-Ala-Glu-Lys which integrate into the micellar surface; the diffusive motion of constituting lipids palmitoyl-oleoyl-phosphatidylcholine and cholesterol is significantly down-regulated by both epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys; CONCLUSIONS: The molecular mode of action of natural compounds epigallocatechin gallate and Ile-Ile-Ala-Glu-Lys is a significant down-regulation of the diffusive motion of micellar lipids. Natural compounds like the green tea ingredient epigallocatechin gallate and a short pentapeptide, Ile-Ile-Ala-Glu-Lys, lead to a significant down-regulation of the diffusive motion of micellar lipids thereby modulating cholesterol absorption into physiological micelles. Copyright © 2018. Published by Elsevier B.V.

  17. The effectiveness and cost-effectiveness of intraoperative imaging in high-grade glioma resection; a comparative review of intraoperative ALA, fluorescein, ultrasound and MRI.

    PubMed

    Eljamel, M Sam; Mahboob, Syed Osama

    2016-12-01

    Surgical resection of high-grade gliomas (HGG) is standard therapy because it imparts significant progression free (PFS) and overall survival (OS). However, HGG-tumor margins are indistinguishable from normal brain during surgery. Hence intraoperative technology such as fluorescence (ALA, fluorescein) and intraoperative ultrasound (IoUS) and MRI (IoMRI) has been deployed. This study compares the effectiveness and cost-effectiveness of these technologies. Critical literature review and meta-analyses, using MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ALA, fluorescein (FLCN), IoUS or IoMRI to guide HGG-surgery. The meta-analyses were conducted according to statistical heterogeneity between studies. If there was no heterogeneity, fixed effects model was used; otherwise, a random effects model was used. Statistical heterogeneity was explored by χ 2 and inconsistency (I 2 ) statistics. To assess cost-effectiveness, we calculated the incremental cost per quality-adjusted life-year (QALY). Gross total resection (GTR) after ALA, FLCN, IoUS and IoMRI was 69.1%, 84.4%, 73.4% and 70% respectively. The differences were not statistically significant. All four techniques led to significant prolongation of PFS and tended to prolong OS. However none of these technologies led to significant prolongation of OS compared to controls. The cost/QALY was $16,218, $3181, $6049 and $32,954 for ALA, FLCN, IoUS and IoMRI respectively. ALA, FLCN, IoUS and IoMRI significantly improve GTR and PFS of HGG. Their incremental cost was below the threshold for cost-effectiveness of HGG-therapy, denoting that each intraoperative technology was cost-effective on its own. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation1[S

    PubMed Central

    Ikei, Kenneth N.; Yeung, Jennifer; Apopa, Patrick L.; Ceja, Jesús; Vesci, Joanne; Holinstat, Michael

    2012-01-01

    Human platelet-type 12-lipoxygenase (12-LOX) has recently been shown to play an important role in regulation of human platelet function by reacting with arachidonic acid (AA). However, a number of other fatty acids are present on the platelet surface that, when cleaved from the phospholipid, can be oxidized by 12-LOX. We sought to characterize the substrate specificity of 12-LOX against six essential fatty acids: AA, dihomo-γ-linolenic acid (DGLA), eicosapentaenoic acid (EPA), α-linolenic acid (ALA), eicosadienoic acid (EDA), and linoleic acid (LA). Three fatty acids were comparable substrates (AA, DGLA, and EPA), one was 5-fold slower (ALA), and two showed no reactivity with 12-LOX (EDA and LA). The bioactive lipid products resulting from 12-LOX oxidation of DGLA, 12-(S)-hydroperoxy-8Z,10E,14Z-eicosatrienoic acid [12(S)-HPETrE], and its reduced product, 12(S)-HETrE, resulted in significant attenuation of agonist-mediated platelet aggregation, granule secretion, αIIbβ3 activation, Rap1 activation, and clot retraction. Treatment with DGLA similarly inhibited PAR1-mediated platelet activation as well as platelet clot retraction. These observations are in surprising contrast to our recent work showing 12(S)-HETE is a prothrombotic bioactive lipid and support our hypothesis that the overall effect of 12-LOX oxidation of fatty acids in the platelet is dependent on the fatty acid substrates available at the platelet membrane. PMID:22984144

  19. Use of Patient-Reported Outcome (PRO) Measures at Group and Patient Levels: Experiences From the Generic Integrated PRO System, WestChronic

    PubMed Central

    Larsen, Louise Pape; Biering, Karin; Johnsen, Soren Paaske; Riiskjær, Erik; Schougaard, Liv Marit

    2014-01-01

    Background Patient-reported outcome (PRO) measures may be used at a group level for research and quality improvement and at the individual patient level to support clinical decision making and ensure efficient use of resources. The challenges involved in implementing PRO measures are mostly the same regardless of aims and diagnostic groups and include logistic feasibility, high response rates, robustness, and ability to adapt to the needs of patient groups and settings. If generic PRO systems can adapt to specific needs, advanced technology can be shared between medical specialties and for different aims. Objective We describe methodological, organizational, and practical experiences with a generic PRO system, WestChronic, which is in use among a range of diagnostic groups and for a range of purposes. Methods The WestChronic system supports PRO data collection, with integration of Web and paper PRO questionnaires (mixed-mode) and automated procedures that enable adherence to implementation-specific schedules for the collection of PRO. For analysis, we divided functionalities into four elements: basic PRO data collection and logistics, PRO-based clinical decision support, PRO-based automated decision algorithms, and other forms of communication. While the first element is ubiquitous, the others are optional and only applicable at a patient level. Methodological and organizational experiences were described according to each element. Results WestChronic has, to date, been implemented in 22 PRO projects within 18 diagnostic groups, including cardiology, neurology, rheumatology, nephrology, orthopedic surgery, gynecology, oncology, and psychiatry. The aims of the individual projects included epidemiological research, quality improvement, hospital evaluation, clinical decision support, efficient use of outpatient clinic resources, and screening for side effects and comorbidity. In total 30,174 patients have been included, and 59,232 PRO assessments have been collected

  20. Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

    PubMed Central

    Campbell, Laura M.; Maxwell, Pamela J.; Waugh, David J.J.

    2013-01-01

    It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations. PMID:24276377

  1. Inducing Behavioral Change in Seekers of Pro-Anorexia Content Using Internet Advertisements: Randomized Controlled Trial

    PubMed Central

    Brunstein-Klomek, Anat; Mandel, Or; Hadas, Arie; Fennig, Silvana

    2018-01-01

    Background The influence of pro-anorexia (pro-ana) websites is debated, with studies indicating both negative and positive effects, as well as significant variation in the effects of different websites for those suffering from eating disorders (EDs) and the general population. Online advertising, known to induce behavioral change both online and in the physical world, has not been used so far to modify the search behavior of people seeking pro-ana content. Objective The objective of this randomized controlled trial (RCT) was to examine if online advertisements (ads) can change online search behaviors of users who are looking for online pro-ana content. Methods Using the Bing Ads system, we conducted an RCT to randomly expose the searchers for pro-ana content to 10 different ads referring people to one of the three websites: the National Eating Disorders Association, the National Institutes of Mental Health, and MyProAna. MyProAna is a pro-ana website that was found in a previous study to be associated with less pathological online behaviors than other pro-ana websites. We followed participants exposed and unexposed to the ads to explore their past and future online searches. The ads were shown 25,554 times and clicked on 217 times. Results Exposure to the ads was associated with a decrease in searches for pro-ana and self-harm content. Reductions were greatest among those referred to MyProAna (reduction of 34.0% [73/215] and 37.2% [80/215] for pro-ana and self-harm, respectively) compared with users who were referred elsewhere (reduction of 15.47% [410/2650] and 3.21% [85/2650], respectively), and with users who were not shown the ads, who increased their behaviors (increase of 57.12% [6462/11,314] and 4.07% [461/11,314], respectively). In addition, those referred to MyProAna increased their search for treatment, as did control users, who did so to a lesser extent. However, users referred elsewhere decreased their searches for this content. Conclusions We found

  2. Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

    PubMed Central

    Glaser, Kirsten; Silwedel, Christine; Fehrholz, Markus; Waaga-Gasser, Ana M.; Henrich, Birgit; Claus, Heike; Speer, Christian P.

    2017-01-01

    Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal

  3. Perl Embedded in PTC's Pro/ENGINEER, Version 1

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

    2003-12-22

    Pro-PERL (AKA Pro/PERL) is a Perl extension to the PTC Pro/TOOLKIT API to the PTC Pro/ENGINEER CAD application including an embedded interpreter. It can be used to automate and customize Pro/ENGINEER, create Vendor Neutral Archive (VNA) format files and re-create CAD models from the VNA files. This has applications in sanitizing classified CAD models created in a classified environment for transfer to an open environment, creating template models for modification to finished models by non-expert users, and transfer of design intent data to other modeling technologies.

  4. Pro-ana versus Pro-recovery: A Content Analytic Comparison of Social Media Users' Communication about Eating Disorders on Twitter and Tumblr.

    PubMed

    Branley, Dawn B; Covey, Judith

    2017-01-01

    Objectives: To compare how people communicate about eating disorders on two popular social media platforms - Twitter and Tumblr. Materials and Methods: Thematic analysis was conducted to characterize the types of communications posted, and a content analysis was undertaken of between-platform differences. Results: Three types of content (pro-ana, anti-ana, and pro-recovery) were posted on each platform. Overall, across both platforms, extreme pro-ana posts were in the minority compared to anti-ana and pro-recovery. Pro-ana posts (including 'thinspiration') were more common on Twitter than Tumblr, whereas anti-ana and pro-recovery posts were more common on Tumblr. Conclusion: The findings have implications for future research and health care relating to the treatment and prevention of eating disorders. Developers of future interventions targeting negative pro-ana content should remain aware of the need to avoid any detrimental impact on positive online support.

  5. Pro-ana versus Pro-recovery: A Content Analytic Comparison of Social Media Users’ Communication about Eating Disorders on Twitter and Tumblr

    PubMed Central

    Branley, Dawn B.; Covey, Judith

    2017-01-01

    Objectives: To compare how people communicate about eating disorders on two popular social media platforms – Twitter and Tumblr. Materials and Methods: Thematic analysis was conducted to characterize the types of communications posted, and a content analysis was undertaken of between-platform differences. Results: Three types of content (pro-ana, anti-ana, and pro-recovery) were posted on each platform. Overall, across both platforms, extreme pro-ana posts were in the minority compared to anti-ana and pro-recovery. Pro-ana posts (including ‘thinspiration’) were more common on Twitter than Tumblr, whereas anti-ana and pro-recovery posts were more common on Tumblr. Conclusion: The findings have implications for future research and health care relating to the treatment and prevention of eating disorders. Developers of future interventions targeting negative pro-ana content should remain aware of the need to avoid any detrimental impact on positive online support. PMID:28848472

  6. Undergraduate Students' Pro-Environmental Behavior in Daily Practice

    NASA Astrophysics Data System (ADS)

    Dewi, Widiaswati; Sawitri, Dian R.

    2018-02-01

    Pro-environmental behavior is an individual action as a manifestation of one's responsibility to create a sustainable environment. University students as one of the agent of change can adopt pro-environmental behaviors concept, even through simple things to do on daily activities such as ride a bicycle or walk for short distance, reuse the shopping bags, separate waste, learn about environmental issues etc. Many studies have examined pro-environmental behavior from various approaches. However, the study about university students' pro-environmental behavior is lacking. The aim of this paper is to examine the undergraduate students' pro-environmental behaviors level. We surveyed 364 first year undergraduate students from a state university in Semarang. The survey included six aspects of pro-environmental behavior in daily practice which include energy conservation, mobility and transportation, waste avoidance, recycling, consumerism, and vicarious behaviors toward conservation. Findings of this study showed the level of pro-environmental behavior of first year undergraduate students is medium. Recommendations for undergraduate students and future researchers are discussed.

  7. AlaScan: A Graphical User Interface for Alanine Scanning Free-Energy Calculations.

    PubMed

    Ramadoss, Vijayaraj; Dehez, François; Chipot, Christophe

    2016-06-27

    Computation of the free-energy changes that underlie molecular recognition and association has gained significant importance due to its considerable potential in drug discovery. The massive increase of computational power in recent years substantiates the application of more accurate theoretical methods for the calculation of binding free energies. The impact of such advances is the application of parent approaches, like computational alanine scanning, to investigate in silico the effect of amino-acid replacement in protein-ligand and protein-protein complexes, or probe the thermostability of individual proteins. Because human effort represents a significant cost that precludes the routine use of this form of free-energy calculations, minimizing manual intervention constitutes a stringent prerequisite for any such systematic computation. With this objective in mind, we propose a new plug-in, referred to as AlaScan, developed within the popular visualization program VMD to automate the major steps in alanine-scanning calculations, employing free-energy perturbation as implemented in the widely used molecular dynamics code NAMD. The AlaScan plug-in can be utilized upstream, to prepare input files for selected alanine mutations. It can also be utilized downstream to perform the analysis of different alanine-scanning calculations and to report the free-energy estimates in a user-friendly graphical user interface, allowing favorable mutations to be identified at a glance. The plug-in also assists the end-user in assessing the reliability of the calculation through rapid visual inspection.

  8. Hand-operated and rotary ProTaper instruments: a comparison of working time and number of rotations in simulated root canals.

    PubMed

    Pasqualini, Damiano; Scotti, Nicola; Tamagnone, Lorenzo; Ellena, Federica; Berutti, Elio

    2008-03-01

    The aim of this study was to compare the effective shaping time and number of rotations required by an endodontist working with hand and rotary ProTaper instruments to completely shape simulated root canals. Eighty Endo Training Blocks (curved canal shape) were used. Manual preflaring was performed with K-Flexofiles #08-10-12-15-17 and #20 Nitiflex at a working length of 18 mm. Specimens were then randomly assigned to 2 different groups (n = 40); group 1 was shaped by using hand ProTaper and group 2 with ProTaper rotary. The number of rotations made in the canal and the effective time required to achieve complete canal shaping were recorded for each instrument. Differences between groups were analyzed with the nonparametric Mann-Whitney U test (P < .05). Hand ProTaper required significantly fewer rotations (P < .001) than rotary ProTaper, whereas the effective working time to fully shape the simulated canal was significantly higher (P < .001) with hand ProTaper.

  9. Antithrombotic Protective Effects of Arg-Pro-Gly-Pro Peptide during Emotional Stress Provoked by Forced Swimming Test in Rats.

    PubMed

    Grigor'eva, M E; Lyapina, L A

    2017-01-01

    Blood coagulation was enhanced and all factors (total, enzyme, and non-enzyme) of the fibrinolytic system were suppressed in rats in 60 min after forced swimming test. Argininecontaining tetrapeptide glyproline Arg-Pro-Gly-Pro administered prior to this test activated fibrinolysis and prevented hypercoagulation. Administration of this peptide in 5 min after swimming test also enhanced anticoagulant, fibrinolytic, and antithrombotic activity of the blood. Therefore, glyproline Arg-Pro-Gly-Pro exerted both preventive and curative effects on the hemostasis system and prevented enhancement of blood coagulation provoked by emotional stress modeled by forced swimming test.

  10. Video-based self-review: comparing Google Glass and GoPro technologies.

    PubMed

    Paro, John A M; Nazareli, Rahim; Gurjala, Anadev; Berger, Aaron; Lee, Gordon K

    2015-05-01

    Professionals in a variety of specialties use video-based review as a method of constant self-evaluation. We believe critical self-reflection will allow a surgical trainee to identify methods for improvement throughout residency and beyond. We have used 2 new popular technologies to evaluate their role in accomplishing the previously mentioned objectives. Our group investigated Google Glass and GoPro cameras. Medical students, residents, and faculty were invited to wear each of the devices during a scheduled operation. After the case, each participant was asked to comment on a number of features of the device including comfort, level of distraction/interference with operating, ease of video acquisition, and battery life. Software and hardware specifications were compiled and compared by the authors. A "proof-of-concept" was also performed using the video-conferencing abilities of Google Glass to perform a simulated flap check. The technical specifications of the 2 cameras favor GoPro over Google Glass. Glass records in 720p with 5-MP still shots, and the GoPro records in 1080p with 12-MP still shots. Our tests of battery life showed more than 2 hours of continuous video with GoPro, and less than 1 hour for Glass. Favorable features of Google Glass included comfort and relative ease of use; they could not comfortably wear loupes while operating, and would have preferred longer hands-free video recording. The GoPro was slightly more cumbersome and required a nonsterile team member to activate all pictures or video; however, loupes could be worn. Google Glass was successfully used in the hospital for a simulated flap check, with overall audio and video being transmitted--fine detail was lost, however. There are benefits and limitations to each of the devices tested. Google Glass is in its infancy and may gain a larger intraoperative role in the future. We plan to use Glass as a way for trainees to easily acquire intraoperative footage as a means to "review tape" and

  11. Structure and function of transmembrane segment XII in osmosensor and osmoprotectant transporter ProP of Escherichia coli.

    PubMed

    Liu, Feng; Culham, Doreen E; Vernikovska, Yaroslava I; Keates, Robert A B; Boggs, Joan M; Wood, Janet M

    2007-05-15

    Escherichia coli transporter ProP acts as both an osmosensor and an osmoregulator. As medium osmolality rises, ProP is activated and mediates H+-coupled uptake of osmolytes like proline. A homology model of ProP with 12-transmembrane (TM) helices and cytoplasmic termini was created, and the protein's topology was substantiated experimentally. Residues 468-497, at the end of the C-terminal domain and linked to TM XII, form an intermolecular, homodimeric alpha-helical coiled-coil that tunes the transporter's response to osmolality. We aim to further define the structure and function of ProP residues Q415-E440, predicted to include TM XII. Each residue was replaced with cysteine (Cys) in a histidine-tagged, Cys-less ProP variant (ProP*). Cys at positions 415-418 and 438-440 were most reactive with Oregon Green Maleimide (OGM), suggesting that residues 419 through 437 are in the membrane. Except for V429-I433, reactivity of those Cys varied with helical periodicity. Cys predicted to face the interior of ProP were more reactive than Cys predicted to face the lipid. The former may be exposed to hydrated polar residues in the protein interior, particularly on the periplasmic side. Intermolecular cross-links formed when ProP* variants with Cys at positions 419, 420, 422, and 439 were treated with DTME. Thus TM XII can participate, along its entire length, in the dimer interface of ProP. Cys substitution E440C rendered ProP* inactive. All other variants retained more than 30% of the proline uptake activity of ProP* at high osmolality. Most variants with Cys substitutions in the periplasmic half of TM XII activated at lower osmolalities than ProP*. Variants with Cys substitutions on one face of the cytoplasmic half of TM XII required a higher osmolality to activate. They included elements of a GXXXG motif that are predicted to form the interface of TM XII with TM VII. These studies define the position of ProP TM XII within the membrane, further support the predicted

  12. Evaluation of a PK/PBAN Analog with an (E)-Alkene, trans-Pro Isostere Identifies the Pro Orientation for Activity in Four Diverse PK/PBAN Bioassays

    DTIC Science & Technology

    2009-01-01

    member of the family, leucopyrokinin (LPK), was isolated from the cockroach Leucophaea maderae [12] with over 30members of this peptide class...myotropic bioassays The results of an evaluation of trans-Pro isosteric analog PK- Etz in the larval pupariation assay of N. bullata and isolated ...001-01R) (RJN). References [1] Abernathy RL, Nachman RJ, Teal PEA , Yamashita O, Tumlinson JH. Pheromo- notropic activity of naturally-occurring

  13. Prognostic value of N-terminal pro-brain natriuretic peptide in hospitalised patients with community-acquired pneumonia.

    PubMed

    Jeong, Ki Young; Kim, Kyuseok; Kim, Tae Yun; Lee, Christopher C; Jo, Si On; Rhee, Joong Eui; Jo, You Hwan; Suh, Gil Joon; Singer, Adam J

    2011-02-01

    The prognostic role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with community-acquired pneumonia (CAP) has not been evaluated. The aim of the present study was to investigate whether NT-proBNP level could predict mortality in hospitalised CAP patients. We performed a structured medical record review of all hospitalised CAP patients from May 2003 to October 2006, and classified patients into the 30-day survival and non-survival group. Data included demographic and clinical characteristics, and laboratory findings including NT-proBNP levels. The APACHE II scores, PSI (pneumonia severity index) and CURB65 (confusion, urea, respiratory rate, blood pressure and aged 65 or more) scores were calculated. Comparisons between survivors and non-survivors were made with χ(2), non-parametric tests and logistic regression and ROC analysis were used to compare the ability of NT-proBNP (adjusted for age, heart failure and creatinine), APACHE II, PSI and CURB65 to predict mortality. Of 502 patients, 61 (12.2%) died within 30 days. NT-proBNP levels were measured in 167 patients and were significantly higher in non-survivors compared to survivors (median 841.7 (IQR 267.1-3137.3) pg/ml vs 3658.0 (1863.0-7025.0) pg/ml, p=0.019). NT-proBNP was an independent predictor of mortality (adjusted OR 1.53; 95% CI 1.16 to 2.02, p=0.002). The AUC for NT-proBNP was 0.712 (95% CI, 0.613 to 0.812), which was comparable to those of PSI (0.749, p=0.531) and CURB65 (0.698, p=0.693), but inferior to that of APACHE II (0.831, p=0.037). Adding NT-proBNP to APACHE II, PSI and CURB65 did not significantly increase the AUCs, respectively. NT-proBNP level is an independent predictor of mortality in hospitalised CAP patients. The performance of NT-proBNP level is comparable to those of PSI and CURB65 in predicting mortality.

  14. Victimization and Exposure to Pro-Self-Harm and Pro-Suicide Websites: A Cross-National Study.

    PubMed

    Minkkinen, Jaana; Oksanen, Atte; Kaakinen, Markus; Keipi, Teo; Räsänen, Pekka

    2017-02-01

    The study of websites displaying methods of both physical self-harm and suicide has become an important aspect of deliberate self-injury and suicide research. However, little is known about contextual factors related to entering such sites. Using data from 3,567 respondents aged 15-30 in the US, UK, Germany, and Finland, we found that experiences of victimization are associated with entering pro-self-harm sites and pro-suicide sites. Also, the victimization context had relevance, as online victimization was particularly related to pro-self-harm behavior. The findings suggest a need to organize more specific online support for the victims of violence and online aggression. © 2016 The American Association of Suicidology.

  15. Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

    PubMed Central

    Galán, Maria; García-Herrero, Carmen-Maria; Azriel, Sharona; Gargallo, Manuel; Durán, Maria; Gorgojo, Juan-Jose; Andía, Victor-Manuel; Navas, Maria-Angeles

    2011-01-01

    Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype. PMID:21170474

  16. The survival of the pro-choice movement.

    PubMed

    Staggenborg, S

    1995-01-01

    In the US, the pro-choice movement has not only survived but grown stronger in the 25 years since the legalization of abortion provided its greatest victory. This longevity is explained through an examination of the internal organizational changes which have taken place in the movement as well as the external changes which have taken place in the political environment surrounding the movement. After providing a theoretical basis for this investigation, the history of the pro-choice movement in the US is traced in light of these elements. In the pre-1973 era, the movement lacked formal organization but was bolstered by external political factors provided by the protest cycle of the 1960s. During 1973-76, the actions of anti-abortion groups forced pro-choice groups to develop the more formalized organizational structures which helped the pro-choice movement survive its initial success and the decline of the era of protests. In the period 1976-83, the anti-abortion movement achieved passage of the Hyde Amendment banning federal funding of abortions. This victory by the opposition led to an expansion in the pro-choice movement which included the formation of many local reproductive rights organizations. Many of these organizations failed to create formalized structures and, therefore, failed to maintain their impetus to survive. However, NARAL (the National Association for Repeal of Abortion Laws) had adopted a more formalized structure and professional leadership following the Hyde legislation and developed strong, formal connections with its state affiliates while continuing to strengthen grassroots actions. The visible threats to abortion laws mounted by the anti-abortion groups added to NARAL's strength. During 1983-89, the pro-choice movement gained some key victories which threatened its survival. Continued activity on the part of the anti-abortion groups (such as release of the movie "The Silent Scream") generated enough pro-choice support, however, to weather

  17. A rapid and cost-effective method of producing recombinant proBNP and NT-proBNP variants in Escherichia coli for immunoassay of heart failure.

    PubMed

    Soleh, Muhammad Tarmizi; Foo, Jared Yong Yang; Bailey, Ulla-Maja; Tan, Nikki Yi; Wan, Yunxia; Cooper-White, Justin; Schulz, Benjamin Luke; Punyadeera, Chamindie

    2014-01-01

    The measurements of plasma natriuretic peptides (NT-proBNP, proBNP and BNP) are used to diagnose heart failure but these are expensive to produce. We describe a rapid, cheap and facile production of proteins for immunoassays of heart failure. DNA encoding N-terminally His-tagged NT-proBNP and proBNP were cloned into the pJexpress404 vector. ProBNP and NT-proBNP peptides were expressed in Escherichia coli, purified and refolded in vitro. The analytical performance of these peptides were comparable with commercial analytes (NT-proBNP EC50 for the recombinant is 2.6 ng/ml and for the commercial material is 5.3 ng/ml) and the EC50 for recombinant and commercial proBNP, are 3.6 and 5.7 ng/ml respectively). Total yield of purified refolded NT-proBNP peptide was 1.75 mg/l and proBNP was 0.088 mg/l. This approach may also be useful in expressing other protein analytes for immunoassay applications. To develop a cost effective protein expression method in E. coli to obtain high yields of NT-proBNP (1.75 mg/l) and proBNP (0.088 mg/l) peptides for immunoassay use.

  18. The presentation of "pro-anorexia" in online group interactions.

    PubMed

    Gavin, Jeff; Rodham, Karen; Poyer, Helen

    2008-03-01

    Although pro-anorexia online support forums and the narratives that occur within them are increasingly the focus of research, none, to date, focuses closely on issues of identity within this online context. Our aim in conducting this study was to examine the presentation of pro-anorexia via an interpretive phenomenological analysis of postings to a pro-anorexia ("pro-ana") online discussion forum. Analysis indicates that pro-anorexic identities are normalized and strengthened through the normalization of participants' pro-ana thoughts and behaviors, and the group bond created through sharing a secret identity. This process renders participants less likely to reveal their pro-ana identity to friends and family in the real world. The implications of our findings are discussed in relation to the theory of identity demarginalization.

  19. Purification and characterization of galanin and scyliorhinin I from the hybrid sturgeon, Scaphirhynchus platorynchus x Scaphirhynchus albus (Acipenseriformes).

    PubMed

    Wang, Y; Barton, B A; Thim, L; Nielsen, P F; Conlon, J M

    1999-01-01

    The sturgeons (order Acipenseriformes) are extant representatives of a group of ancient Actinopterygian (ray-finned) fish. Galanin and scyliorhinin I (a tachykinin with limited structural similarity to mammalian substance P) have been isolated from an extract of the gastrointestinal tract of a sturgeon (an F1 hybrid between the shovelnose sturgeon, Scaphirhynchus platorynchus, and the pallid sturgeon, Scaphirhynchus albus). The primary structure of sturgeon galanin (Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu10-Leu-Gly-Pro-His-Ala-Val -As p-Gly-His-Arg20-Ser-Leu-Ser-Asp-Lys-His-Gly-Leu-Pro.NH2) contains only two amino acid substitutions (Ser23 --> Asn and Pro29 --> Ala) compared with galanin from the bowfin, Amia calva (Amiiformes), but five amino acid substitutions compared with galanin from the trout (Teleostei). Similarly, the sturgeon tachykinin (Ser-Lys-Tyr-His-Gln-Phe-Tyr-Gly-Leu-Met.NH2) contains only one amino acid substitution (Tyr3 --> Ser) compared with scyliorhinin I previously isolated from bowfin stomach but five amino acid substitutions compared with trout substance P. The data support the hypothesis that the Acipenseriformes and the basal Neopterygians (gars and bowfin) share a close phylogenetic relationship. Copyright 1999 Academic Press.

  20. No effect of group-based aerobic interval training on N-terminal pro- B-type natriuretic peptide levels in patients with chronic heart failure.

    PubMed

    Nilsson, Birgitta Blakstad; Westheim, Arne; Risberg, May Arna; Arnesen, Harald; Seljeflot, Ingebjørg

    2010-08-01

    Exercise training might improve cardiac function as well as functional capacity in patients with chronic heart failure (CHF). N-terminal pro-B-type natriuretic peptide (NT pro-BNP), is associated with the severity of the disease, and has been reported to be an independent predictor of outcome in CHF. We evaluated the effect of a four months group-based aerobic interval training program on circulating levels of NT pro-BNP in patients with CHF. We have previously reported improved functional capacity in 80 patients after exercise in this exercise program. Seventy-eight patients with stable CHF (21% women; 70+/-8 years; left ventricular ejection fraction 30+/-8.6%) on optimal medical treatment were randomized either to interval training (n=39), or to a control group (n=39). Circulating levels of NT pro-BNP, a six minute walk test (6MWT) and cycle ergometer test were evaluated at baseline, post exercise, and further after 12 months. There were no significant differences in NT pro-BNP levels from baseline to either post exercise or long-term follow-up between or within the groups. Inverse correlations were observed between NT pro-BNP and 6MWT (r=-0.24, p=0.035) and cycle exercise time (r=-0.48, p<0.001) at baseline. But no significant correlations were observed between change in NT pro-BNP and change in functional capacity (6MWT; r=0.12, p=0.33, cycle exercise time; r=0.04, p=0.72). No significant changes in NT pro-BNP levels were observed after interval training, despite significant improvement of functional capacity.

  1. The Role of mDia1 in the Aberrant Innate Immune Signaling in del(5q) Myelodysplastic Syndromes

    DTIC Science & Technology

    2017-10-01

    especially in cells with sensitized innate immune signaling8,9,20. To analyze whether treatment of DAMPs could induce the over-production of pro...AWARD NUMBER: W81XWH-15-1-0335 TITLE: The Role of mDia1 in the Aberrant Innate Immune Signaling in del(5q) Myelodysplastic Syndromes...TITLE AND SUBTITLE 5a. CONTRACT NUMBER WThe Role of mDia1 in the Aberrant Innate Immune Signaling in del(5q) Myelodysplastic Syndromes 5b. GRANT

  2. THz emission of donor and acceptor doped GaAs/AlGaAs quantum well structures with inserted thin AlAs monolayer

    NASA Astrophysics Data System (ADS)

    van Dommelen, Paphavee; Daengngam, Chalongrat; Kalasuwan, Pruet

    2018-04-01

    In this paper, we explore THz range optical intersubband transition energies in a donor doped quantum well of a GaAs/AlGaAs system as a function of the insertion position of an AlAs monolayer in the GaAs quantum well. In simulated models, the optical transition energies between electron subband levels 1 and 2 were higher in the doped structure than in the undoped structure. This may be because the envelope wave function of the second electron subband strongly overlapped the envelope wave function of the first electron subband and influenced the optical intersubband transition between the two levels in the THz range. At different levels of bias voltage at the Schottky barrier on the donor doped structure, the electric field in the growth direction of the structure linearly increased the further away the AlAs monolayer was placed from the reference position. We also simulated the optical transition energies between acceptor energy levels of the acceptor doped structure as a function of the insertion position of the AlAs monolayer. The acceptor doped structure induced THz range emission whereas the undoped structure induced mid-IR emission.

  3. Technology evaluation: PRO-542, Progenics Pharmaceuticals inc.

    PubMed

    Mukhtar, M; Parveen, Z; Pomerantz, R J

    2000-12-01

    Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the Aaron Diamond AIDS Research Center (ADARC) in New York and the Center for Disease Control and Prevention in Atlanta [178410]. In February 2000, Progenics and Genzyme Transgenics Corp signed an agreement to continue the development of a transgenic source of PRO-542. Genzyme will develop transgenic goats that produce PRO-542 in their milk in exchange for undisclosed fees and milestone payments. Genzyme will supply PRO-542 to Progenics for clinical trials with a possibility for eventual commercial supply [357291]. Following on from this, in October 2000, Progenics received an SBIR grant to fund a two-year project with Genzyme Transgenics into the development of cost-effective methods for the manufacture of PRO-542, by optimization of the production of the drug in the milk of transgenic dairy animals [385982]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of PRO-542 and GMK (Progenics Pharmaceuticals) in 2002 [390063].

  4. Inducing Behavioral Change in Seekers of Pro-Anorexia Content Using Internet Advertisements: Randomized Controlled Trial.

    PubMed

    Yom-Tov, Elad; Brunstein-Klomek, Anat; Mandel, Or; Hadas, Arie; Fennig, Silvana

    2018-02-22

    The influence of pro-anorexia (pro-ana) websites is debated, with studies indicating both negative and positive effects, as well as significant variation in the effects of different websites for those suffering from eating disorders (EDs) and the general population. Online advertising, known to induce behavioral change both online and in the physical world, has not been used so far to modify the search behavior of people seeking pro-ana content. The objective of this randomized controlled trial (RCT) was to examine if online advertisements (ads) can change online search behaviors of users who are looking for online pro-ana content. Using the Bing Ads system, we conducted an RCT to randomly expose the searchers for pro-ana content to 10 different ads referring people to one of the three websites: the National Eating Disorders Association, the National Institutes of Mental Health, and MyProAna. MyProAna is a pro-ana website that was found in a previous study to be associated with less pathological online behaviors than other pro-ana websites. We followed participants exposed and unexposed to the ads to explore their past and future online searches. The ads were shown 25,554 times and clicked on 217 times. Exposure to the ads was associated with a decrease in searches for pro-ana and self-harm content. Reductions were greatest among those referred to MyProAna (reduction of 34.0% [73/215] and 37.2% [80/215] for pro-ana and self-harm, respectively) compared with users who were referred elsewhere (reduction of 15.47% [410/2650] and 3.21% [85/2650], respectively), and with users who were not shown the ads, who increased their behaviors (increase of 57.12% [6462/11,314] and 4.07% [461/11,314], respectively). In addition, those referred to MyProAna increased their search for treatment, as did control users, who did so to a lesser extent. However, users referred elsewhere decreased their searches for this content. We found that referring users interested in ED

  5. Developmental changes in shortening of pro-saccade reaction time while maintaining neck flexion position.

    PubMed

    Kunita, Kenji; Fujiwara, Katsuo; Kiyota, Naoe; Yaguchi, Chie; Kiyota, Takeo

    2018-01-10

    We investigated developmental changes in shortening of pro-saccade reaction time while maintaining neck flexion. Subjects comprised 135 children (3-14 years) and 29 young adults (19-23 years). Children were divided into six groups in 2-year age strata. Pro-saccade reaction tasks for 30 s were performed in neck rest and flexion positions. Reaction times under each position were averaged in every 10-s period. Under neck rest position, reaction time in the 0-10 s period was significantly longer in the 3- to 4-year-old group than in the 5- to 6-year-old group and above. No significant age effect was found for reaction time in the 0-10 s period in the 5- to 6-year-old group and above. Although a significant effect of neck flexion was not observed until the 9- to 10-year-old group, significant shortening of reaction time with neck flexion was found in the 11- to 12-year-old group and above. Furthermore, this shortening was maintained until the first 20-s period in the 11- to 12-year-old group and during the entire 30 s in the 13- to 14-year-old and above. These results suggest that brain activation with the maintenance of neck flexion, related to shortening of the pro-saccade reaction time, was found from a later age of approximately 11 years and above, compared with the age at which information-processing function in the pro-saccade was enhanced. In addition, brain activation with the maintenance of neck flexion was sustained longer with age.

  6. Elevated NT-proBNP is associated with unfavorably altered plasma fibrin clot properties in atrial fibrillation.

    PubMed

    Matusik, Paweł T; Matusik, Patrycja S; Kornacewicz-Jach, Zdzisława; Małecka, Barbara; Ząbek, Andrzej; Undas, Anetta

    2017-09-15

    Dense fibrin clot formation and hypofibrinolysis have been reported in atrial fibrillation (AF). It is unclear which factors affect fibrin clot properties in AF. We investigated plasma fibrin clot permeability (K s ), clot lysis time (CLT), endogenous thrombin potential (ETP) as well as other coagulation and fibrinolysis parameters along with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in 160 AF patients (median age, 70.5years). Previous stroke (n=15; 9.4%) was associated with decreased K s (P=0.04) and longer CLT (P=0.005), together with higher antiplasmin (P=0.03) and lower tissue-type plasminogen activator (P=0.01). Lower K s (P=0.04) and tendency towards longer CLT (P=0.10) were observed in patients with a left atrium diameter>40mm. Patients with a CHA 2 DS 2 -VASc score of 3 or more (82.5%) were characterized by higher thrombin-activatable fibrinolysis inhibitor antigen (P=0.009). K s was inversely correlated with log NT-proBNP (r=-0.34, P<0.0001), plasminogen activator inhibitor-1 (PAI-1) antigen (r=-0.24, P=0.002) and C-reactive protein (r=-0.18, P=0.02), while CLT was positively correlated with log NT-proBNP (R=0.61, P<0.0001) and ETP (r=0.37, P<0.0001), which were interrelated (r=0.59, P<0.0001). After adjustment for potential confounders, PAI-1 (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.02-1.26) was the only independent predictor of low K s (the lowest quartile,≤6×10 -9 cm 2 ), while NT-proBNP (OR: 1.21; 95% CI: 1.12-1.31) and PAI-1 (OR: 1.30; 95% CI: 1.12-1.51) both predicted prolonged CLT (the top quartile,≥109min). In AF patients prothrombotic fibrin clot properties assessed ex vivo are determined by PAI-1 and NT-proBNP and this phenotype is associated with prior ischemic stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Effect of 6-min Walk Test on pro-BNP Levels in Patients with Pulmonary Arterial Hypertension.

    PubMed

    Pathak, Vikas; Aris, Robert; Jensen, Brian C; Huang, Wei; Ford, Hubert James

    2018-06-01

    Plasma pro-BNP (brain natriuretic peptide) levels are often elevated in response to right ventricular (RV) volume and pressure overload, parameters potentially affected by exercise. Plasma pro-BNP levels change in association with long-term changes in pulmonary hemodynamics, thereby serving as a potential biomarker in pulmonary arterial hypertension (PAH). The 6-min Walk Test (6MWT) and pro-BNP level are often checked in a single office visit. There is no universal standard for measuring Pro-BNP levels relative to the timing of the 6MWT. Based on the studies in normal subjects indicating that pro-BNP levels changes after exercise, we hypothesized that the pro-BNP might rise after the 6MWT in PAH patients, potentially impacting clinical decisions. Patients at our center with WHO Group 1 PAH on active therapy at a stable dose for 30 days or more were enrolled. After resting the patient for 30 min, blood was drawn for baseline pro-BNP and a 6MWT was performed. Pro-BNP levels were drawn immediately after the 6MWT and 1 and 2 h later. Pro-BNP was measured using a commercially available ELISA kit. The levels before exercise and after exercise were compared using student's paired t tests. There were 17 females and 3 male subjects. The mean age was 53 ± 11 years. Seven patients had systemic lupus erythematosus-related PAH, six had idiopathic PAH, three had scleroderma, three had portopulmonary hypertension, and one had HIV-related PAH. The mean PA pressure was 50 ± 15 mmHg with a mean pulmonary vascular resistance of 10 ± 4 Wood units. The majority of the patients were on multimodality PAH therapy, including parenteral prostacyclins. Mean 6MWT distance was 377 ± 140 m. In 14/20 patients, the pro-BNP level increased immediately after the 6MWT; in 12/20 patients, the pro-BNP level was elevated at 1 h post exercise. In the majority of the patients, the pro-BNP fell to baseline 2 h post 6MWT. There appears to be a trend of pro-BNP level increasing

  8. Stability of pro-gastrin-releasing peptide in serum versus plasma.

    PubMed

    Yoshimura, Toru; Fujita, Kenju; Kawakami, Satoshi; Takeda, Katsumichi; Chan, Sabrina; Beligere, Gangamani; Dowell, Barry

    2008-01-01

    Although serum assays for pro-gastrin-releasing peptide (ProGRP) assays have been commercially available in Japan for several years, the stability of ProGRP in serum and plasma has not been well documented. We investigated the stability of ProGRP in serum and plasma with fresh and stored (frozen) specimens, as well as the cause of the observed instability in serum. ProGRP concentrations in fresh serum were decreased by 6-28% after room temperature storage for 2 h and by 8-32% after 2-8 degrees C storage for 24 h. The average change in ProGRP concentrations in fresh plasma was within +/-10% of baseline for more than 4 h at room temperature and for more than 24 h at 2-8 degrees C. The incubation of a serine protease, thrombin (activated blood coagulation factor II), in a buffer solution containing ProGRP caused decreases in ProGRP concentrations. Following the addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to serum, the serum stability for ProGRP was similar to that in plasma. ProGRP is significantly more stable in plasma than in serum. We speculate that thrombin in serum is one of the factors that inactivate ProGRP in serum by proteolysis of the ProGRP antigen. The use of plasma samples for ProGRP may improve the clinical reliability of this marker by minimizing preanalytical changes in ProGRP concentrations. (c) 2008 S. Karger AG, Basel.

  9. Hot topic: Changes in angiotensin-converting enzyme inhibition and concentrations of the tripeptides Val-Pro-Pro and Ile-Pro-Pro during ripening of different Swiss cheese varieties.

    PubMed

    Meyer, J; Bütikofer, U; Walther, B; Wechsler, D; Sieber, R

    2009-03-01

    The angiotensin-converting enzyme (ACE) inhibitory activity and the concentration of the 2 ACE-inhibiting tripeptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) were studied during cheese ripening in 7 Swiss cheese varieties. The semi-hard cheeses Tilsiter, Appenzeller 1/4 fat, Tête de Moine, and Vacherin fribourgeois and the extra-hard and hard cheeses Berner Hobelkäse, Le Gruyère, and Emmentaler were investigated. Three loaves of each variety manufactured in different cheese factories were purchased at the beginning of commercial ripeness and investigated at constant intervals until the end of the usual sale period. Good agreement was found between ACE-inhibitory activity and the total concentration of VPP and IPP at advanced ripening stages. In most of the investigated varieties ACE-inhibitory activity and the concentration of the 2 tripeptides initially increased during the study period. A decline in the concentration of VPP and IPP was obtained toward the end of the investigated period for Tilsiter and Gruyère. The ratio of VPP/IPP decreased during ripening in all varieties with the exception of Emmentaler. However, large variations were observed among the cheese varieties as well as the individual loaves of the same variety. Chemical characterization of the investigated cheeses revealed that qualitative differences in the proteolysis pattern, not quantitative differences in the degree of proteolysis, are responsible for the observed variations in the concentrations of VPP and IPP. The presence of Lactobacillus helveticus in the starter culture was associated with elevated concentrations of VPP and IPP. The results of the present study show that concentrations of VPP and IPP above 100 mg/kg are attainable in semi-hard cheese varieties after ripening periods of about 4 to 7 mo and that stable concentrations of the 2 antihypertensive tripeptides can be expected over several weeks of cheese ripening.

  10. Up-regulation of Rho-associated kinase 1/2 by glucocorticoids promotes migration, invasion and metastasis of melanoma.

    PubMed

    Huang, Gao-Xiang; Wang, Yan; Su, Jie; Zhou, Peng; Li, Bo; Yin, Li-Juan; Lu, Jian

    2017-12-01

    Although glucocorticoids (GCs) regulate proliferation, differentiation and apoptosis of tumor cells, their influence on metastasis of tumor cells is poorly understood. Melanoma is a type of skin cancers with high metastasis. We investigated the effect of GCs on metastasis of melanoma cells and its mechanism. We found that GCs significantly promoted the adhesion, migration, invasion of melanoma cells in vitro and lung metastasis in experimental melanoma metastasis mice. Dexamethasone (Dex), a synthetic GC, did not change the RhoA, RhoB and RhoC signalings, but significantly increased the expression and activity of Rho-associated kinase 1/2 (ROCK1/2). The effect of Dex was to increase ROCK1/2 stability mediated by glucocorticoid receptor. Inhibiting ROCK1/2 activity with Y-27632, a ROCK1/2 inhibitor abrogated the pro-migration and pro-metastasis effects of GCs in vitro and in vivo, indicating that ROCK1/2 mediated the pro-metastasis effects of GCs. Activation of PI3K/AKT also contributed to the pro-migration and pro-invasion effects of Dex partially through up-regulating ROCK1/2 expression. Additionally, Dex also down-regulated the expression of tissue inhibitors of matrix metalloproteinase-2. Taken together, our findings provide new data to understand the possible promoting roles and mechanisms of GCs in melanoma metastasis. Copyright © 2017. Published by Elsevier B.V.

  11. Possible Release of an ArgGlyArgProGln Pentapeptide with Innate Immunity Properties from Acidic Proline-Rich Proteins by Proteolytic Activity in Commensal Streptococcus and Actinomyces Species

    PubMed Central

    Li, Tong; Bratt, Per; Jonsson, Andreas P.; Ryberg, Mats; Johansson, Ingegerd; Griffiths, William J.; Bergman, Tomas; Strömberg, Nicklas

    2000-01-01

    This study suggests degradation of salivary acidic proline-rich proteins (PRPs) into potential innate-immunity-like peptides by oral Streptococcus and Actinomyces species. PRP degradation paralleled cleavage of Pro-containing substrates. PRP degradation by S. gordonii strain SK12 instantly released a Pyr1-Pro104Pro105 and a Gly111-Pro149Gln150 peptide together with a presumed Arg106Gly107Arg108Pro109Gln110 pentapeptide. The synthetic Arg106Gly107Arg108Pro109Gln110 peptide desorbed bound bacteria and counteracted sucrose-induced decrease of dental plaque pH in vitro. PMID:10948176

  12. The effects of viewing pro-eating disorder websites: a systematic review.

    PubMed

    Talbot, T Sloper

    2010-12-01

    To determine health-related effects of viewing pro-eating disorder (Pro-ED) websites. A systematic review was carried out addressing: 1. The effect of viewing pro-ED websites on eating disorder behaviour 2. The effect of viewing pro-ED websites on viewers' negative and positive affect. Seven studies were included. Pro-ED viewers compared with controls showed higher levels of dieting and exercise (3 studies, 2 suggesting causation); higher levels of drive for thinness, body dissatisfaction and perfectionism (2 studies, both associative); a reduced likelihood of binging/purging (one study); increased negative affect (two studies); and a positive correlation between viewing pro-ED websites, disease duration and hospitalisations (one study). Viewing pro-ED websites may increase eating disorder behaviour but might not cause it. It may cause increased negative affect after a single short website exposure. For those with eating disorders, viewing is positively correlated with disease duration and hospitalisations. Professionals should be aware of these sites and their potential damage for health.

  13. Structure and activation of pro-activin A

    PubMed Central

    Wang, Xuelu; Fischer, Gerhard; Hyvönen, Marko

    2016-01-01

    Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain. The complex remains associated in conditions used for biochemical analysis with a dissociation constant of 5 nM, but the pro-domain can be actively displaced from the complex by follistatin. Our high-resolution structures of pro-activin A share features seen in the pro-TGF-β1 and pro-BMP-9 structures, but reveal a new oligomeric arrangement, with a domain-swapped, cross-armed conformation for the protomers in the dimeric protein. PMID:27373274

  14. Can venous ProBNP levels predict placenta accreta?

    PubMed

    Ersoy, Ali Ozgur; Oztas, Efser; Ozler, Sibel; Ersoy, Ebru; Erkenekli, Kudret; Uygur, Dilek; Caglar, Ali Turhan; Danisman, Nuri

    2016-12-01

    Placenta previa (PP) is a potential life-threatening pregnancy complication. Pro-brain natriuretic peptide (ProBNP), creatine kinase (CK), cardiac form of CK (CK-MB) and Troponin I are circulatory biomarkers related to cardiac functions. We aimed to determine whether these biomarkers are related to PP and placenta accreta. In this case-control study, fifty-four pregnant women who attended our tertiary care center for perinatology with the diagnosis of PP totalis, and of them, 14 patients with placenta accreta were recruited as the study groups. Forty-six uncomplicated control patients who were matched for age, BMI were also included. Maternal venous ProBNP, CK, CK-MB and Troponin I levels were compared between the three groups. Obstetric history characteristics were comparable among groups, generally. CK and CK-MB levels were similar among three groups. Troponin I levels in the previa and accreta groups were significantly higher than the controls. ProBNP levels in the accreta group were significantly higher than other two groups. The multivariate regression model revealed that ProBNP could predict placental adhesion anomalies. Troponin I and ProBNP levels in PP cases were higher than controls and ProBNP could predict placenta accreta.

  15. Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients.

    PubMed

    Gelhorn, Heather L; Skalicky, Anne M; Balantac, Zaneta; Eremenco, Sonya; Cimms, Tricia; Halling, Katarina; Hollen, Patricia J; Gralla, Richard J; Mahoney, Martin C; Sexton, Chris

    2018-07-01

    Obtaining qualitative data directly from the patient perspective enhances the content validity of patient-reported outcome (PRO) instruments. The objective of this qualitative study was to evaluate the content validity of the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) and its usability on an electronic device. A cross-sectional methodological study, using a qualitative approach, was conducted among patients recruited from four clinical sites. The primary target population included patients with pleural mesothelioma; data were also collected from patients with peritoneal mesothelioma on an exploratory basis. Semi-structured interviews were conducted consisting of concept elicitation, cognitive interviewing, and evaluation of electronic patient-reported outcome (ePRO) usability. Participants (n = 21) were interviewed in person (n = 9) or by telephone (n = 12); 71% were male with a mean age of 69 years (SD = 14). The most common signs and symptoms experienced by participants with pleural mesothelioma (n = 18) were shortness of breath, fluid build-up, pain, fatigue, coughing, and appetite loss. The most commonly described symptoms for those with peritoneal mesothelioma (n = 4) were bloating, changes in appetite, fatigue, fluid build-up, shortness of breath, and pain. Participants with pleural mesothelioma commonly described symptoms assessed by the LCSS-Meso in language consistent with the questionnaire and a majority understood and easily completed each of the items. The ePRO version was easy to use, and there was no evidence that the electronic formatting changed the way participants responded to the questions. Results support the content validity of the LCSS-Meso and the usability of the electronic format for use in assessing symptoms among patients with pleural mesothelioma.

  16. Comparison of Abbott AxSYM and Roche Elecsys 2010 for measurement of BNP and NT-proBNP.

    PubMed

    Chien, Tzu-I; Chen, Hui-Hou; Kao, Jau-Tsuen

    2006-07-15

    B-type natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are small cardiac hormones released from the heart. They can be used as an important aid to diagnose congestive heart failure (CHF). We compared the performances of the Abbott AxSYM and Roche Elecsys 2010 for the measurement of BNP and NT-proBNP. The first method uses a microparticle enzyme-linked immunoassay, whereas the other uses chemiluminescent immunometric assay. The CVs using pooled sera ranged from 3.7% to 12.7% for the AxSYM and 0.9% to 2.2% for the Elecsys 2010. The Passing and Bablok regression was Elecsys 2010 NT-proBNP=7.23xAxSYM BNP+2.53. The BNP in EDTA plasma was more stable than in serum. The immunoreactivity difference of NT-proBNP in serum or EDTA plasma was within 10% when stored at 4 degrees Celsius or 25 degrees Celsius for 72 h. Receiver operating characteristic (ROC) curves were different for both assays, and the areas under the curves were 0.704 and 0.841 for the AxSYM and Elecsys 2010 method, respectively. Both assays were not entirely specific for heart failure. The precision and stability for NT-proBNP was better than for BNP in serum. It is important to use method-appropriate reference ranges (or cutoff) for the BNP and NT-proBNP, respectively, in the assessment of CHF.

  17. Integrated Programs and Pro-Environmental Behaviour

    ERIC Educational Resources Information Center

    Smith, Tiffany

    2008-01-01

    Research suggested that "nature experience as an education method played a role in developing environmental value and attitudes, and was influential in pro-environmental behaviour." Few of these studies however, assessed the long-term influences of outdoor education experiences on participants' pro-environmental behaviour. The Outward…

  18. ProUCL version 4.00.04 Documentation Downloads

    EPA Pesticide Factsheets

    ProUCL Version 4.00.04 is an upgrade of ProUCL Version 4.0 (EPA, 2007). ProUCL 4.00.02 contains statistical methods to address various environmental issues for both full data sets without nondetects and for data sets with NDs (also known as left-censored d

  19. Pro-sociality and strategic reasoning in economic decisions

    PubMed Central

    Arruñada, Benito; Casari, Marco; Pancotto, Francesca

    2015-01-01

    We study the relationship between pro-social preferences and strategic reasoning. These aspects are typically studied separately but little is known about their joint distribution. In an experiment, for each participant we elicit individual concerns toward pro-sociality—inequality aversion and efficiency—as well as the number of steps of reasoning through a guessing game. We report that self-regarding and pro-social participants exhibit similar levels of strategic reasoning, which supports the view that pro-sociality and strategic reasoning can be studied independently. PMID:26074799

  20. NT-proBNP concentrations in mountain marathoners.

    PubMed

    Banfi, Giuseppe; Lippi, Giuseppe; Susta, Daniele; Barassi, Alessandra; D'Eril, Gianvico Melzi; Dogliotti, Giada; Corsi, Massimiliano M

    2010-05-01

    The 76 amino acid N-terminal proB-type natriuretic peptide (NT-proBNP) is proposed for evaluating and monitoring heart pathologies characterized by myocardial wall stress. Strenuous exercise might generate transitory ischemia, myocardial stress, and diastolic left ventricular dysfunction, possibly inducing an increase of some biochemical parameter concentrations. An alert has been claimed owing to biochemical and instrumental signs of heart dysfunction in recreational athletes during marathon races. We studied the behaviour of NT-proBNP in 15 mountain marathoners before and after a race. The concentrations of the parameter were lower than that observed in controls at rest and were similar to that observed in professional soccer and rugby players. The concentrations significantly increased after the race. NT-proBNP is low at rest in professional athletes, and the increase after physical exercise is physiological. The marathoners, even when performing races in a high-altitude environment, show NT-proBNP concentrations similar to those of athletes from other sports disciplines, characterized by low levels of effort and by a mix of aerobic and anaerobic metabolism. The increase of NT-proBNP is linked to strenuous physical exercise and to heavy heart effort, testified also by an increase of troponin I. However, the role of the NT-proBNP could be important to screen recreational and professional marathoners to avoid possible heart problems and sudden cardiac death in subjects with occult heart disease. The results of the present study are relevant to the design and evaluation of training programs for improving strength and function of professional marathoners.

  1. Proline residues in transmembrane segment IV are critical for activity, expression and targeting of the Na+/H+ exchanger isoform 1.

    PubMed Central

    Slepkov, Emily R; Chow, Signy; Lemieux, M Joanne; Fliegel, Larry

    2004-01-01

    NHE1 (Na+/H+ exchanger isoform 1) is a ubiquitously expressed integral membrane protein that regulates intracellular pH in mammalian cells. Proline residues within transmembrane segments have unusual properties, acting as helix breakers and increasing flexibility of membrane segments, since they lack an amide hydrogen. We examined the importance of three conserved proline residues in TM IV (transmembrane segment IV) of NHE1. Pro167 and Pro168 were mutated to Gly, Ala or Cys, and Pro178 was mutated to Ala. Pro168 and Pro178 mutant proteins were expressed at levels similar to wild-type NHE1 and were targeted to the plasma membrane. However, the mutants P167G (Pro167-->Gly), P167A and P167C were expressed at lower levels compared with wild-type NHE1, and a significant portion of P167G and P167C were retained intracellularly, possibly indicating induced changes in the structure of TM IV. P167G, P167C, P168A and P168C mutations abolished NHE activity, and P167A and P168G mutations caused markedly decreased activity. In contrast, the activity of the P178A mutant was not significantly different from that of wild-type NHE1. The results indicate that both Pro167 and Pro168 in TM IV of NHE1 are required for normal NHE activity. In addition, mutation of Pro167 affects the expression and membrane targeting of the exchanger. Thus both Pro167 and Pro168 are strictly required for NHE function and may play critical roles in the structure of TM IV of the NHE. PMID:14680478

  2. 48 CFR 352.237-70 - Pro-Children Act.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Pro-Children Act. 352.237...-Children Act. As prescribed in 337.103-70(a), the Contracting Officer shall insert the following clause: Pro-Children Act (January 2006) (a) Public Law 103-227, Title X, Part C, also known as the Pro...

  3. 48 CFR 352.237-70 - Pro-Children Act.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Pro-Children Act. 352.237...-Children Act. As prescribed in 337.103-70(a), the Contracting Officer shall insert the following clause: Pro-Children Act (January 2006) (a) Public Law 103-227, Title X, Part C, also known as the Pro...

  4. 48 CFR 352.237-70 - Pro-Children Act.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Pro-Children Act. 352.237...-Children Act. As prescribed in 337.103-70(a), the Contracting Officer shall insert the following clause: Pro-Children Act (January 2006) (a) Public Law 103-227, Title X, Part C, also known as the Pro...

  5. 48 CFR 352.237-70 - Pro-Children Act.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Pro-Children Act. 352.237...-Children Act. As prescribed in 337.103-70(a), the Contracting Officer shall insert the following clause: Pro-Children Act (January 2006) (a) Public Law 103-227, Title X, Part C, also known as the Pro...

  6. 48 CFR 352.237-70 - Pro-Children Act.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Pro-Children Act. 352.237...-Children Act. As prescribed in 337.103-70(a), the Contracting Officer shall insert the following clause: Pro-Children Act (January 2006) (a) Public Law 103-227, Title X, Part C, also known as the Pro...

  7. Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.

    PubMed

    Donaldson, Scott H; Pilewski, Joseph M; Griese, Matthias; Cooke, Jon; Viswanathan, Lakshmi; Tullis, Elizabeth; Davies, Jane C; Lekstrom-Himes, Julie A; Wang, Linda T

    2018-01-15

    Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV 1 (ppFEV 1 ) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV 1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV 1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

  8. Photodynamic Therapy (PDT) using intratumoral injection of the 5- aminolevulinic acid (5-ALA) for the treatment of eye cancer in cattle

    NASA Astrophysics Data System (ADS)

    Hage, Raduan; Mancilha, Geraldo; Zângaro, Renato A.; Munin, Egberto; Plapler, Hélio

    2007-02-01

    A six-year old Holstein cow with an eye cancer (ocular squamous cell carcinoma) involving the third eyelid and conjunctiva was submitted to photodynamic therapy using intratumoral 20% aminolevulinic acid (5-ALA - Aldrich Chemical Company, Milwaukee, USA) and a light emitting diode (LED - VET LED - MMOptics (R)) with wavelength between 600 and 700 nm, 2 cm diameter circular light beam, power of 150 mW, light dose of 50 J/cm2 as a source of irradiation. Fifteen days after the experimental procedure we observed about 50% tumor reduction and complete remission after 3 months. Relapse was not observed up to 12 months after the treatment. Although the study only includes one animal not allowing definite conclusions, it indicates that PDT represents a safe and technically feasible approach in the treatment of eye cancer in cattle.

  9. Early trends in N-terminal pro-brain natriuretic peptide values after left ventricular assist device implantation for chronic heart failure.

    PubMed

    Hasin, Tal; Kushwaha, Sudhir S; Lesnick, Timothy G; Kremers, Walter; Boilson, Barry A; Schirger, John A; Clavell, Alfredo L; Rodeheffer, Richard J; Frantz, Robert P; Edwards, Brooks S; Pereira, Naveen L; Stulak, John M; Joyce, Lyle; Daly, Richard; Park, Soon J; Jaffe, Allan S

    2014-10-15

    Left ventricular assist devices (LVADs) acutely decrease left ventricular wall stress. Thus, early postoperative levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) should decrease. This study investigated postoperative changes in NT-proBNP levels, the parameters related to changes, and the possible association with complications by performing a retrospective analysis of changes in daily NT-proBNP (pg/ml) levels from admission to discharge both before and after LVAD implantation in a tertiary referral center. For 72 patients implanted with HeartMate II LVADs, baseline NT-proBNP levels were elevated at 3,943 ng/ml (interquartile range 1,956 to 12,964). Preoperative stabilization led to marked decreases in NT-proBNP. Levels peaked 3 days after surgery and subsequently decreased. Patients with complicated postoperative courses had higher early postoperative elevations. By discharge, NT-proBNP decreased markedly but was still 2.83 (1.60 to 5.76) times the age-based upper limit of normal. The 26% reduction in NT-proBNP between admission and discharge was due mostly to the preoperative reductions and not those induced by the LVAD itself. The decrease was not associated with decreases in LV volume. In conclusion, preoperative treatment reduces NT-proBNP values. The magnitude of early postoperative changes is related to the clinical course. Levels at discharge remain markedly elevated and similar to values after preoperative stabilization despite presumptive acute LV unloading. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Relationship between the occlusal plane corresponding to the lateral borders of the tongue and ala-tragus line in edentulous patients.

    PubMed

    Ghosn, Carole Abi; Zogheib, Carla; Makzoumé, Joseph E

    2012-09-01

    Definitions of the ala-tragus line (ATL) cause confusion, because the exact points of reference for this line do not agree. This study determined the relationship between the prosthetic occlusal plane (OP) corresponding to the lateral borders of the tongue and ATL which was established by using the inferior border of the ala of the nose and (1) the superior border of the tragus (ATL 1), (2) the tip (ATL 2) and (3) the inferior border of the tragus (ATL 3). Neutral zone moldings using phonation and autopolymerizing acrylic resin were recorded and leveled with the lateral borders of the tongue. Lateral cephalometric radiographs were taken of each subject by a standard method. Tracings were obtained on acetate paper to show the prosthetic OP and the three ATLs. The relationship between the prosthetic OP and each of ATL was measured for each subject. Mean and standard deviation values were then calculated for the relationship. Statistical analysis was performed using repeated measure analysis of variance followed by Bonferroni pairwise comparisons and Student's t-test (α = 0.05). Significant difference was found between the three mean angles (p = 0.001). There was no significant difference between the mean angle (5.00° ± 4.38) formed by OP and ATL 2, and the mean angle (4.90° ± 3.50) formed by OP and ATL 3 (p = 1.00) which revealed the smallest. The findings of this study indicated that ATLs, extending from the inferior border of the ala of the nose to (1) the tip of the tragus of the ear, and (2) the inferior border of the tragus presented the closest relationship to the prosthetic OP corresponding to the lateral borders of the tongue. When the ATL is used for orientation of the OP in denture construction, it would seem preferable to define it as running from the inferior border of the ala of the nose to the tip or to the inferior border of the tragus of the ear.

  11. Glycosylation and Processing of Pro-B-type Natriuretic Peptide in Cardiomyocytes

    PubMed Central

    Peng, Jianhao; Jiang, Jingjing; Wang, Wei; Qi, Xiaofei; Sun, Xue-Long; Wu, Qingyu

    2011-01-01

    B-type natriuretic peptide (BNP) and its related peptides are biomarkers for the diagnosis of heart failure. Recent studies identified several O-glycosylation sites, including Thr-71, on human pro-BNP but the functional significance was unclear. In this study, we analyzed glycosylation and proteolytic processing of pro-BNP in cardiomyocytes. Human pro-BNP wild-type (WT) and mutants were expressed in HEK 293 cells and murine HL-1 cardiomyocytes. Pro-BNP and BNP were analyzed by immunoprecipitation and Western blotting. Glycosidases and glycosylation inhibitors were used to examine carbohydrates on pro-BNP. The effects of furin and corin expression on pro-BNP processing in cells also were examined. We found that in HEK 293 cells, recombinant pro-BNP contained significant amounts of O-glycans with terminal oligosialic acids. Mutation at Thr-71 reduced O-glycans on pro-BNP and increased pro-BNP processing. In HL-1 cardiomyocytes, residue Thr-71 contained little O-glycans, and pro-BNP WT and T71A mutant were processed similarly. In HEK 293 cells, pro-BNP was processed by furin. Mutations at Arg-73 and Arg-76, but not Lys-79, prevented pro-BNP processing. In HL-1 cardiomyocytes, which express furin and corin, single or double mutations at Arg-73, Arg-76 and Lys-79 did not prevent pro-BNP processing. Only when all these three residues were mutated, was pro-BNP processing completely blocked. Our data indicate that pro-BNP glycosylation in cardiomyocytes differed significantly from that in HEK 293 cells. In HEK 293 cells, furin cleaved pro-BNP at Arg-76 whereas in cardiomyocytes corin cleaved pro-BNP at multiple residues including Arg-73, Arg-76 and Lys-79. PMID:21763278

  12. The Garbage Gospel: Using the Theory of Planned Behavior to Explain the Role of Religious Institutions in Affecting Pro-Environmental Behavior among Ethnic Minorities

    ERIC Educational Resources Information Center

    Lakhan, Calvin

    2018-01-01

    This study used Azjen's Theory of Planned Behavior to examine how pro-recycling and pro-environmental messaging delivered by religious leaders affects stated recycling behavior among ethnic minorities. Using data collected from 12 religious institutions in three Ontario, Canada, communities, a promotion and education program was developed to: (1)…

  13. Structure and receptor-binding activity of insulin from a holostean fish, the bowfin (Amia calva).

    PubMed

    Conlon, J M; Youson, J H; Whittaker, J

    1991-05-15

    The holostean fishes are the extant representatives of the primitive ray-finned fishes from which the present-day teleosts may have evolved. The primary structure of insulin from a holostean fish, the bowfin (Amia calva), was established as: A-chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Leu-Lys-Pro-Cys-Thr-Ile-Tyr-Glu-Met-Glu- Lys-Tyr-Cys-Asn B-chain: Ala-Ala-Ser-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Phe-Leu- Val-Cys-Gly-Glu-Ser-Gly-Phe-Phe-Tyr-Asn-Pro-Asn-Lys-Ser This amino acid sequence contains several substitutions (methionine at A16, phenylalanine at B16 and serine at B22) at sites that have been strongly conserved in other vertebrate species and that may be expected to influence biological activity. Consistent with this prediction, bowfin insulin was approx. 14-fold less potent than pig insulin in inhibiting the binding of [125I-Tyr-A14](human insulin) to transfected mouse NIH 3T3 cells expressing the human insulin receptor.

  14. Structure and receptor-binding activity of insulin from a holostean fish, the bowfin (Amia calva).

    PubMed Central

    Conlon, J M; Youson, J H; Whittaker, J

    1991-01-01

    The holostean fishes are the extant representatives of the primitive ray-finned fishes from which the present-day teleosts may have evolved. The primary structure of insulin from a holostean fish, the bowfin (Amia calva), was established as: A-chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Leu-Lys-Pro-Cys-Thr-Ile-Tyr-Glu-Met-Glu- Lys-Tyr-Cys-Asn B-chain: Ala-Ala-Ser-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Phe-Leu- Val-Cys-Gly-Glu-Ser-Gly-Phe-Phe-Tyr-Asn-Pro-Asn-Lys-Ser This amino acid sequence contains several substitutions (methionine at A16, phenylalanine at B16 and serine at B22) at sites that have been strongly conserved in other vertebrate species and that may be expected to influence biological activity. Consistent with this prediction, bowfin insulin was approx. 14-fold less potent than pig insulin in inhibiting the binding of [125I-Tyr-A14](human insulin) to transfected mouse NIH 3T3 cells expressing the human insulin receptor. PMID:2039477

  15. Direct comparison of mid-regional pro-atrial natriuretic peptide with N-terminal pro B-type natriuretic peptide in the diagnosis of patients with atrial fibrillation and dyspnoea.

    PubMed

    Eckstein, Jens; Potocki, Mihael; Murray, Karsten; Breidthardt, Tobias; Ziller, Ronny; Mosimann, Tamina; Klima, Theresia; Hoeller, Rebeca; Moehring, Berit; Sou, Seoung Mann; Rubini Gimenez, Maria; Morgenthaler, Nils G; Mueller, Christian

    2012-10-01

    Due to different release mechanisms, mid-regional pro-atrial natriuretic peptide (MR proANP) may be superior to N-terminal pro-B-type natriuretic peptide (NT proBNP) in the diagnosis of acute heart failure (AHF) in patients with atrial fibrillation (AF). We compared MR proANP and NT proBNP for their diagnostic value in patients with AF and sinus rhythm (SR). Prospective cohort study. University hospital, emergency department. 632 consecutive patients presenting with acute dyspnoea. MR proANP and NT proBNP plasma levels were determined. The diagnosis of AHF was adjudicated by two independent cardiologists using all available data. Patients received long-term follow-up. AF was present in 151 patients (24%). MR proANP and NT proBNP levels were significantly higher in the AF group compared with the SR group (385 (258-598) versus 201 (89-375) pmol/l for MR proANP, p<0.001 and 4916 (2169-10285) versus 1177 (258-5166) pg/ml, p<0.001 for NT proBNP). Diagnostic accuracy in AF patients was similar for MR proANP (0.90, 95% CI 0.84 to 0.95) and NT proBNP (0.89, 95% CI 0.81 to 0.96). Optimal cut-off levels in AF patients were significantly higher compared with the optimal cut-off levels for patients in SR (MR proANP 240 vs 200 pmol/l; NT proBNP 2670 vs 1500 pg/ml respectively). After adjustment in multivariable Cox proportional hazard analysis, MR proANP strongly predicted one-year all-cause mortality (HR=1.13 (1.09-1.17), per 100 pmol/l increase, p<0.001). In AF patients, NT proBNP and MR proANP have similar diagnostic value for the diagnosis of AHF. The rhythm at presentation has to be taken into account because plasma levels of both peptides are significantly higher in patients with AF compared with SR.

  16. Plasma pro-brain natriuretic peptide and electrocardiographic changes in combination improve risk prediction in persons without known heart disease.

    PubMed

    Jørgensen, Peter G; Jensen, Jan S; Appleyard, Merete; Jensen, Gorm B; Mogelvang, Rasmus

    2015-12-15

    Though the electrocardiogram(ECG) and plasma pro-brain-natriuretic-peptide (pro-BNP) are widely used markers of subclinical cardiac injury and can be used to predict future cardiovascular disease(CVD), they could merely be markers of the same underlying pathology. We aimed to determine if ECG changes and pro-BNP are independent predictors of CVD and if the combination improves risk prediction in persons without known heart disease. Pro-BNP and ECG were obtained on 5454 persons without known heart disease from the 4th round of the Copenhagen City Heart Study, a prospective cohort study. Median follow-up was 10.4 years. High pro-BNP was defined as above 90th percentile of age and sex adjusted levels. The end-points were all-cause mortality and the combination of admission with ischemic heart disease, heart failure or CVD death. ECG changes were present in 907 persons and were associated with high levels of pro-BNP. In a fully adjusted model both high pro-BNP and ECG changes remained significant predictors: all-cause mortality(high pro-BNP, no ECG changes: HR: 1.43(1.12-1.82);P=0.005, low pro-BNP, ECG changes: HR: 1.22(1.05-1.42);P=0.009, and both high pro-BNP and ECG changes: HR: 1.99(1.54-2.59);P<0.001), CVD event(high pro-BNP, no ECG changes: HR: 1.94(1.45-2.58);P<0.001, low pro-BNP, ECG changes: HR: 1.55(1.29-1.87);P<0.001, and both high pro-BNP and ECG changes: HR: 3.86(2.94-5.08);P<0.001). Adding the combination of pro-BNP and ECG changes to a fully adjusted model correctly reclassified 33.9%(26.5-41.3);P<0.001 on the continuous net reclassification scale for all-cause mortality and 49.7%(41.1-58.4);P<0.001 for CVD event. Combining ECG changes and pro-BNP improves risk prediction in persons without known heart disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Novel biomarkers in acute heart failure: MR-pro-adrenomedullin.

    PubMed

    Peacock, W Frank

    2014-10-01

    First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR-proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP.

  18. AnswerPro: Designing to Motivate Interaction

    ERIC Educational Resources Information Center

    AlSugair, Balsam; Hopkins, Gail; FitzGerald, Elizabeth; Brailsford, Tim

    2014-01-01

    This paper describes the design and initial testing of AnswerPro, a mobile academic peer support system for school pupils aged 11-16 years. AnswerPro is a mobile optimised web application that enables pupils to seek support with school work from knowledgeable peers on various subjects. This paper presents research findings from the project, and in…

  19. The interrelationship between preoperative anemia and N-terminal pro-B-type natriuretic peptide: the effect on predicting postoperative cardiac outcome in vascular surgery patients.

    PubMed

    Goei, Dustin; Flu, Willem-Jan; Hoeks, Sanne E; Galal, Wael; Dunkelgrun, Martin; Boersma, Eric; Kuijper, Ruud; van Kuijk, Jan-Peter; Winkel, Tamara A; Schouten, Olaf; Bax, Jeroen J; Poldermans, Don

    2009-11-01

    N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts adverse cardiac outcome in patients undergoing vascular surgery. However, several conditions might influence this prognostic value, including anemia. In this study, we evaluated whether anemia confounds the prognostic value of NT-proBNP for predicting cardiac events in patients undergoing vascular surgery. A detailed cardiac history, resting echocardiography, and hemoglobin and NT-proBNP levels were obtained in 666 patients before vascular surgery. Anemia was defined as serum hemoglobin <13 g/dL for men and <12 g/dL for women. Troponin T measurements and 12-lead electrocardiograms were performed on postoperative days 1, 3, 7, and 30 and whenever clinically indicated. The primary end point of the study was the composite of 30-day postoperative cardiovascular death, nonfatal myocardial infarction, and troponin T release. Receiver operating characteristic curve analysis was used to assess the optimal cutoff value of NT-proBNP for the prediction of the composite end point. Multivariable regression analysis was used to assess the additional value of NT-proBNP for the prediction of postoperative cardiac events in nonanemic and anemic patients. Anemia was present in 206 patients (31%) before surgery. Hemoglobin level was inversely related with the NT-proBNP levels (beta coefficient = -2.242; P = 0.025). The optimal predictive cutoff value of NT-proBNP for predicting the composite cardiovascular outcome was 350 pg/mL. After adjustment for clinical cardiac risk factors, both anemia (odds ratio [OR] 1.53; 95% confidence interval [CI]: 1.07-2.99) and increased levels of NT-proBNP (OR 4.09; 95% CI: 2.19-7.64) remained independent predictors for postoperative cardiac events. However, increased levels of NT-proBNP were not predictive for the risk of adverse cardiac events in the subgroup of anemic patients (OR 2.16; 95% CI: 0.90-5.21). Both anemia and NT-proBNP are independently associated with an increased risk for

  20. Propulsive Small Expendable Deployer System (ProSEDS)

    NASA Technical Reports Server (NTRS)

    1999-01-01

    NASA's Propulsive Small Expendable Deployer System experiment (ProSEDS) will demonstrate the use of an electrodynamic tether, basically a long, thin wire, for propulsion. An electrodynamic tether uses the same principles as electric motors in toys, appliances and computer disk drives, and generators in automobiles and power plants. When electrical current is flowing through the tether, a magnetic field is produced that pushes against the magnetic field of the Earth. For ProSEDS, the current in the tether results by virtue of the voltage generated when the tether moves through the Earth's magnetic field at more than 17,000 mph. This approach can produce drag thrust generating useable power. Since electrodynamic tethers require no propellant, they could substantially reduce the weight of the spacecraft and provide a cost-effective method of reboosting spacecraft. The initial flight of ProSEDS is scheduled to fly aboard an Air Force Delta II rocket in the summer of 2002. In orbit, ProSEDS will deploy from a Delta II second stage. It will be a 3.1-mile (5 kilometer) long, ultrathin base-wire cornected with a 6.2-mile (10 kilometer) long nonconducting tether. This photograph shows Less Johnson, a scientist at MSFC inspecting the nonconducting part of a tether as it exits a deployer similar to the one to be used in the ProSEDS experiment. The ProSEDS experiment is managed by the Space Transportation Directorate at MSFC.

  1. Inherited functional variants of the lymphocyte receptor CD5 influence melanoma survival

    PubMed Central

    Potrony, Miriam; Carreras, Esther; Aranda, Fernando; Zimmer, Lisa; Puig-Butille, Joan-Anton; Tell-Martí, Gemma; Armiger, Noelia; Sucker, Antje; Giménez-Xavier, Pol; Martínez-Florensa, Mario; Carrera, Cristina; Malvehy, Josep; Schadendorf, Dirk; Puig, Susana; Lozano, Francisco

    2017-01-01

    Despite the recent progress in treatment options, malignant melanoma remains a deadly disease. Besides therapy, inherited factors might modulate clinical outcome, explaining in part widely varying survival rates. T-cell effector function regulators on antitumor immune responses could also influence survival. CD5, a T-cell receptor inhibitory molecule, contributes to the modulation of antimelanoma immune responses as deduced from genetically-modified mouse models. The CD5 SNPs rs2241002 (NM_014207.3:c.671C>T, p.Pro224Leu) and rs2229177 (NM_014207.3:c.1412C>T, p.Ala471Val) constitute an ancestral haplotype (Pro224-Ala471) that confers T-cell hyper-responsiveness and worsens clinical autoimmune outcome. The assessment of these SNPs on survival impact from two melanoma patient cohorts (Barcelona, N=493 and Essen, N=216) reveals that p.Ala471 correlates with a better outcome (OR= 0.57, 95% CI=0.33-0.99, Adj. P=0.043, in Barcelona OR=0.63, 95% CI=0.40-1.01, Adj. P=0.051, in Essen). While, p.Leu224 was associated with increased melanoma-associated mortality in both cohorts (OR=1.87, 95% CI=1.07-3.24, Adj. P=0.030 in Barcelona and OR=1.84, 95% CI=1.04-3.26, Adj. P=0.037, in Essen). Furthermore survival analyses showed that the Pro224-Ala471 haplotype in homozygosis improved melanoma survival in the entire set of patients (HR=0.27, 95% CI 0.11 to 0.67, Adj. P=0.005). These findings highlight the relevance of genetic variability in immune-related genes for clinical outcome in melanoma. PMID:27169428

  2. ProQ3: Improved model quality assessments using Rosetta energy terms

    PubMed Central

    Uziela, Karolis; Shu, Nanjiang; Wallner, Björn; Elofsson, Arne

    2016-01-01

    Quality assessment of protein models using no other information than the structure of the model itself has been shown to be useful for structure prediction. Here, we introduce two novel methods, ProQRosFA and ProQRosCen, inspired by the state-of-art method ProQ2, but using a completely different description of a protein model. ProQ2 uses contacts and other features calculated from a model, while the new predictors are based on Rosetta energies: ProQRosFA uses the full-atom energy function that takes into account all atoms, while ProQRosCen uses the coarse-grained centroid energy function. The two new predictors also include residue conservation and terms corresponding to the agreement of a model with predicted secondary structure and surface area, as in ProQ2. We show that the performance of these predictors is on par with ProQ2 and significantly better than all other model quality assessment programs. Furthermore, we show that combining the input features from all three predictors, the resulting predictor ProQ3 performs better than any of the individual methods. ProQ3, ProQRosFA and ProQRosCen are freely available both as a webserver and stand-alone programs at http://proq3.bioinfo.se/. PMID:27698390

  3. The Simultaneous Electrochemical Detection of Catechol and Hydroquinone with [Cu(Sal-β-Ala)(3,5-DMPz)2]/SWCNTs/GCE

    PubMed Central

    Alshahrani, Lina Abdullah; Li, Xi; Luo, Hui; Yang, Linlin; Wang, Mengmeng; Yan, Songling; Liu, Peng; Yang, Yuqin; Li, Quanhua

    2014-01-01

    A glassy carbon electrode was modified with a copper(II) complex [Cu(Sal-β-Ala) (3,5-DMPz)2] (Sal = salicylaldehyde, β-Ala = β-alanine, 3,5-DMPz = 3,5-dimethylpyrazole) and single-walled carbon nanotubes (SWCNTs). The modified electrode was used to detect catechol (CT) and hydroquinone (HQ) and exhibited good electrocatalytic activities toward the oxidation of CT and HQ. The peak currents were linear with the CT and HQ concentrations over the range of 5–215 μmol·L−1 and 5–370 μmol·L−1 with corresponding detection limits of 3.5 μmol·L−1 and 1.46 μmol·L−1 (S/N = 3) respectively. Moreover, the modified electrode exhibited good sensitivity, stability and reproducibility for the determination of CT and HQ, indicating the promising applications of the modified electrode in real sample analysis. PMID:25429411

  4. ALA-induced photodynamic effect on vitality, apoptosis, and secretion of vascular endothelial growth factor (VEGF) by colon cancer cells in normoxic environment in vitro.

    PubMed

    Kawczyk-Krupka, A; Sieroń-Stołtny, K; Latos, W; Czuba, Z P; Kwiatek, B; Potempa, M; Wasilewska, K; Król, W; Stanek, A

    2016-03-01

    Cancer therapy is often based on combination of conventional methods of cancer treatment with immunotherapy. Photodynamic therapy (PDT) is one of the immunomodulating methods used in oncology. We examined how PDT influences the secretory activity of colon cancer cells in vitro, especially the secretion of vascular endothelial growth factor (VEGF) in aerobic conditions. We used two cancer cell lines with different malignancy potentials: a metastatic SW620 line and a non-metastatic SW480 line. In the first stage of the experiment, we exposed each cell line to three different concentrations of photosensitizer's precursor: 5-aminolevulinic acid (ALA) and varying levels of light radiation, after which we assessed cell viability and apoptosis induction in these lines, using the MTT and LDH assays. Then, we determined the secretion of VEGF by these cells in aerobic conditions and under the ALA-PDT parameters at which cells presented the highest viability. Photodynamic treatment with ALA did not influence on VEGF secretion by the non-metastatic SW480 cells, but caused a decrease in VEGF secretion by the metastatic SW 620 cell line by 29% (p<0.05). SW 620 cell line secreted more actively VEGF than the SW480 cells, both before and after photo dynamic therapy (p<0.05). The outcome of this in vitro study presented a beneficial effect of ALA-PDT, resulting in a decrease of VEGF secretion in the more malignant SW620 cell lines. Further studies should be considered to confirm the clinical relevance of this finding. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. NT-proBNP in cardiac surgery: a new tool for the management of our patients?

    PubMed

    Reyes, Guillermo; Forés, Gloria; Rodríguez-Abella, R Hugo; Cuerpo, Gregorio; Vallejo, José Luis; Romero, Carlos; Pinto, Angel

    2005-06-01

    Our aim was to determine NT-proBNP levels in patients undergoing cardiac surgery and if those levels are related to any of the baseline clinical characteristics of patients before surgery or any of the outcomes or events after surgery. Prospective, analytic study including 83 consecutive patients undergoing cardiac surgery. Preoperatory and postoperatory data were collected. NT-proBNP levels were measured before surgery, the day of surgery, twice the following day and every 24 h until a total of nine determinations. Venous blood was obtained by direct venipuncture and collected into serum separator tubes. Samples were centrifuged within 20 min from sampling and stored for a maximum of 12 h at 2-8 degrees C before the separation of serum. Serum was stored frozen at -40 degrees C and thawed only once at the time of analysis. Mean age was 65+/-11.8 years. An Euroscore 6 was found in 30% of patients. NYHA classification was as follows: I:27.7%; II:47%; III:25.3%. Preoperative atrial fibrilation occurred in 20.5% of patients. After surgery 18.1% of patients required inotropes. Only one death was recorded. A great variability was found in preoperative NT-proBNP levels; 759.9 (S.D.:1371.1); CI 95%: 464.9 to 1054.9 pg/ml, with a wide range (6.39-8854). Median was 366.5 pg/ml. Preoperative NT-proBNP levels were unrelated to the type of surgery (CABG vs. others), sex, age and any of the cardiovascular risk factors. NT-proBNP levels were higher in high risk patients (Euroscore 6); (P=0.021), worse NYHA class (P=0.020) and patients with preoperative atrial fibrilation (m 1767 (2205) vs m 621 (1017); P=0.001). After surgery NT-proBNP levels started increasing the following day until the fourth day (P=0.03), decreasing afterwards (P=0.019). These levels were significantly higher in patients requiring inotropes after surgery (P<0.001). We did not find any relationship between NT-proBNP levels and complications rate (P=0.59). Preoperative NT-proBNP levels depend on preoperative

  6. Diagnostic value of N-terminal pro-brain natriuretic peptide for pleural effusion due to heart failure: a meta-analysis.

    PubMed

    Zhou, Q; Ye, Z J; Su, Y; Zhang, J C; Shi, H Z

    2010-08-01

    N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker useful in diagnosis of pleural effusion due to heart failure. Thus far, its overall diagnostic accuracy has not been systematically reviewed. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of the measurement of pleural NT-proBNP for identifying pleural effusion due to heart failure. After a systematic review of English-language studies, sensitivity, specificity, and other measures of accuracy of NT-proBNP concentrations in pleural fluid in the diagnosis of pleural effusion resulting from heart failure were pooled using fixed-effects models. Summary receiver operating characteristic curves were used to summarise overall test performance. Eight publications met the inclusion criteria. The summary estimates for pleural NT-proBNP in the diagnosis of pleural effusion attributable to heart failure were: sensitivity 0.95 (95% CI 0.92 to 0.97), specificity 0.94 (0.92 to 0.96), positive likelihood ratio 14.12 (10.23 to 19.51), negative likelihood ratio 0.06 (0.04 to 0.09) and diagnostic OR 213.87 (122.50 to 373.40). NT-proBNP levels in pleural fluid showed a high diagnostic accuracy and may help accurately differentiate cardiac from non-cardiac conditions in patients presenting with pleural effusion.

  7. Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A)

    PubMed Central

    Iida, Joji; Wilhelmson, Krista L.; Ng, Janet; Lee, Peter; Morrison, Charlotte; Tam, Eric; Overall, Christopher M.; McCarthy, James B.

    2007-01-01

    We previously reported that CS (chondroitin sulfate) GAG (glycosaminoglycan), expressed on MCSP (melanoma-specific CS proteoglycan), is important for regulating MT3-MMP [membrane-type 3 MMP (matrix metalloproteinase)]-mediated human melanoma invasion and gelatinolytic activity in vitro. In the present study, we sought to determine if CS can directly enhance MT3-MMP-mediated activation of pro-MMP-2. Co-immunoprecipitation studies suggest that MCSP forms a complex with MT3-MMP and MMP-2 on melanoma cell surface. When melanoma cells were treated with βDX (p-nitro-β-D-xylopyranoside) to inhibit coupling of CS on the core protein, both active form and proform of MMP-2 were no longer co-immunoprecipitated with either MCSP or MT3-MMP, suggesting a model in which CS directly binds to MMP-2 and presents the gelatinase to MT3-MMP to be activated. By using recombinant proteins, we determined that MT3-MMP directly activates pro-MMP-2 and that this activation requires the interaction of the C-terminal domain of pro-MMP-2 with MT3-MMP. Activation of pro-MMP-2 by suboptimal concentrations of MT3-MMP is also significantly enhanced in the presence of excess C4S (chondroitin 4-sulfate), whereas C6S (chondroitin 6-sulfate) or low-molecular-mass hyaluronan was ineffective. Affinity chromatography studies using CS isolated from aggrecan indicate that the catalytic domain of MT3-MMP and the C-terminal domain of MMP-2 directly bind to the GAG. Thus the direct binding of pro-MMP-2 with CS through the C-domain would present the catalytic domain of pro-MMP-2 to MT3-MMP, which facilitates the generation of the active form of MMP-2. These results suggest that C4S, which is expressed on tumour cell surface, can function to bind to pro-MMP-2 and facilitate its activation by MT3-MMP-expressing tumour cells to enhance invasion and metastasis. PMID:17217338

  8. Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease.

    PubMed

    Eriksson, Anders S; Häggström, Jens; Pedersen, Henrik Duelund; Hansson, Kerstin; Järvinen, Anna-Kaisa; Haukka, Jari; Kvart, Clarence

    2014-09-01

    To evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and nitric oxide end-products (NOx) as markers for progression of mitral regurgitation caused by myxomatous mitral valve disease. Seventy-eight privately owned Cavalier King Charles spaniels with naturally occurring myxomatous mitral valve disease. Prospective longitudinal study comprising 312 measurements over a 4.5 year period. Clinical values were recorded, NT-proANP concentrations were measured by radioimmunoassay, and NOx were analyzed colorimetrically. To predict congestive heart failure (CHF), Cox proportional hazards models with time-varying covariates were constructed. The hazard ratio for NT-proANP (per 1000 pmol/l increase) to predict future CHF was 6.7 (95% confidence interval, 3.6-12.5; p < 0.001). The median time to CHF for dogs with NT-proANP levels >1000 pmol/l was 11 months (95% confidence interval, 5.6-12.6 months), compared to 54 months (46 - infinity) for dogs with concentrations ≤ 1000 pmol/l (p < 0.001). Due to intra- and inter-individual variability, most corresponding analyses for NOx were insignificant but dogs reaching CHF had a lower mean NOx concentration than dogs not reaching CHF (23 vs. 28 μmol/l, p = 0.016). Risk of CHF increased with increase in heart rate (>130 beats per minute) and grade of murmur (≥ 3/6). The risk of CHF due to mitral regurgitation is increased in dogs with blood NT-proANP concentrations above 1000 pmol/l. Measurement of NT-proANP can be a valuable tool to identify dogs that may develop CHF within months. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. IL6R Variation Asp358Ala Is a Potential Modifier of Lung Function in Asthma

    PubMed Central

    Hawkins, Gregory A; Robinson, Mac B; Hastie, Annette T; Li, Xingnan; Li, Huashi; Moore, Wendy C; Howard, Timothy D; Busse, William W.; Erzurum, Serpil C.; Wenzel, Sally E.; Peters, Stephen P; Meyers, Deborah A; Bleecker, Eugene R

    2012-01-01

    Background The IL6R SNP rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2=1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL6 receptor shedding and promotes IL6 transsignaling. Objectives To evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL6 receptor (sIL6R) levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL6R protein expression in BAL cells and endobronchial biopsies. Results The minor C allele of IL6R SNP rs2228145 was associated with lower ppFEV1 in the SARP cohort (p=0.005), the CSGA cohort (0.008), and in combined cohort analysis (p=0.003). Additional associations with ppFVC, FEV1/FVC, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum sIL6R was associated with lower ppFEV1 (p=0.02) and lower ppFVC (p=0.008) (N=146). IL6R protein expression was observed in BAL macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions The IL6R coding SNP rs2228145 (Asp358Ala) is a potential modifier of lung function in asthma and may identify subjects at risk for more severe asthma. IL6 transsignaling may have a pathogenic role in the lung. PMID:22554704

  10. In-vivo kinetics of ALA-induced fluorescence in the canine oral cavity: influence of drug dose and tissue type

    NASA Astrophysics Data System (ADS)

    Vaidyanathan, Vijay; Rastegar, Sohi; Fossum, Theresa W.; Flores, P.; van der Breggen, E. W. J.; Egger, N. G.; Jacques, Steven L.; Motamedi, Massoud

    1997-06-01

    Fluorescence spectroscopic detection and photodynamic therapy may provide an effective approach for early detection and treatment of oral cancer. Thus the development of a safe photosensitizer that could enhance the spectroscopic contrast between normal and neoplastic tissue, while allowing for selective photosensitization and treatment of pre-malignant and malignant lesions in the oral cavity, is highly desired. In this study, the pharmacokinetics and a safety of 5-aminolevulinic acid (ALA) that could induce an endogenous precursor of protoporphyrin IX and heme in the biosynthetic pathway was investigated. Two doses of ALA:25 and 75 mg/kg were administered intravenously to 4 and 3 dogs, respectively. A 'wash-out' period of 1 week between administration of each does was allowed to ensure against PpIX build-up. Using an optical multichannel analyzer, the fluorescence from the oral cavity was recorded at 3 sites: buccal mucosa, gums, and the tongue, and also from a remote site, the skin. A fiber optic probe was used to deliver excitation and collect the emitted fluorescence. Results showed that the ALA-induced fluorescence reached a peak at 2-4 hours, and returned to baseline in 24-31 hours. The dogs were stable during the course of the study, minimal vomiting was noted. In conclusion, the study showed that higher doses result in a higher peak at a later time.It was observed that different tissues have different pharmacokinetic response, the tongue and the gums have the highest peak fluorescence values, followed by the buccal mucosa and skin.

  11. The Interplay among Environmental Attitudes, Pro-Environmental Behavior, Social Identity, and Pro-Environmental Institutional Climate. A Longitudinal Study

    ERIC Educational Resources Information Center

    Prati, Gabriele; Albanesi, Cinzia; Pietrantoni, Luca

    2017-01-01

    By using a panel design in a sample of 298 undergraduate/master students at an Italian public university, the present study aimed to test longitudinally the interplay among environmental attitudes, pro-environmental behavior, social identity, and pro-environmental institutional climate. The relationships were tested with cross-lagged analysis…

  12. Variability of NT‐proBNP plasma and urine levels in patients with stable heart failure: a 2‐year follow‐up study

    PubMed Central

    Cortés, Raquel; Rivera, Miguel; Salvador, Antonio; Bertomeu, Vicente; de Burgos, Fernando García; Roselló‐Lletí, Esther; Portolés, Manuel; Payá, Rafael; Martínez‐Dolz, Luis; Climent, Vicente

    2007-01-01

    Objectives To examine N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) variability in plasma and urine samples of patients with stable heart failure (HF) during a 24‐month follow‐up. Design Prospective study. Setting Teaching hospital based study. Patients 74 clinically and functionally stable patients (NYHA class 2±0.5) out of 114 patients diagnosed with HF were followed up, and NT‐proBNP plasma and urine levels were measured at baseline, 12 and 24 months. Results Significant differences in mean urinary levels (p<0.01) were found during follow‐up, but no changes were found in plasma. Bland–Altman plots showed few variations in plasma percentages in the three intervals (stage I–basal; stage II–stage I; stage II–basal) with a coefficient of reproducibility (CR) of 22%, 21% and 25%, respectively. Changes in NT‐proBNP urinary levels had a CR of 7.1%, 6.8% and 9.4% at the three intervals, respectively. A good correlation was found between plasma and urinary levels of NT‐proBNP (p<0.001) and between the different NT‐proBNP plasma (p<0.001) and urine measurements (p<0.001). Conclusions NT‐proBNP plasma and urine levels show good stability in a 24‐month follow‐up of patients with stable heart failure. Thus, assessment of urinary and plasma NT‐proBNP concentrations may be a useful tool for monitoring patients with HF during follow‐up. The results suggest that variations in peptide concentrations exceeding 22% in plasma and 7% in urine in a 12‐month follow‐up and 25% and 9% in a 24‐month follow‐up may indicate pathophysiological changes. PMID:17488774

  13. Interaction between the mu-agonist dermorphin and the delta-agonist [D-Ala2, Glu4]deltorphin in supraspinal antinociception and delta-opioid receptor binding.

    PubMed Central

    Negri, L.; Improta, G.; Lattanzi, R.; Potenza, R. L.; Luchetti, F.; Melchiorri, P.

    1995-01-01

    1. In rats, the interaction between the mu-opioid agonist dermorphin and the delta-opioid agonist [D-Ala2, Glu4]deltorphin was studied in binding experiments to delta-opioid receptors and in the antinociceptive test to radiant heat. 2. When injected i.c.v., doses of [D-Ala2, Glu4]deltorphin higher than 20 nmol produced antinociception in the rat tail-flick test to radiant heat. Lower doses were inactive. None of the doses tested elicited the maximum achievable response. This partial antinociception was accomplished with an in vivo occupancy of more than 97% of brain delta-opioid receptors and of 17% of mu-opioid receptors. Naloxone (0.1 mg kg-1, s.c.), and naloxonazine (10 mg kg-1, i.v., 24 h before), but not the selective delta-opioid antagonist naltrindole, antagonized the antinociception. 3. In vitro competitive inhibition studies in rat brain membranes showed that [D-Ala2, Glu4]deltorphin displaced [3H]-naltrindole from two delta-binding sites of high and low affinity. The addition of 100 microM Gpp[NH]p produced a three fold increase in the [D-Ala2, Glu4]deltorphin Ki value for both binding sites. The addition of 10 nM dermorphin increased the Ki value of the delta-agonist for the high affinity site five times. When Gpp[NH]p was added to the incubation medium together with 10 nM dermorphin, the high affinity Ki of the delta-agonist increased 15 times. 4. Co-administration into the rat brain ventricles of subanalgesic doses of dermorphin and [D-Ala2, Glu4]deltorphin resulted in synergistic antinociceptive responses. 5. Pretreatment with naloxone or with the non-equilibrium mu-antagonists naloxonazine and beta-funaltrexamine completely abolished the antinociceptive response of the mu-delta agonist combinations. 6. Pretreatment with the delta-opioid antagonists naltrindole and DALCE reduced the antinociceptive response of the dermorphin-[D-Ala2, Glu4]deltorphin combinations to a value near that observed after the mu-agonist alone. At the dosage used, naltrindole

  14. TOXIRAE PRO PID

    EPA Science Inventory

    The ToxiRAE Pro PID measures total volatile organic compounds (VOCs) using a photoionization detector (PID). This sensor can be programmed to measure concentrations of a specified compound automatically and has a real time reading of VOC concentrations in parts per million (ppm) ...

  15. In vitro effect of short peptides on expression of interleukin-2 gene in splenocytes.

    PubMed

    Kazakova, T B; Barabanova, S V; Khavinson, V Kh; Glushikhina, M S; Parkhomenko, E P; Malinin, V V; Korneva, E A

    2002-06-01

    Synthetic peptides Vilon (Lys-Glu), Epithalon (Ala-Glu-Asp-Gly), and Cortagen (Ala-Glu-Asp-Pro) in vitro activated interleukin-2 mRNA synthesis in splenocytes from CBA mice in the absence of specific inductors. The intensity of interleukin-2 mRNA synthesis in splenocytes depended on the type, concentration, and duration of treatment with the peptides. Vilon and Epithalon were most potent, while Cortagen produced a less pronounced effect on interleukin-2 mRNA synthesis.

  16. The performance of the progressive resolution optimizer (PRO) for RapidArc planning in targets with low-density media.

    PubMed

    Kan, Monica W K; Leung, Lucullus H T; Yu, Peter K N

    2013-11-04

    A new version of progressive resolution optimizer (PRO) with an option of air cavity correction has been implemented for RapidArc volumetric-modulated arc therapy (RA). The purpose of this study was to compare the performance of this new PRO with the use of air cavity correction option (PRO10_air) against the one without the use of the air cavity correction option (PRO10_no-air) for RapidArc planning in targets with low-density media of different sizes and complexities. The performance of PRO10_no-air and PRO10_air was initially compared using single-arc plans created for four different simple heterogeneous phantoms with virtual targets and organs at risk. Multiple-arc planning of 12 real patients having nasopharyngeal carcinomas (NPC) and ten patients having non-small cell lung cancer (NSCLC) were then performed using the above two options for further comparison. Dose calculations were performed using both the Acuros XB (AXB) algorithm with the dose to medium option and the analytical anisotropic algorithm (AAA). The effect of using intermediate dose option after the first optimization cycle in PRO10_air and PRO10_no-air was also investigated and compared. Plans were evaluated and compared using target dose coverage, critical organ sparing, conformity index, and dose homogeneity index. For NSCLC cases or cases for which large volumes of low-density media were present in or adjacent to the target volume, the use of the air cavity correction option in PRO10 was shown to be beneficial. For NPC cases or cases for which small volumes of both low- and high-density media existed in the target volume, the use of air cavity correction in PRO10 did not improve the plan quality. Based on the AXB dose calculation results, the use of PRO10_air could produce up to 18% less coverage to the bony structures of the planning target volumes for NPC cases. When the intermediate dose option in PRO10 was used, there was negligible difference observed in plan quality between

  17. Diacerein inhibits the pro-atherogenic & pro-inflammatory effects of IL-1 on human keratinocytes & endothelial cells.

    PubMed

    Mohan, Girish C; Zhang, Huayi; Bao, Lei; Many, Benjamin; Chan, Lawrence S

    2017-01-01

    We investigated IL-1-induced regulation of genes related to inflammation and atherogenesis in human keratinocytes and endothelial cells, and if 'diacerein', an oral IL-1 inhibiting drug currently approved for use in osteoarthritis, would reverse IL-1's effects on these cells. Primary human keratinocytes and coronary artery endothelial cells were treated with either IL-1α or IL-1β, with and without diacerein. Using PCR-array, we assessed differential gene-expression regulated by IL-1 and diacerein. We identified 34 pro-atherogenic genes in endothelial cells and 68 pro-inflammatory genes in keratinocytes significantly (p<0.05) regulated at least 2-fold by IL-1, in comparison to control. Diacerein completely or partially reversed this regulation on almost all genes. Using ELISA, we confirmed diacerein's ability to reverse IL-1-driven gene-regulation of 11 selected factors, at the protein level. The results support a novel idea that diacerein acts as an inhibitor of the pro-atherogenic and pro-inflammatory effects of IL-1. Diacerein may have therapeutic applications to diminish IL-1-induced skin inflammation in psoriasis and attenuate IL-1-induced development of atherosclerosis. Further investigation into diacerein's effect on skin inflammation, atherogenesis and cardiovascular risk in animal models or humans is warranted.

  18. Diacerein inhibits the pro-atherogenic & pro-inflammatory effects of IL-1 on human keratinocytes & endothelial cells

    PubMed Central

    Bao, Lei; Many, Benjamin; Chan, Lawrence S.

    2017-01-01

    We investigated IL-1-induced regulation of genes related to inflammation and atherogenesis in human keratinocytes and endothelial cells, and if ‘diacerein’, an oral IL-1 inhibiting drug currently approved for use in osteoarthritis, would reverse IL-1’s effects on these cells. Primary human keratinocytes and coronary artery endothelial cells were treated with either IL-1α or IL-1β, with and without diacerein. Using PCR-array, we assessed differential gene-expression regulated by IL-1 and diacerein. We identified 34 pro-atherogenic genes in endothelial cells and 68 pro-inflammatory genes in keratinocytes significantly (p<0.05) regulated at least 2-fold by IL-1, in comparison to control. Diacerein completely or partially reversed this regulation on almost all genes. Using ELISA, we confirmed diacerein’s ability to reverse IL-1-driven gene-regulation of 11 selected factors, at the protein level. The results support a novel idea that diacerein acts as an inhibitor of the pro-atherogenic and pro-inflammatory effects of IL-1. Diacerein may have therapeutic applications to diminish IL-1-induced skin inflammation in psoriasis and attenuate IL-1-induced development of atherosclerosis. Further investigation into diacerein’s effect on skin inflammation, atherogenesis and cardiovascular risk in animal models or humans is warranted. PMID:28323859

  19. Computerized tomography measured liver fat is associated with low levels of N-terminal pro-brain natriuretic protein (NT-proBNP). Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Sanchez, Otto A.; Mariana, Lazo-Elizondo; Irfan, Zeb; Tracy, Russell P; Bradley, Ryan; Duprez, Daniel A.; Bahrami, Hossein; Peralta, Carmen A.; Daniels, Lori B.; Lima, João A.; Maisel, Alan; Jacobs, David R.; MJ, Budoff

    2016-01-01

    Background and aims N-terminal pro B-type natriuretic peptide (NT-proBNP) is inversely associated with diabetes mellitus, obesity and metabolic syndrome. We aim to characterize the association between NT-proBNP and nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with metabolic syndrome. Methods 4529 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) free of cardiovascular disease, without self-reported liver disease and not diabetic at their baseline visit in 2000- 2002 were included in this analysis. NAFLD was defined by a liver attenuation <40 HU. Relative prevalence (RP) for NAFLD was assessed adjusted for age, race, and sex, percent of dietary calories derived from fat, total intentional exercise, alcoholic drinks per week, and interleukin-6 by quintiles of NT-proBNP. Adjusted linear spline model was used to characterize a non-linear association between NT-proBNP and liver fat. The inflection point (IP) was the NT-proBNP concentration where there was a change in slope in the association between liver attenuation and NT-proBNP. Results RP for NAFLD decreased by 30% from the lowest to the highest quintile of NT-proBNP, p = 0.01. We observed an inverse linear association between NT-proBNP and liver fat, which plateaued (IP) at an NT-proBNP concentration of 45 pg/mL. Linear regression coefficient (SE) per unit of NT-proBNP < and ≥ IP was of 0.05 (0.02), p = 0.001 and 0.0006 (0.0008), p = 0.5, respectively, differences between slopes p < 0.0001. Conclusions In this cross-sectional study of a community based multiethnic sample of non-diabetic adults, low levels of NT-proBNP are associated with greater prevalence of NAFLD. PMID:27085779

  20. Particles from wood smoke and traffic induce differential pro-inflammatory response patterns in co-cultures

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

    Kocbach, Anette; Herseth, Jan Inge; Lag, Marit

    2008-10-15

    The inflammatory potential of particles from wood smoke and traffic has not been well elucidated. In this study, a contact co-culture of monocytes and pneumocytes was exposed to 10-40 {mu}g/cm{sup 2} of particles from wood smoke and traffic for 12, 40 and 64 h to determine their influence on pro-inflammatory cytokine release (TNF-{alpha}, IL-1, IL-6, IL-8) and viability. To investigate the role of organic constituents in cytokine release the response to particles, their organic extracts and the washed particles were compared. Antagonists were used to investigate source-dependent differences in intercellular signalling (TNF-{alpha}, IL-1). The cytotoxicity was low after exposure tomore » particles from both sources. However, wood smoke, and to a lesser degree traffic-derived particles, induced a reduction in cell number, which was associated with the organic fraction. The release of pro-inflammatory cytokines was similar for both sources after 12 h, but traffic induced a greater release than wood smoke particles with increasing exposure time. The organic fraction accounted for the majority of the cytokine release induced by wood smoke, whereas the washed traffic particles induced a stronger response than the corresponding organic extract. TNF-{alpha} and IL-1 antagonists reduced the release of IL-8 induced by particles from both sources. In contrast, the IL-6 release was only reduced by the IL-1 antagonist during exposure to traffic-derived particles. In summary, particles from wood smoke and traffic induced differential pro-inflammatory response patterns with respect to cytokine release and cell number. Moreover, the influence of the organic particle fraction and intercellular signalling on the pro-inflammatory response seemed to be source-dependent.« less

  1. The Role of NT-proBNP in the Diagnosis of Ventricular Arrhythmias in Patients with Systemic Sclerosis

    PubMed Central

    MURESAN, Lucian; PETCU, Ana; MURESAN, Crina; RINZIS, Mirela; GUSETU, Gabriel; POP, Dana; ZDRENGHEA, Dumitru; REDNIC, Simona

    2017-01-01

    Background: In patients with systemic sclerosis, NT-proBNP is a useful diagnostic marker for pulmonary hypertension and ventricular dysfunction, with important prognostic significance. The aim of this study was to assess the relationship between the NT-proBNP levels and the presence and severity of ventricular arrhythmias in patients with scleroderma. Methods: Forty consecutive patients with a diagnostic of systemic sclerosis according to the EULAR criteria admitted at the Rheumatology Clinic of Cluj-Napoca, Romania, from Jan 2014 to Apr 2014 were enrolled. Patients underwent a 12-lead ECG and a 24-hour Holter ECG monitoring for ventricular arrhythmias evaluation. Blood sample testing (including NT-proBNP level measurements), echocardiography, spirometry, chest X-ray and, when considered appropriate, high-resolution chest CT were performed. Results: Sixty percent of patients (n=24) had abnormal NT-proBNP serum levels (>125 pg/ml) and 10 patients had >100 PVC/24 h. There was a statistically significant correlation between the NT-proBNP levels and the total number of premature ventricular contractions (PVC) (r=0.445, P=0.006), total number of isolated PVC (r=0,493, P=0.002), total number of ventricular couplets (r=0.379, P=0.021) and the number of PVC morphologies (r=0.501, P=0.002). The presence of an NT-proBNP serum level >287 pg/ml had a sensitivity of 55% and a specificity of 93% in predicting the presence of complex ventricular arrhythmias on 24-hour Holter ECG monitoring. Conclusion: NT-proBNP levels could become a useful ventricular arrhythmia marker for assessing the arrhythmic risk in patients with systemic sclerosis. PMID:28845401

  2. Novel angiotensin I-converting enzyme inhibitory peptides isolated from Alcalase hydrolysate of mung bean protein.

    PubMed

    Li, Guan-Hong; Wan, Ju-Zhen; Le, Guo-Wei; Shi, Yong-Hui

    2006-08-01

    Mung bean protein isolates were hydrolyzed for 2 h by Alcalase. The generated hydrolysate showed angiotensin I-converting enzyme (ACE) inhibitory activity with the IC(50) value of 0.64 mg protein/ml. Three kinds of novel ACE inhibitory peptides were isolated from the hydrolysate by Sephadex G-15 and reverse-phase high performance liquid chromatography (RP-HPLC). These peptides were identified by amino acid composition analysis and matrix assisted-laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS/MS), as Lys-Asp-Tyr-Arg-Leu, Val-Thr-Pro-Ala-Leu-Arg and Lys-Leu-Pro-Ala-Gly-Thr-Leu-Phe with the IC(50) values of 26.5 microM, 82.4 microM and 13.4 microM, respectively. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.

  3. The substitution of cysteine 17 of recombinant human G-CSF with alanine greatly enhanced its stability.

    PubMed

    Ishikawa, M; Iijima, H; Satake-Ishikawa, R; Tsumura, H; Iwamatsu, A; Kadoya, T; Shimada, Y; Fukamachi, H; Kobayashi, K; Matsuki, S

    1992-02-01

    Human recombinant granulocyte-colony stimulating factor (rhG-CSF) has one free cysteine at position 17 and has two disulfide bridges (Cys36-Cys42 and Cys64-Cys74). The Cys17 of rhG-CSF was substituted with Gly, Ala, Ser, Ile, Tyr, Arg, and Pro, or deleted using site-directed mutagenesis in order to improve its thermostability. With the exception of Pro17-rhG-CSF, all mutant proteins retained biological activity which promotes the growth of mouse bone marrow cells in vitro. Among these mutant proteins, Ala17-rhG-CSF had more than 5 times higher stability than rhG-CSF. But Ser17-rhG-CSF had almost same stability as rhG-CSF and other mutant proteins had only lower stability.

  4. Control of Helical Chirality of Ferrocene-Dipeptide Conjugates by the Secondary Structure of Dipeptide Chains.

    PubMed

    Moriuchi, Toshiyuki; Nishiyama, Taiki; Nobu, Masaki; Hirao, Toshikazu

    2017-09-18

    Controlling helical chirality and creating protein secondary structures in cyclic/acyclic ferrocene-dipeptide bioorganometallic conjugates were achieved by adjusting the conformational flexibility of the dipeptide chains. In systems reported to date, the helical chirality of a conjugate was determined by the absolute configuration of the adjacent amino acid reside. In contrast, it was possible to induce both M- and P-helical chirality, even when the configuration of the adjacent amino acid was the same. It is particularly interesting to note that M-helical chirality was produced in a cyclic ferrocene-dipeptide conjugate composed of the l-Ala-d-Pro-cystamine-d-Pro-l-Ala dipeptide sequence (1), in which a type II β-turn-like secondary structure was established. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. [Comparison between Goldmann, Icare Pro and Corvis ST tonometry].

    PubMed

    Bañeros-Rojas, P; Martinez de la Casa, J M; Arribas-Pardo, P; Berrozpe-Villabona, C; Toro-Utrera, P; García-Feijoó, J

    2014-07-01

    To compare intraocular pressure (IOP) between the new non-contact tonometer Corvis ST (CST), the Goldmann applanation tonometry (GAT) and Icare Pro rebound tonometer (PRO). A total of 178 eyes of 178 healthy subjects were selected for the study. Measurements of IOP were made in a random order with GAT, PRO and CST. Central corneal thickness (CCT) was determined by ultrasound pachymetry. The mean of three valid measurements of each variable was used in the statistical analysis. The relationship between the tonometers was established using Bland-Altman plots. Mean IOP was 15.5 ± 2.8 mmHg for GAT, 15.4 ± 2.8 mmHg for CST, and 14.6 ± 2.3 mmHg for PRO. The mean differences between pairs of tonometers were: GAT-PRO=0.9 ± 1.7 mmHg (P<.001), GAT-CST: 0.1 ± 2.2 (P=.398), and PRO-CST: -0.8 ±-0.7 mmHg, p<0.001. A positive relationship was detected between CCT and the three tonometers: GAT: r=0.325, P<.001; PRO: r = 0.385, P<.001, and CST: r = 0.428; P<.001. The differences found between PRO and GAT were significantly higher than those found between CST and GAT, which showed non-significant differences. The measurements of the three tonometers were affected by the CCT. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  6. TGF-β Determines the Pro-migratory Potential of bFGF Signaling in Medulloblastoma.

    PubMed

    Santhana Kumar, Karthiga; Neve, Anuja; Guerreiro Stucklin, Ana S; Kuzan-Fischer, Claudia M; Rushing, Elisabeth J; Taylor, Michael D; Tripolitsioti, Dimitra; Behrmann, Lena; Kirschenbaum, Daniel; Grotzer, Michael A; Baumgartner, Martin

    2018-06-26

    The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  7. ProFound: Source Extraction and Application to Modern Survey Data

    NASA Astrophysics Data System (ADS)

    Robotham, A. S. G.

    2018-04-01

    ProFound detects sources in noisy images, generates segmentation maps identifying the pixels belonging to each source, and measures statistics like flux, size, and ellipticity. These inputs are key requirements of ProFit (ascl:1612.004), our galaxy profiling package; these two packages used in unison semi-automatically profile large samples of galaxies. The key novel feature introduced in ProFound is that all photometry is executed on dilated segmentation maps that fully contain the identifiable flux, rather than using more traditional circular or ellipse-based photometry. Also, to be less sensitive to pathological segmentation issues, the de-blending is made across saddle points in flux. ProFound offers good initial parameter estimation for ProFit, and also segmentation maps that follow the sometimes complex geometry of resolved sources, whilst capturing nearly all of the flux. A number of bulge-disc decomposition projects are already making use of the ProFound and ProFit pipeline.

  8. Paleoglaciology of the Ala-Archa and Ak-Shyrak areas, Kyrgyz Tian Shan

    NASA Astrophysics Data System (ADS)

    Blomdin, R.; Beel, C.; Caffee, M. W.; Codilean, A.; Gribenski, N.; Harbor, J.; Heyman, J.; Hattestrand, C.; Ivanov, M.; Kassab, C.; Lifton, N. A.; Petrakov, D.; Rogozhina, I.; Stroeven, A. P.; Usubaliev, R.

    2012-12-01

    We employed detailed glacial geomorphological mapping of the Ala-Archa and Ak-Shyrak areas, Kyrgyz Tian Shan (Shan = Mountains) to build a paleoglaciological reconstruction. These two areas were selected because their glaciers constitute important freshwater reservoirs for downstream communities (the Kyrgyz capital Bishkek, and cities along the Syr Darja which drains towards the Aral Sea, respectively), and because fluctuations in their extent cause both variations in water supply and risks for glacial hazards. Five landform categories were mapped; glacial valleys, marginal moraines, glacial lineations, hummocky terrain, and melt-water channels. These landforms were mapped using a SRTM digital elevation model (DEM) with a 90 m resolution, Landsat 7 ETM+ satellite imagery with a 30 m resolution, Aster GDEM with a 30 m resolution, and Google Earth. This remotely sensed mapping was also checked and complemented by field mapping. The distribution of mapped landforms indicates restricted glaciations, mainly concentrated to the mountain areas. In both ranges marginal moraines extend beyond the furthest extent of glacial valleys. Furthermore, extensive areas of hummocky moraine in Ak-Shyrak extending beyond montane glacial valleys indicate glacial extents into the intermontane basins. Several series of lateral and terminal moraines in the Ala-Archa and Ak-Shyrak ranges have been identified and sampled for cosmogenic nuclide 10Be dating, while associated glaciofluvial sediment was sampled for optically-stimulated luminescence (OSL) and electron spin resonance (ESR) dating. Future work will involve using these samples to build a consistent chronology for glaciation and investigation of contrasts between paleoglaciological reconstructions of valleys within a single range but with different aspects, as well as between ranges. In the final stages of the project we will use intermediate complexity glacier flow models to examine paleoclimatic implications of the observed spatial

  9. Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

    PubMed

    Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

    2016-12-01

    Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

  10. Assessing High School Students’ Pro-Environmental Behaviour

    NASA Astrophysics Data System (ADS)

    Hidayah, N.; Agustin, R. R.

    2017-09-01

    This paper aims to reveal students’ pro-environmental behavior in a High School. Self-reported behavior assessment was administered in this study involving students with age range 15 to 18 years. Pro-environmental behavior in this study comprises six domains. Those are recycling, waste avoidance, consumerism, energy conservation, mobility and transportation, and vicarious conservation behavior. Pro-environmental behavior (PEB) of science class students was compared to behavior of non-science class students. Effect of students’ grade level and extracurricular activity on the behavior was evaluated. Study revealed that science could improve students’ PEB. It is because environmental topics are covered in science class. Student’s involvement in extracurricular activity may enhance PEB as well. In conclusion, students’ PEB is influenced by class program (science or non-science) but it is not influenced by time length in learning science. This finding could be consider by science educator in choosing strategy to enhance student’s pro-environmental behaviour.

  11. Toxicity of leucine-containing peptides in Escherichia coli caused by circumvention of leucine transport regulation.

    PubMed Central

    Tavori, H; Kimmel, Y; Barak, Z

    1981-01-01

    A variety of leucine-containing peptides (LCP), Phe-Leu, Gly-Leu, Pro-Leu, Ala-Leu, Ala-Leu-Lys, Leu-Phe-Ala, Leu-Leu-Leu, and Leu-Gly-Gly, inhibited the growth of a prototrophic strain of Escherichia coli K-12 at concentrations between 0.05 and 0.28 mM. Toxicity requires normal uptake of peptides. When peptide transport was impaired by mutations, strains became resistant to the respective LCP. Inhibition of growth occurred immediately after the addition of LCP, and was relieved when 0.4 mM isoleucine was added. The presence of Gly-Leu in the medium correlated with the inhibition of growth, and the bacteria began to grow at the normal rate 70 min after Gly-Leu became undetectable. Disappearance of the peptide corresponded with the appearance of free leucine and glycine in the medium. The concentration of leucine inside the LCP-treated bacteria was higher than that in the leucine-treated and the control cultures. We suggest that entry of LCP into the cells via peptide transport systems circumvents the regulation of leucine transport, thereby causing abnormality high concentrations of leucine inside the cells. This accumulation of leucine interferes with the biosynthesis of isoleucine and inhibits the growth of the bacteria. Images PMID:7012134

  12. 25 CFR 273.32 - Pro rata requirement.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Pro rata requirement. 273.32 Section 273.32 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR INDIAN SELF-DETERMINATION AND EDUCATION ASSISTANCE ACT PROGRAM EDUCATION CONTRACTS UNDER JOHNSON-O'MALLEY ACT Funding Provisions § 273.32 Pro rata...

  13. 25 CFR 273.32 - Pro rata requirement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Pro rata requirement. 273.32 Section 273.32 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR INDIAN SELF-DETERMINATION AND EDUCATION ASSISTANCE ACT PROGRAM EDUCATION CONTRACTS UNDER JOHNSON-O'MALLEY ACT Funding Provisions § 273.32 Pro rata...

  14. 25 CFR 273.32 - Pro rata requirement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Pro rata requirement. 273.32 Section 273.32 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR INDIAN SELF-DETERMINATION AND EDUCATION ASSISTANCE ACT PROGRAM EDUCATION CONTRACTS UNDER JOHNSON-O'MALLEY ACT Funding Provisions § 273.32 Pro rata...

  15. 25 CFR 273.32 - Pro rata requirement.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Pro rata requirement. 273.32 Section 273.32 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR INDIAN SELF-DETERMINATION AND EDUCATION ASSISTANCE ACT PROGRAM EDUCATION CONTRACTS UNDER JOHNSON-O'MALLEY ACT Funding Provisions § 273.32 Pro rata...

  16. The Evidence for α-Linolenic Acid and Cardiovascular Disease Benefits: Comparisons with Eicosapentaenoic Acid and Docosahexaenoic Acid12

    PubMed Central

    Fleming, Jennifer A.; Kris-Etherton, Penny M.

    2014-01-01

    Our understanding of the cardiovascular disease (CVD) benefits of α-linolenic acid (ALA, 18:3n–3) has advanced markedly during the past decade. It is now evident that ALA benefits CVD risk. The expansion of the ALA evidence base has occurred in parallel with ongoing research on eicosapentaenoic acid (EPA, 20:5n–3) and docosahexaenoic acid (DHA, 22:6n–3) and CVD. The available evidence enables comparisons to be made for ALA vs. EPA + DHA for CVD risk reduction. The epidemiologic evidence suggests comparable benefits of plant-based and marine-derived n–3 (omega-3) PUFAs. The clinical trial evidence for ALA is not as extensive; however, there have been CVD event benefits reported. Those that have been reported for EPA + DHA are stronger because only EPA + DHA differed between the treatment and control groups, whereas in the ALA studies there were diet differences beyond ALA between the treatment and control groups. Despite this, the evidence suggests many comparable CVD benefits of ALA vs. EPA + DHA. Thus, we believe that it is time to revisit what the contemporary dietary recommendation should be for ALA to decrease the risk of CVD. Our perspective is that increasing dietary ALA will decrease CVD risk; however, randomized controlled clinical trials are necessary to confirm this and to determine what the recommendation should be. With a stronger evidence base, the nutrition community will be better positioned to revise the dietary recommendation for ALA for CVD risk reduction. PMID:25398754

  17. Effects of amaranth addition on the pro-vitamin A content, and physical and antioxidant properties of extruded pro-vitamin A-biofortified maize snacks.

    PubMed

    Beswa, Daniso; Dlamini, Nomusa R; Amonsou, Eric O; Siwela, Muthulisi; Derera, John

    2016-01-15

    Pro-vitamin A-biofortified maize snacks with added leafy vegetable may have a potential as nutritious and health-promoting products, especially in addressing vitamin A deficiency, which is prevalent in developing regions. The objective of the study was to determine the effects of adding amaranth leaf powder on the physical, antioxidant properties and pro-vitamin A content of extruded pro-vitamin A-biofortified maize snacks. Extruded snacks were processed using four pro-vitamin A-biofortified maize varieties that were composited with amaranth leaf powder at 0%, 1% and 3% (w/w) substitution levels. At higher amaranth concentration, the expansion ratio of the snacks decreased, while their hardness increased by as much as 93%. The physical quality of the snacks may therefore need improvement. As amaranth was increased, the phenolic content and antioxidant activity of the snacks increased as well as the pro-vitamin A content. Pro-vitamin A-biofortified maize with added amaranth has a potential for use in nutritious and healthy extruded snacks. There are limited studies reporting on processing pro-vitamin A maize with complementary plant foods, which is common with white maize in southern Africa; thus the current study serves as a baseline. © 2015 Society of Chemical Industry.

  18. Synthesis and pharmacology of halogenated δ-opioid-selective [d-Ala(2)]deltorphin II peptide analogues.

    PubMed

    Pescatore, Robyn; Marrone, Gina F; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E; Pasternak, Gavril W; Wilson, Krista R; Majumdar, Susruta

    2015-06-17

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [(35)S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which (125)I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe(3). The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology.

  19. Synthesis and Pharmacology of Halogenated δ-Opioid-Selective [D-Ala2]Deltorphin II Peptide Analogues

    PubMed Central

    Pescatore, Robyn; Marrone, Gina F.; Sedberry, Seth; Vinton, Daniel; Finkelstein, Netanel; Katlowitz, Yitzchak E.; Pasternak, Gavril W.; Wilson, Krista R.; Majumdar, Susruta

    2015-01-01

    Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-D-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [D-Ala2]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [35S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which 125I isincorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe3. The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology. PMID:25844930

  20. Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death

    PubMed Central

    2012-01-01

    Background Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process. Results An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague–Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73