Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS

PubMed Central

Nesheim, Nils; Ellem, Stuart; Dansranjavin, Temuujin; Hagenkötter, Christina; Berg, Elena; Schambeck, Rupert; Schuppe, Hans-Christian; Pilatz, Adrian; Risbridger, Gail; Weidner, Wolfgang

2018-01-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III (n = 50; median age 39.8, range 23–65) and age-matched controls (n = 61; median age 36.8, range 20–69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes (ESR1 and ESR2) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E2) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E2 –treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E2 –treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy. PMID:29731970

Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS.

PubMed

Nesheim, Nils; Ellem, Stuart; Dansranjavin, Temuujin; Hagenkötter, Christina; Berg, Elena; Schambeck, Rupert; Schuppe, Hans-Christian; Pilatz, Adrian; Risbridger, Gail; Weidner, Wolfgang; Wagenlehner, Florian; Schagdarsurengin, Undraga

2018-04-13

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is associated with urinary tract symptoms and hormonal imbalances amongst others. The heterogeneous clinical presentation, unexplored molecular background and lack of prostate biopsies complicate therapy. Here, using liquid biopsies, we performed a comprehensive translational study on men diagnosed with CP/CPPS type III ( n = 50; median age 39.8, range 23-65) and age-matched controls ( n = 61; median age 36.8, range 20-69), considering biochemical parameters of blood and ejaculates, and epigenetic regulation of the estrogen receptor genes ( ESR1 and ESR2 ) in leukocytes isolated from blood (systemic regulation) and in somatic cells isolated from ejaculates (local regulation). We found elevated 17β-estradiol (E 2 ) levels in seminal plasma, but not in blood plasma, that was significantly associated with CP/CPPS and impaired urinary tract symptoms. In ejaculated somatic cells of CP/CPPS patients we found that ESR1 and ESR2 were both significantly higher methylated in CpG-promoters and expressionally down-regulated in comparison to controls. Mast cells are reported to contribute to CP/CPPS and are estrogen responsive. Consistent with this, we found that E 2 -treatment of human mast cell lines (HMC-1 and LAD2) resulted in altered cytokine and chemokine expression. Interestingly, in HMC-1 cells, possessing epigenetically inactivated ESR1 and ESR2, E 2 -treatment led to a reduced transcription of a number of inflammatory genes. Overall, these data suggest that elevated local E 2 levels associate with an epigenetic down-regulation of the estrogen receptors and have a prominent role in CP/CPPS. Investigating E 2 levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy.

[Optimization of lime milk precipitation process of Lonicera Japonica aqueous extract based on quality by design concept].

PubMed

Shen, Jin-Jing; Gong, Xing-Chu; Pan, Jian-Yang; Qu, Hai-Bin

2017-03-01

Design space approach was applied in this study to optimize the lime milk precipitation process of Lonicera Japonica (Jinyinhua) aqueous extract. The evaluation indices for this process were total organic acid purity and amounts of 6 organic acids obtained from per unit mass of medicinal materials. Four critical process parameters (CPPs) including drop speed of lime milk, pH value after adding lime milk, settling time and settling temperature were identified by using the weighted standardized partial regression coefficient method. Quantitative models between process evaluation indices and CPPs were established by a stepwise regression analysis. A design space was calculated by a Monte-Carlo simulation method, and then verified. The verification test results showed that the operation within the design space can guarantee the stability of the lime milk precipitation process. The recommended normal operation space is as follows： drop speed of lime milk of 1.00-1.25 mL•min⁻¹, pH value of 11.5-11.7, settling time of 1.0-1.2 h, and settling temperature of 10-20 ℃.. Copyright© by the Chinese Pharmaceutical Association.

Process signatures in glatiramer acetate synthesis: structural and functional relationships.

PubMed

Campos-García, Víctor R; Herrera-Fernández, Daniel; Espinosa-de la Garza, Carlos E; González, German; Vallejo-Castillo, Luis; Avila, Sandra; Muñoz-García, Leslie; Medina-Rivero, Emilio; Pérez, Néstor O; Gracia-Mora, Isabel; Pérez-Tapia, Sonia Mayra; Salazar-Ceballos, Rodolfo; Pavón, Lenin; Flores-Ortiz, Luis F

2017-09-21

Glatiramer Acetate (GA) is an immunomodulatory medicine approved for the treatment of multiple sclerosis, whose mechanisms of action are yet to be fully elucidated. GA is comprised of a complex mixture of polypeptides with different amino acid sequences and structures. The lack of sensible information about physicochemical characteristics of GA has contributed to its comprehensiveness complexity. Consequently, an unambiguous determination of distinctive attributes that define GA is of highest relevance towards dissecting its identity. Herein we conducted a study of characteristic GA heterogeneities throughout its manufacturing process (process signatures), revealing a strong impact of critical process parameters (CPPs) on the reactivity of amino acid precursors; reaction initiation and polymerization velocities; and peptide solubility, susceptibility to hydrolysis, and size-exclusion properties. Further, distinctive GA heterogeneities were correlated to defined immunological and toxicological profiles, revealing that GA possesses a unique repertoire of active constituents (epitopes) responsible of its immunological responses, whose modification lead to altered profiles. This novel approach established CPPs influence on intact GA peptide mixture, whose physicochemical identity cannot longer rely on reduced properties (based on complete or partial GA degradation), providing advanced knowledge on GA structural and functional relationships to ensure a consistent manufacturing of safe and effective products.

Negative Illness Perceptions are Associated with a Pro-nociceptive Modulation Profile and Augmented Pelvic Pain.

PubMed

Grinberg, Keren; Granot, Michal; Lowenstein, Lior; Abramov, Liora; Weissman-Fogel, Irit

2018-05-25

A patient's personal interpretations of a health threat or "illness perceptions" (IPs) are associated with their clinical outcomes. This study explored whether IPs are associated with pain severity and ability to modulate pain in women with chronic pelvic pain syndrome (CPPS), as well as the predictive value of IPs on Myofascial Physical Therapy (MPT) success. Illness Perceptions Questionnaire - Revised (IPQ-R), mechanical and heat pain thresholds, mechanical temporal summation (mTS), and conditioned pain modulation (CPM) were evaluated in CPPS patients (n=39) before, and 3 months after MPT. CPPS severity was obtained by the Brief Pain Inventory (BPI). Stronger perceptions of illness chronicity were correlated with less efficient CPM (r=0.488, P=0.002) and increased mechanical pain intensity (r=0.405, P=0.02). Lower perceptions of control over illness were associated with enhanced mTS (r=0.399, P=0.01). Higher BPI scores were correlated with emotional representations ("negative emotional representations") and severe consequences due to CPPS. Regression analyses revealed that negative IPs predict less efficient MPT. Cognitive representations play a unique role in CPPS expression and MPT outcomes. The interplay between negative IPs and a pro-nociceptive modulation profile, mediated by enhanced facilitatory and reduced inhibitory processes, may be involved in the manifestation of CPPS.

(R-X-R)4 -Motif Peptides Containing Conformationally Constrained Cyclohexane-Derived Spacers: Effect on Cellular Uptake.

PubMed

Bhosle, Govind S; Fernandes, Moneesha

2017-11-08

Arginine-rich peptides having the (R-X-R) n motif are among the most effective cell-penetrating peptides (CPPs). Herein we report a several-fold increase in the efficacy of such CPPs if the linear flexible spacer (-X-) in the (R-X-R) motif is replaced by constrained cyclic 1,4-substituted-cyclohexane-derived spacers. Internalization of these oligomers in mammalian cell lines was found to be an energy-dependent process. Incorporation of these constrained, non-proteinogenic amino acid spacers in the CPPs is shown to enhance their proteolytic stability. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Engineering of an inhalable DDA/TDB liposomal adjuvant: a quality-by-design approach towards optimization of the spray drying process.

PubMed

Ingvarsson, Pall Thor; Yang, Mingshi; Mulvad, Helle; Nielsen, Hanne Mørck; Rantanen, Jukka; Foged, Camilla

2013-11-01

The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB). A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis. Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes. The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.

Quality by Design in the development of hydrophilic interaction liquid chromatography method with gradient elution for the analysis of olanzapine.

PubMed

Tumpa, Anja; Stajić, Ana; Jančić-Stojanović, Biljana; Medenica, Mirjana

2017-02-05

This paper deals with the development of hydrophilic interaction liquid chromatography (HILIC) method with gradient elution, in accordance with Analytical Quality by Design (AQbD) methodology, for the first time. The method is developed for olanzapine and its seven related substances. Following step by step AQbD methodology, firstly as critical process parameters (CPPs) temperature, starting content of aqueous phase and duration of linear gradient are recognized, and as critical quality attributes (CQAs) separation criterion S of critical pairs of substances are investigated. Rechtschaffen design is used for the creation of models that describe the dependence between CPPs and CQAs. The design space that is obtained at the end is used for choosing the optimal conditions (set point). The method is fully validated at the end to verify the adequacy of the chosen optimal conditions and applied to real samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Application of quality by design concept to develop a dual gradient elution stability-indicating method for cloxacillin forced degradation studies using combined mixture-process variable models.

PubMed

Zhang, Xia; Hu, Changqin

2017-09-08

Penicillins are typical of complex ionic samples which likely contain large number of degradation-related impurities (DRIs) with different polarities and charge properties. It is often a challenge to develop selective and robust high performance liquid chromatography (HPLC) methods for the efficient separation of all DRIs. In this study, an analytical quality by design (AQbD) approach was proposed for stability-indicating method development of cloxacillin. The structures, retention and UV characteristics rules of penicillins and their impurities were summarized and served as useful prior knowledge. Through quality risk assessment and screen design, 3 critical process parameters (CPPs) were defined, including 2 mixture variables (MVs) and 1 process variable (PV). A combined mixture-process variable (MPV) design was conducted to evaluate the 3 CPPs simultaneously and a response surface methodology (RSM) was used to achieve the optimal experiment parameters. A dual gradient elution was performed to change buffer pH, mobile-phase type and strength simultaneously. The design spaces (DSs) was evaluated using Monte Carlo simulation to give their possibility of meeting the specifications of CQAs. A Plackett-Burman design was performed to test the robustness around the working points and to decide the normal operating ranges (NORs). Finally, validation was performed following International Conference on Harmonisation (ICH) guidelines. To our knowledge, this is the first study of using MPV design and dual gradient elution to develop HPLC methods and improve separations for complex ionic samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Alterations in regional homogeneity of resting-state cerebral activity in patients with chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Lin, Yusong; Bai, Yan; Liu, Peng; Yang, Xuejuan; Qin, Wei; Gu, Jianqin; Ding, Degang; Tian, Jie; Wang, Meiyun

2017-01-01

The purpose of this study was to explore the neural mechanism in Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) using resting-state functional magnetic resonance imaging. The functional magnetic resonance imaging was performed on 31 male CP/CPPS-patients and 31 age and education matched male healthy controls on a 3-T magnetic resonance imaging unit. A two-sample t-test was adopted to reveal the regional homogeneity between the patients and healthy controls. The mean regional homogeneity values in the alerted brain regions of patients were correlated with the clinical measurements by using Pearson's correlation analyses. The CP/CPPS-patients had significantly decreased regional homogeneity in the bilateral anterior cingulate cortices, insular cortices and right medial prefrontal cortex, while significantly increased regional homogeneity in the brainstem and right thalamus compared with the healthy controls. In the CP/CPPS-patients, the mean regional homogeneity value in the left anterior cingulate cortex, bilateral insular cortices and brainstem were respectively correlated with the National Institutes of Health Chronic Prostatitis Symptom Index total score and pain subscale. These brain regions are important in the pain modulation process. Therefore, an impaired pain modulatory system, either by decreased descending pain inhibition or enhanced pain facilitation, may explain the pain symptoms in CP/CPPS.

Cepstral analysis of normal and pathological voice in Spanish adults. Smoothed cepstral peak prominence in sustained vowels versus connected speech.

PubMed

Delgado-Hernández, Jonathan; León-Gómez, Nieves M; Izquierdo-Arteaga, Laura M; Llanos-Fumero, Yanira

In recent years, the use of cepstral measures for acoustic evaluation of voice has increased. One of the most investigated parameters is smoothed cepstral peak prominence (CPPs). The objectives of this paper are to establish the usefulness of this acoustic measure in the objective evaluation of alterations of the voice in Spanish and to determine what type of voice sample (sustained vowels or connected speech) is the most sensitive in evaluating the severity of dysphonia. Forty subjects participated in this study 40, 20 controls and 20 with dysphonia. Two voice samples were recorded for each subject (one sustained vowel/a/and four phonetically balanced sentences) and the CPPs was calculated using the Praat programme. Three raters perceptually evaluated the voice sample with the Grade parameter of GRABS scale. Significantly lower values were found in the dysphonic voices, both for/a/(t [38] = 4.85, P<.000) and for phrases (t [38] = 5,75, P<.000). In relation to the type of voice sample most suitable for evaluating the severity of voice alterations, a strong correlation was found with the acoustic-perceptual scale of CPPs calculated from connected speech (r s = -0.73) and moderate correlation with that calculated from the sustained vowel (r s = -0,56). The results of this preliminary study suggest that CPPs is a good measure to detect dysphonia and to objectively assess the severity of alterations in the voice. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

Using an innovative combination of quality-by-design and green analytical chemistry approaches for the development of a stability indicating UHPLC method in pharmaceutical products.

PubMed

Boussès, Christine; Ferey, Ludivine; Vedrines, Elodie; Gaudin, Karen

2015-11-10

An innovative combination of green chemistry and quality by design (QbD) approach is presented through the development of an UHPLC method for the analysis of the main degradation products of dextromethorphan hydrobromide. QbD strategy was integrated to the field of green analytical chemistry to improve method understanding while assuring quality and minimizing environmental impacts, and analyst exposure. This analytical method was thoroughly evaluated by applying risk assessment and multivariate analysis tools. After a scouting phase aimed at selecting a suitable stationary phase and an organic solvent in accordance with green chemistry principles, quality risk assessment tools were applied to determine the critical process parameters (CPPs). The effects of the CPPs on critical quality attributes (CQAs), i.e., resolutions, efficiencies, and solvent consumption were further evaluated by means of a screening design. A response surface methodology was then carried out to model CQAs as function of the selected CPPs and the optimal separation conditions were determined through a desirability analysis. Resulting contour plots enabled to establish the design space (DS) (method operable design region) where all CQAs fulfilled the requirements. An experimental validation of the DS proved that quality within the DS was guaranteed; therefore no more robustness study was required before the validation. Finally, this UHPLC method was validated using the concept of total error and was used to analyze a pharmaceutical drug product. Copyright © 2015 Elsevier B.V. All rights reserved.

Phosphorylated Codonopsis pilosula polysaccharide could inhibit the virulence of duck hepatitis A virus compared with Codonopsis pilosula polysaccharide.

PubMed

Ming, Ke; Chen, Yun; Yao, Fangke; Shi, Jintong; Yang, Jingjing; Du, Hongxu; Wang, Xunyi; Wang, Yixuan; Liu, Jiaguo

2017-01-01

To screen effective anti-duck hepatitis A virus (DHAV) drugs, we applied STMP-STPP method to prepare phosphorylated Codonopsis pilosula polysaccharide (pCPPS), the phosphorylation-modified product of Codonopsis pilosula polysaccharide (CPPS). The IR spectrum and field emission scanning electron microscope (FE-SEM) were subsequently used to analyze the structure of pCPPS. Several tests were conducted to compare the anti-DHAV activities of CPPS and pCPPS. The MTT method was used to compare the effect of the drugs on DHAV-infected duck embryonic hepatocytes (DEHs), and the Reed-Muench assay was employed to observe changes in the virulence of DHAV. We also applied real-time PCR to examine the relationship between virus replication and the expression of IFN-β. The results indicated that CPPS could not inhibit the replication of DHAV. In contrast, pCPPS increased the virus TCID 50 , inhibited viral replication and, accordingly, increased the survival rate of DEHs infected with DHAV. Because DHAV induced the expression of IFN-β, and the IFN-β expression level was positively associated with the number of DHAV, the reduction of IFN-β expression levels after pCPPS treatment demonstrated a decrease in the number of virus particles. These results indicated that pCPPS, which reduces the number of DHAV, was more effective than CPPS in anti-DHAV activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Toe spreading ability in men with chronic pelvic pain syndrome

PubMed Central

Yilmaz, Ugur; Rothman, Ivan; Ciol, Marcia A; Yang, Claire C; Berger, Richard E

2005-01-01

Background We examined toe-spreading ability in subjects with chronic pelvic pain syndrome (CPPS) to test the hypothesis that subjects with CPPS could have deficiencies in lower extremity functions innervated by sacral spinal roots. Methods Seventy two subjects with CPPS and 98 volunteer controls were examined as part of a larger study on CPPS. All the subjects underwent a detailed urologic and neurological examination including a toe-spreading examination with a quantitative scoring system. We compared the groups in terms of ability of toe-spreading as either "complete" (all toes spreading) or "incomplete" (at least one interdigital space not spreading) and also by comparing the number of interdigital spaces. For CPPS subjects only, we also analyzed the variation of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scales by toe-spreading categories. Results CPPS subjects were less often able to spread all toes than subjects without CPPS (p = 0.005). None of the NIH-CPSI sub-scales (pain, urinary symptoms, and quality of life), nor the total score showed an association with toe spreading ability. Conclusion We found toe spreading to be diminished in subjects with CPPS. We hypothesize that incomplete toe spreading in subjects with CPPS may be related to subtle deficits involving the most caudal part of the spinal segments. PMID:15949041

The Perception of Being a Burden in Acute and Chronic Pain Patients Is Associated with Affirmation of Different Types of Suicidality.

PubMed

Fishbain, David A; Bruns, Daniel; Bruns, Alexander; Gao, Jinrun; Lewis, John E; Meyer, Laura J; Disorbio, John Mark

2016-03-01

The perception of being a burden or self-perceived burden (SPB) is associated with suicide ideation in chronic pain patients (CPPs). The objective of this study was to determine if SPB is associated with five types of suicidality (wish to die, active suicide ideation, presence of suicide plan, history of suicide attempts, and preference for death over being disabled) in CPPs and acute pain patients (APPs). Affirmation of SPB was statistically compared between community nonpatients without pain (CNPWP), APPs, and CPPs. APPs and CPPs who had affirmed any of the five types of suicidality were compared statistically for affirmation of SPB. Hierarchical regression analysis was utilized to determine the significance of SPB in predicting each of the five types of suicidality in APPs and CPPs controlling for age, gender, race, education status, and two types of measures of depression (current depression and vegetative depression). APPs and CPPs were statistically more likely to affirm SPB than CNPWPs and CPPs were more likely than APPs to do so. There were no differences between APPs and CPPs in affirming SPB in APPs and CPPs who had affirmed any of the five types of suicidality. In CPPs, SPB predicted each type of suicidality in a significant fashion utilizing both types of depression measures. For APPs, SPB predicted each type of suicidality in a significant fashion except for history of suicide attempt controlling for vegetative depression. SPB is associated with the vast majority of different types of suicidality in APPs and CPPs. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Chronic prostatitis/chronic pelvic pain syndrome in adolescents compared with that in young adults.

PubMed

Lee, Keon-Cheol; Cho, In-Rae

2017-07-01

Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) has been studied mainly in adults; reports in adolescents are rare. We compared the clinical characteristics of adolescent CP/CPPS patients with those of young adults. We retrospectively analyzed 20 adolescents with CP/CPPS aged <20 years who visited our outpatient department from August 2005 to April 2012. The control group comprised 120 young adult CP/CPPS patients. A complete medical history, physical examination, the national institute of health-chronic prostatitis symptoms index (NIH-CPSI) questionnaire, urinalysis, expressed prostatic secretion (EPS) or semen analysis, transrectal prostate ultrasonography, and prostate-specific antigen (PSA) were performed. Based on the EPS or semen analysis, patients were divided into category III-A or III-B. The mean age was 16.5±2.0 and 32.8±5.0 years in the adolescent and control groups, respectively. A sexual activity history was seen in 2 patients; 9 and 11 patients were in category III-A and III-B, respectively. The PSA was 0.65±0.39 and 1.22±0.48 ng/mL in the adolescent and control groups, respectively. The prostate size was 12.4±4.4 and 21.0±4.9 g in the adolescent and control groups, respectively. The NIH-CPSI scores in the adolescent group were 9.2±5.2, 5.5±3.5, 7.5±3.2, and 22.2±8.1 for pain, voiding, quality of life (QoL) domains, and total scores, respectively. The adolescent group showed a tendency to exhibit high voiding symptom scores. CPPS has an equally severe impact on QoL in adults and adolescents. Apart from high voiding symptom scores in adolescents, no difference was found in terms of urologic clinical parameters.

Redundant prepuce increases the odds of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

PubMed

Zhao, Yu-Yang; Xu, Dong-Liang; Zhao, Fu-Jun; Han, Bang-Min; Shao, Yi; Zhao, Wei; Xia, Shu-Jie

2014-01-01

Some published evidence has revealed that the dendritic cells can interact with pathogens that exist in the inner foreskin. This information provides a new vision that pathogens could play a role through the redundant prepuce; numerous studies have failed to find pathogens in prostates of patients who had chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, no studies have reported an association between foreskin length and CP/CPPS. Hence, we conducted a retrospective case-control study of clinical data from 322 CP/CPPS patients (case group) and 341 nonCP/CPPS patients (control group). Demographic characteristics, lifestyle factors, and foreskin lengths were collected and analyzed. Multivariate logistic regression was adopted to calculate the odds of foreskin length for CP/CPPS. According to the multivariate logistic regression results, when the foreskin length covered up more than half of the glans penis, the odds for CP/CPPS were higher with an increased foreskin (odds ratio (OR): 1.66, 95% confidence interval (CI): 1.04-2.66). In comparison, when the glans penis was completely covered by the foreskin, the OR value increased to 1.86 (95% CI, 1.2-2.88). The study results showed an association between foreskin length and the odds of CP/CPPS. When the foreskin length covered up more than half of the glans penis, there were greater odds for CP/CPPS. This possible mechanism might result from interaction between pathogens and DCs in the inner foreskin, consequently activating T-cells to mediate allergic inflammation in the prostate and producing the autoimmunizations causing CP/CPPS.

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

PubMed Central

Hu, Chao; Yang, Hualan; Zhao, Yanfang; Chen, Xiang; Dong, Yinying; Li, Long; Dong, Yehao; Cui, Jiefeng; Zhu, Tongyu; Zheng, Ping; Lin, Ching-Shwun; Dai, Jican

2016-01-01

Mental health disorders(MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. However, the underlying role of inflammatory cytokines and their associated signaling pathways have not been investigated. Here, we report the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model. CP/CPPS patients (n = 810) and control subjects (n = 992) were enrolled in this case-control multicenter study, and serum cytokine levels were measured. Male Sprague-Dawley rats received multiple intracutaneous injections of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP/CPPS development. The results revealed that, in CP/CPPS patients with significant MHD, elevated IL-1α, IL-1β, IL-4, IL-13, and TNF-α serum levels were observed. The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue (p < 0.05), and IL-1β levels were elevated in serum and cerebrospinal fluid. In behavioral tests, CP/CPPS rats showed anxiety- and depression-like symptoms, and impaired spatial and associative memory performance (p < 0.05). In the CP/CPPS group, ERK1/2 phosphorylation levels were increased in the amygdala and nucleus accumbens, and decreased in the hippocampus, but not caudate nucleus. Thus, prostate-derived cytokines, especially IL-1β, cross the blood brain barrier and may lead to enhanced ERK1/2 signaling in several brain areas, possibly underlying induction of CP/CPPS-related MHD. PMID:27334333

Characterization of casein phosphopeptides from fermented milk products.

PubMed

Kawahara, Takeshi; Aruga, Kaori; Otani, Hajime

2005-10-01

This study dealt with the potential of fermented milk products as a source of functional casein phosphopeptides (CPPs) using plain yogurts and Camembert cheeses. The CPPs were prepared by tryptic digestion from four commercially available plain yogurts (P1-P4), five Camembert cheeses (C1-C5), and raw milk. From portions with a 1-g protein content of the plain yogurts, the Camembert cheeses, and the raw milk, 171 mg, 139 mg, and 146 mg of CPPs were obtained, respectively. The Camembert cheeses retained high amounts of organic phosphorus (32 microg) per 1 mg CPPs compared to the raw milk (15 microg) and plain yogurts (16 microg). Reverse-phase high-performance liquid chromatographic analysis showed that the elution patterns and retention times of the three major peaks of CPPs from P1 and C1 were similar to those from raw milk. Moreover, CPPs from P1 and C1 showed a mitogenic effect, while CPPs from C1 showed an IgA-enhancing effect in mouse spleen cell cultures. These results suggest that fermented milk products such as plain yogurts and Camembert cheeses generate functional CPPs in the body and exert beneficial effects on the immune system.

Differential expression of immune factor between patients with chronic prostatitis/chronic pelvic pain syndrome and the healthy volunteers.

PubMed

Ye, Chen; Xiao, Guang'an; Xu, Jian; Qin, Shengfei; Luo, Yuhua; Chen, Guanghua; Lai, H Henry; Zhou, Tie

2018-03-01

Immune mechanisms have been hypothesized to contribute to the development of CP/CPPS. In this study, we investigated the differential expression of immune factors between patients with CP/CPPS and healthy volunteers. This study was registered in Australian New Zealand Clinical Trials Registry. Healthy volunteers and patients with CP/CPPS were enrolled in this study. The inclusion criteria for patients were below: (1) aged 18-45 years old; (2) prostatitis-related syndrome longer than 3 months; (3) normal routine urine culture and negative bacterial culture in prostatic fluid. Patients were further classified into two groups: types IIIA and IIIB CP/CPPS according to the results of EPS routine test. Serum immune markers include IgA, IgM, IgG, CD4 + and CD8 + . There are total 23 CP/CPPS patients, including 12 type IIIB and 11 type IIIA. Relatively, there are 26 healthy volunteers. The serum levels of IgG were higher in CP/CPPS patients compared to healthy volunteers (1141.2 ± 204.3 vs 1031.9 ± 173.7 mg/L, p = 0.045), while the serum levels of CD8 + were lower in CP/CPPS patients compared to healthy volunteers (492.8 ± 185.6 vs 640.0 ± 246.8 cells/μL, p = 0.021). Furthermore, serum levels of IgG were higher in patients with IIIA CP/CPPS compared to those with IIIB (1244.3 ± 151.6 vs 1054.3 ± 209.3 mg/L, p = 0.023). Differential levels of IgG and CD8 + between CPPS patients and healthy volunteers suggest a contributing role of immune mechanisms to the development of CP/CPPS; and IgG may play an important role in inflammatory CPPS. Clinical Study registration number ACTRN12613000792729.

Predicting Voice Disorder Status From Smoothed Measures of Cepstral Peak Prominence Using Praat and Analysis of Dysphonia in Speech and Voice (ADSV).

PubMed

Sauder, Cara; Bretl, Michelle; Eadie, Tanya

2017-09-01

The purposes of this study were to (1) determine and compare the diagnostic accuracy of a single acoustic measure, smoothed cepstral peak prominence (CPPS), to predict voice disorder status from connected speech samples using two software systems: Analysis of Dysphonia in Speech and Voice (ADSV) and Praat; and (2) to determine the relationship between measures of CPPS generated from these programs. This is a retrospective cross-sectional study. Measures of CPPS were obtained from connected speech recordings of 100 subjects with voice disorders and 70 nondysphonic subjects without vocal complaints using commercially available ADSV and freely downloadable Praat software programs. Logistic regression and receiver operating characteristic (ROC) analyses were used to evaluate and compare the diagnostic accuracy of CPPS measures. Relationships between CPPS measures from the programs were determined. Results showed acceptable overall accuracy rates (75% accuracy, ADSV; 82% accuracy, Praat) and area under the ROC curves (area under the curve [AUC] = 0.81, ADSV; AUC = 0.91, Praat) for predicting voice disorder status, with slight differences in sensitivity and specificity. CPPS measures derived from Praat were uniquely predictive of disorder status above and beyond CPPS measures from ADSV (χ 2 (1) = 40.71, P < 0.001). CPPS measures from both programs were significantly and highly correlated (r = 0.88, P < 0.001). A single acoustic measure of CPPS was highly predictive of voice disorder status using either program. Clinicians may consider using CPPS to complement clinical voice evaluation and screening protocols. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

The Effect of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) on Erectile Function: A Systematic Review and Meta-Analysis.

PubMed

Chen, Xiang; Zhou, ZhiRui; Qiu, XiaoChun; Wang, Bin; Dai, JiCan

2015-01-01

High prevalence of erectile dysfunction (ED) has been observed in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, whether or not CP/CPPS is a risk factor of ED remains unknown and controversial. Therefore, we conducted this systematic review and meta-analysis to evaluate the relationship between CP/CPPS and ED. PubMed, Embase, Web of Science, and The Cochrane Library were searched up to November 11, 2014 to identify studies reporting the association between CP/CPPS and ED. Case-control, cohort and cross-sectional studies were included. Quality of the included studies was assessed. The odds ratio of ED and the mean difference of five-item International Index of Erectile Function (IIEF-5) score were pooled using a random effects model. Subgroup analysis and sensitivity analyses were performed. Three cross-sectional studies, two case-control studies, and four retrospective studies with 31,956 participants were included to calculate the pooled odds ratio of ED, and two studies with 1499 participants were included to calculate the pooled mean difference of IIEF-5 scores. A strong correlation was found between CP/CPPS and ED (pooled odds ratio: 3.02, 95% CI: 2.18-4.17, P < 0.01), with heterogeneity across studies (I2 = 65%; P < 0.01). A significant decrease in the IIFE-5 score was observed in the CP/CPPS group (pooled mean difference: -4.54, 95% CI: -5.11--3.98; P < 0.01). Our study indicates that patients with CP/CPPS have an increased risk of suffering from ED. Assessment of erectile function is necessary for the therapy of patients with CP/CPPS. Further evidence is necessary to confirm the relationship between CP/CPPS and ED.

Resource use efficiency of closed plant production system with artificial light: Concept, estimation and application to plant factory

PubMed Central

KOZAI, Toyoki

2013-01-01

Extensive research has recently been conducted on plant factory with artificial light, which is one type of closed plant production system (CPPS) consisting of a thermally insulated and airtight structure, a multi-tier system with lighting devices, air conditioners and fans, a CO2 supply unit, a nutrient solution supply unit, and an environment control unit. One of the research outcomes is the concept of resource use efficiency (RUE) of CPPS. This paper reviews the characteristics of the CPPS compared with those of the greenhouse, mainly from the viewpoint of RUE, which is defined as the ratio of the amount of the resource fixed or held in plants to the amount of the resource supplied to the CPPS. It is shown that the use efficiencies of water, CO2 and light energy are considerably higher in the CPPS than those in the greenhouse. On the other hand, there is much more room for improving the light and electric energy use efficiencies of CPPS. Challenging issues for CPPS and RUE are also discussed. PMID:24334509

Resource use efficiency of closed plant production system with artificial light: concept, estimation and application to plant factory.

PubMed

Kozai, Toyoki

2013-01-01

Extensive research has recently been conducted on plant factory with artificial light, which is one type of closed plant production system (CPPS) consisting of a thermally insulated and airtight structure, a multi-tier system with lighting devices, air conditioners and fans, a CO2 supply unit, a nutrient solution supply unit, and an environment control unit. One of the research outcomes is the concept of resource use efficiency (RUE) of CPPS.This paper reviews the characteristics of the CPPS compared with those of the greenhouse, mainly from the viewpoint of RUE, which is defined as the ratio of the amount of the resource fixed or held in plants to the amount of the resource supplied to the CPPS.It is shown that the use efficiencies of water, CO2 and light energy are considerably higher in the CPPS than those in the greenhouse. On the other hand, there is much more room for improving the light and electric energy use efficiencies of CPPS. Challenging issues for CPPS and RUE are also discussed.

Optimization of the Ethanol Recycling Reflux Extraction Process for Saponins Using a Design Space Approach

PubMed Central

Gong, Xingchu; Zhang, Ying; Pan, Jianyang; Qu, Haibin

2014-01-01

A solvent recycling reflux extraction process for Panax notoginseng was optimized using a design space approach to improve the batch-to-batch consistency of the extract. Saponin yields, total saponin purity, and pigment yield were defined as the process critical quality attributes (CQAs). Ethanol content, extraction time, and the ratio of the recycling ethanol flow rate and initial solvent volume in the extraction tank (RES) were identified as the critical process parameters (CPPs) via quantitative risk assessment. Box-Behnken design experiments were performed. Quadratic models between CPPs and process CQAs were developed, with determination coefficients higher than 0.88. As the ethanol concentration decreases, saponin yields first increase and then decrease. A longer extraction time leads to higher yields of the ginsenosides Rb1 and Rd. The total saponin purity increases as the ethanol concentration increases. The pigment yield increases as the ethanol concentration decreases or extraction time increases. The design space was calculated using a Monte-Carlo simulation method with an acceptable probability of 0.90. Normal operation ranges to attain process CQA criteria with a probability of more than 0.914 are recommended as follows: ethanol content of 79–82%, extraction time of 6.1–7.1 h, and RES of 0.039–0.040 min−1. Most of the results of the verification experiments agreed well with the predictions. The verification experiment results showed that the selection of proper operating ethanol content, extraction time, and RES within the design space can ensure that the CQA criteria are met. PMID:25470598

Process analytical technology (PAT) in insect and mammalian cell culture processes: dielectric spectroscopy and focused beam reflectance measurement (FBRM).

PubMed

Druzinec, Damir; Weiss, Katja; Elseberg, Christiane; Salzig, Denise; Kraume, Matthias; Pörtner, Ralf; Czermak, Peter

2014-01-01

Modern bioprocesses demand for a careful definition of the critical process parameters (CPPs) already during the early stages of process development in order to ensure high-quality products and satisfactory yields. In this context, online monitoring tools can be applied to recognize unfavorable changes of CPPs during the production processes and to allow for early interventions in order to prevent losses of production batches due to quality issues. Process analytical technologies such as the dielectric spectroscopy or focused beam reflectance measurement (FBRM) are possible online monitoring tools, which can be applied to monitor cell growth as well as morphological changes. Since the dielectric spectroscopy only captures cells with intact cell membranes, even information about dead cells with ruptured or leaking cell membranes can be derived. The following chapter describes the application of dielectric spectroscopy on various virus-infected and non-infected cell lines with respect to adherent as well as suspension cultures in common stirred tank reactors. The adherent mammalian cell lines Vero (African green monkey kidney cells) and hMSC-TERT (telomerase-immortalized human mesenchymal stem cells) are thereby cultured on microcarrier, which provide the required growth surface and allow the cultivation of these cells even in dynamic culture systems. In turn, the insect-derived cell lines S2 and Sf21 are used as examples for cells typically cultured in suspension. Moreover, the FBRM technology as a further monitoring tool for cell culture applications has been included in this chapter using the example of Drosophila S2 insect cells.

[Chronic Pelvic Pain Syndrome and Personality--Association of Somatic Symptoms and Psychic Structure].

PubMed

Albrecht, Rebecca; Löwe, Bernd; A Brünahl, Christian; Riegel, Björn

2015-11-01

Despite its high prevalence, little is known about the aetiology and maintenance of Chronic Pelvic Pain Syndrome (CPPS). CPPS is is considered to be a multi-causal syndrome with discomfort and pain in the pelvis. Recent literature suggests that psychosocial factors are important for understanding CPPS. For example, CPPS has been associated with deficits in mentalization and bonding experiences. Our study aims to characterize features of personality disorders according to DSM-IV and psychic structure according to OPD-2 in CPPS patients. Furthermore, we examine the association of personality aspects with urological symptoms (NIH Questionnaire) and pain perception (MPQ Questionnaire). Personality aspects were assessed in a total of 109 patients from our CPPS outpatient clinic using standardized questionnaires. To characterize CPPS patients, we compared the sample's scores with reference groups, mostly the general population. In addition, the associations between personality aspects and both the urologic symptoms and pain perception were assessed using correlations. Missing data were replaced using multiple imputation methods. Compared to reference values, we found 'experiencing emotions' and 'creating relationships' as specific deficits in CPPS patients. Furthermore, patients' self-image (more dominant, higher depressive mood) differs from the general population. A higher pain perception was correlated with deficits in most personality aspects we measured. However, this was not the case for the severity of urological symptoms. Compared to the reference values, only a few personality aspects differed in CPPS patients but there was a correlational association between different personality traits and pain perception. Despite the extend of symptoms, pain perception is associated with difficulty (emotional ability) in dealing with emotions, self-management and relationships. These personality aspects should be taken into account when planning therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Coffee polyphenols extracted from green coffee beans improve skin properties and microcirculatory function.

PubMed

Fukagawa, Satoko; Haramizu, Satoshi; Sasaoka, Shun; Yasuda, Yuka; Tsujimura, Hisashi; Murase, Takatoshi

2017-09-01

Coffee polyphenols (CPPs), including chlorogenic acid, exert various physiological activities. The purpose of this study was to investigate the effects of CPPs on skin properties and microcirculatory function in humans. In this double-blind, placebo-controlled study, 49 female subjects with mildly xerotic skin received either a test beverage containing CPPs (270 mg/100 mL/day) or a placebo beverage for 8 weeks. The ingestion of CPPs significantly lowered the clinical scores for skin dryness, decreased transepidermal water loss, skin surface pH, and increased stratum corneum hydration and the responsiveness of skin blood flow during local warming. Moreover, the amounts of free fatty acids and lactic acid in the stratum corneum significantly increased after the ingestion of CPPs. These results suggest that an 8-week intake of CPPs improve skin permeability barrier function and hydration, with a concomitant improvement in microcirculatory function, leading to efficacy in the alleviation of mildly xerotic skin.

A quality by design approach using artificial intelligence techniques to control the critical quality attributes of ramipril tablets manufactured by wet granulation.

PubMed

Aksu, Buket; Paradkar, Anant; de Matas, Marcel; Özer, Özgen; Güneri, Tamer; York, Peter

2013-02-01

Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.

Reinventing Cell Penetrating Peptides Using Glycosylated Methionine Sulfonium Ion Sequences.

PubMed

Kramer, Jessica R; Schmidt, Nathan W; Mayle, Kristine M; Kamei, Daniel T; Wong, Gerard C L; Deming, Timothy J

2015-05-27

Cell penetrating peptides (CPPs) are intriguing molecules that have received much attention, both in terms of mechanistic analysis and as transporters for intracellular therapeutic delivery. Most CPPs contain an abundance of cationic charged residues, typically arginine, where the amino acid compositions, rather than specific sequences, tend to determine their ability to enter cells. Hydrophobic residues are often added to cationic sequences to create efficient CPPs, but typically at the penalty of increased cytotoxicity. Here, we examined polypeptides containing glycosylated, cationic derivatives of methionine, where we found these hydrophilic polypeptides to be surprisingly effective as CPPs and to also possess low cytotoxicity. X-ray analysis of how these new polypeptides interact with lipid membranes revealed that the incorporation of sterically demanding hydrophilic cationic groups in polypeptides is an unprecedented new concept for design of potent CPPs.

Effects and Mechanisms of Low-Intensity Pulsed Ultrasound for Chronic Prostatitis and Chronic Pelvic Pain Syndrome

PubMed Central

Lin, Guiting; Reed-Maldonado, Amanda B.; Lin, Maofan; Xin, Zhongcheng; Lue, Tom F.

2016-01-01

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is one of the most common urologic diseases, and no curative treatments have been identified. Low-intensity pulsed ultrasound (LIPUS) has been successfully used in promoting tissue healing, inhibiting inflammation and pain, differentiating stem cells, and stimulating nerve regeneration/muscle regeneration, as well as enhancing angiogenesis. Very recently, LIPUS has been proven an effective approach for CP/CPPS. This review summarizes the possible mechanisms responsible for the therapeutic effect of LIPUS for CP/CPPS. To search publications relevant to the topics of this review, the search engine for life sciences of Entrez was used. We reviewed the available evidence from 1954 through 2015 concerning LIPUS for CP/CPPS. According to the literature, both transrectal and transperineal approaches of LIPUS are effective for CP/CPPS. PMID:27376284

Effects and Mechanisms of Low-Intensity Pulsed Ultrasound for Chronic Prostatitis and Chronic Pelvic Pain Syndrome.

PubMed

Lin, Guiting; Reed-Maldonado, Amanda B; Lin, Maofan; Xin, Zhongcheng; Lue, Tom F

2016-07-01

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is one of the most common urologic diseases, and no curative treatments have been identified. Low-intensity pulsed ultrasound (LIPUS) has been successfully used in promoting tissue healing, inhibiting inflammation and pain, differentiating stem cells, and stimulating nerve regeneration/muscle regeneration, as well as enhancing angiogenesis. Very recently, LIPUS has been proven an effective approach for CP/CPPS. This review summarizes the possible mechanisms responsible for the therapeutic effect of LIPUS for CP/CPPS. To search publications relevant to the topics of this review, the search engine for life sciences of Entrez was used. We reviewed the available evidence from 1954 through 2015 concerning LIPUS for CP/CPPS. According to the literature, both transrectal and transperineal approaches of LIPUS are effective for CP/CPPS.

Reinventing cell penetrating peptides using glycosylated methionine sulfonium ion sequences

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

Kramer, Jessica R.; Schmidt, Nathan W.; Mayle, Kristine M.

2015-04-15

Cell penetrating peptides (CPPs) are intriguing molecules that have received much attention, both in terms of mechanistic analysis and as transporters for intracellular therapeutic delivery. Most CPPs contain an abundance of cationic charged residues, typically arginine, where the amino acid compositions, rather than specific sequences, tend to determine their ability to enter cells. Hydrophobic residues are often added to cationic sequences to create efficient CPPs, but typically at the penalty of increased cytotoxicity. Here, we examined polypeptides containing glycosylated, cationic derivatives of methionine, where we found these hydrophilic polypeptides to be surprisingly effective as CPPs and to also possess lowmore » cytotoxicity. X-ray analysis of how these new polypeptides interact with lipid membranes revealed that the incorporation of sterically demanding hydrophilic cationic groups in polypeptides is an unprecedented new concept for design of potent CPPs.« less

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP

PubMed Central

Kutch, Jason J.; Yani, Moheb S.; Asavasopon, Skulpan; Kirages, Daniel J.; Rana, Manku; Cosand, Louise; Labus, Jennifer S.; Kilpatrick, Lisa A.; Ashe-McNalley, Cody; Farmer, Melissa A.; Johnson, Kevin A.; Ness, Timothy J.; Deutsch, Georg; Harris, Richard E.; Apkarian, A. Vania; Clauw, Daniel J.; Mackey, Sean C.; Mullins, Chris; Mayer, Emeran A.

2015-01-01

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing. PMID:26106574

Adrenocortical Hormone Abnormalities in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Dimitrakov, Jordan; Joffe, Hylton V.; Soldin, Steven J.; Bolus, Roger; Buffington, C.A. Tony; Nickel, J Curtis

2007-01-01

Objectives To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in CP/CPPS. Methods We simultaneously measured the serum concentrations of 12 steroids in CP/CPPS and control patients, using isotope dilution liquid chromatography followed by atmospheric pressure photospray ionization and tandem mass spectrometry. Results Twenty-seven CP/CPPS patients and 29 age-matched asymptomatic healthy controls were evaluated. In the mineralocorticoid pathway, progesterone was significantly higher, whereas corticosterone and aldosterone concentrations were significantly lower, in CP/CPPS than in controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower, and cortisol concentrations were not different between patients and controls. In the sex steroid pathway, androstenedione and testosterone concentrations were significantly higher in CP/CPPS than in controls. Estradiol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrations were not different between patients and controls. NIH-CPSI total and pain domain scores correlated positively with 17-hydroxyprogesterone and aldosterone (P<0.001) and negatively with cortisol concentrations (P<0.001). Conclusions Results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone, and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biological basis of CP/CPPS. Follow-up studies should explore the possibility that CP/CPPS patients meet the diagnostic criteria for nonclassical CAH and if hormonal findings improve or worsen in parallel with symptom severity. PMID:18308097

Trace Detection of Metalloporphyrin-Based Coordination Polymer Particles via Modified Surface-Enhanced Raman Scattering Assisted by Surface Metallization.

PubMed

Sun, Yu; Caravella, Alessio

2016-01-01

This study proposed a facile method to detect metalloporphyrin-based coordination polymer particles (Z-CPPs) in aqueous solution by modified surface-enhanced Raman scattering (SERS). The SERS-active particles are photodeposited on the surface of Z-CPPs, offering an enhanced Raman signal for the trace detection of Z-CPPs.

Diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline.

PubMed

Rees, Jon; Abrahams, Mark; Doble, Andrew; Cooper, Alison

2015-10-01

To improve awareness and recognition of chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among non-specialists and patients. To provide guidance to healthcare professionals treating patients with CBP and CP/CPPS, in both non-specialist and specialist settings. To promote efficient referral of care between non-specialists and specialists and the involvement of the multidisciplinary team (MDT). The guideline population were men with CBP or CP/CPPS (persistent or recurrent symptoms and no other urogenital pathology for ≥3 of the previous 6 months). Consensus recommendations for the guidelines were based on a search to identify literature on the diagnosis and management of CBP and CP/CPPS (published between 1999 and February 2014). A Delphi panel process was used where high-quality, published evidence was lacking. CBP and CP/CPPS can present with a wide range of clinical manifestations. The four main symptom domains are urogenital pain, lower urinary tract symptoms (LUTS - voiding or storage symptoms), psychological issues and sexual dysfunction. Patients should be managed according to their individual symptom pattern. Options for first-line treatment include antibiotics, α-adrenergic antagonists (if voiding LUTS are present) and simple analgesics. Repeated use of antibiotics, such as quinolones, should be avoided if there is no obvious symptomatic benefit from infection control or cultures do not support an infectious cause. Early use of treatments targeting neuropathic pain and/or referral to specialist services should be considered for patients who do not respond to initial measures. An MDT approach (urologists, pain specialists, nurse specialists, specialist physiotherapists, general practitioners, cognitive behavioural therapists/psychologists, and sexual health specialists) is recommended. Patients should be fully informed about the possible underlying causes and treatment options, including an explanation of the chronic pain cycle. Chronic prostatitis can present with a wide variety of signs and symptoms. Identification of individual symptom patterns and a symptom-based treatment approach are recommended. Further research is required to evaluate management options for CBP and CP/CPPS. © 2015 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.

Prediction of cell penetrating peptides by support vector machines.

PubMed

Sanders, William S; Johnston, C Ian; Bridges, Susan M; Burgess, Shane C; Willeford, Kenneth O

2011-07-01

Cell penetrating peptides (CPPs) are those peptides that can transverse cell membranes to enter cells. Once inside the cell, different CPPs can localize to different cellular components and perform different roles. Some generate pore-forming complexes resulting in the destruction of cells while others localize to various organelles. Use of machine learning methods to predict potential new CPPs will enable more rapid screening for applications such as drug delivery. We have investigated the influence of the composition of training datasets on the ability to classify peptides as cell penetrating using support vector machines (SVMs). We identified 111 known CPPs and 34 known non-penetrating peptides from the literature and commercial vendors and used several approaches to build training data sets for the classifiers. Features were calculated from the datasets using a set of basic biochemical properties combined with features from the literature determined to be relevant in the prediction of CPPs. Our results using different training datasets confirm the importance of a balanced training set with approximately equal number of positive and negative examples. The SVM based classifiers have greater classification accuracy than previously reported methods for the prediction of CPPs, and because they use primary biochemical properties of the peptides as features, these classifiers provide insight into the properties needed for cell-penetration. To confirm our SVM classifications, a subset of peptides classified as either penetrating or non-penetrating was selected for synthesis and experimental validation. Of the synthesized peptides predicted to be CPPs, 100% of these peptides were shown to be penetrating.

Contemporary Management of Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

PubMed

Magistro, Giuseppe; Wagenlehner, Florian M E; Grabe, Magnus; Weidner, Wolfgang; Stief, Christian G; Nickel, J Curtis

2016-02-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition that causes severe symptoms, bother, and quality-of-life impact in the 8.2% of men who are believed to be affected. Research suggests a complex pathophysiology underlying this syndrome that is mirrored by its heterogeneous clinical presentation. Management of patients diagnosed with CP/CPPS has always been a formidable task in clinical practice. Due to its enigmatic etiology, a plethora of clinical trials failed to identify an efficient monotherapy. A comprehensive review of published randomized controlled trials (RCTs) on the treatment of CP/CPPS and practical best evidence recommendations for management. Medline and the Cochrane database were screened for RCTs on the treatment of CP/CPPS from 1998 to December 2014, using the National Institutes of Health Chronic Prostatitis Symptom Index as an objective outcome measure. Published data in concert with expert opinion were used to formulate a practical best evidence statement for the management of CP/CPPS. Twenty-eight RCTs identified were eligible for this review and presented. Trials evaluating antibiotics, α-blockers, anti-inflammatory and immune-modulating substances, hormonal agents, phytotherapeutics, neuromodulatory drugs, agents that modify bladder function, and physical treatment options failed to reveal a clear therapeutic benefit. With its multifactorial pathophysiology and its various clinical presentations, the management of CP/CPPS demands a phenotypic-directed approach addressing the individual clinical profile of each patient. Different categorization algorithms have been proposed. First studies applying the UPOINTs classification system provided promising results. Introducing three index patients with CP/CPPS, we present practical best evidence recommendations for management. Our current understanding of the pathophysiology underlying CP/CPPS resulting in this highly variable syndrome does not speak in favor of a monotherapy for management. No efficient monotherapeutic option is available. The best evidence-based management of CP/CPPS strongly suggests a multimodal therapeutic approach addressing the individual clinical phenotypic profile. Chronic prostatitis/chronic pelvic pain syndrome presents a variable syndrome. Successful management of this condition is challenging. It appears that a tailored treatment strategy addressing individual patient characteristics is more effective than one single therapy. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Complementary and Alternative Medicine for Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

2005-01-01

To discuss challenges concerning treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and review complementary and alternative medical (CAM) therapies being evaluated for this condition, we performed a comprehensive search of articles published from 1990–2005 using the PubMed, Medline databases. Data from the articles were abstracted and pooled by subject. Keywords cross-searched with CP/CPPS included: complementary, alternative, integrative, therapies, interventions, nutrition, antioxidants, herbs, supplements, biofeedback and acupuncture. Listed articles with no abstracts were not included. Various CAM therapies for CP/CPPS exist including biofeedback, acupuncture, hyperthermia and electrostimulation. Additionally, a variety of in vitro and in vivo studies testing herbal and nutritional supplements were found. Saw palmetto, cernilton and quercetin were the most frequently tested supplements for CP/CPPS. Although many CAM therapies demonstrate positive preliminary observations as prospective treatments for CP/CPPS, further exploratory studies including more randomized, controlled trials are necessary for significant validation as treatment options for this complex disorder. PMID:16322807

Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides.

PubMed

Dissanayake, Shama; Denny, William A; Gamage, Swarna; Sarojini, Vijayalekshmi

2017-03-28

Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included. Copyright © 2017 Elsevier B.V. All rights reserved.

[International focuses in the studies of chronic pelvic pain syndrome: A social network analysis].

PubMed

Wen, Li-Jie; Pan, Xian-Wei; Yang, Bo

2016-10-01

To analyze the internationally published literature relevant to chronic pelvic pain syndrome (CPPS) using bibliometrics and social network analysis, and investigate the current status and focuses of CPPS studies. We identified 692 publications on CPPS by searching PubMed up to December 2015, extracted their subject headings, calculated the frequencies of the headings, and constructed a co-occurrence network of the high-frequency (≥10) subject headings. Then we studied the features and structure of the co-occurrence network by analyzing its attributes and topological structure. The density of the constructed co-occurrence network was 0.111, with an average distance of 2.886 and a clustering coefficient of 0.685. Its low density, long average distance and high clustering coefficient indicated that it was a sparse network, with a slow speed of information spreading among nodes but a strong potential coherence, which suggested that the current topics in the study of CPPS were scattered and weakly correlated, with a high possibility of being integrated. Based on the topological structure of the co-occurrence network, the topics in the study of CPPS were divided into six aspects: diagnosis and classification, drug therapy, treatment, etiology, microbiology, psychology, and epidemiology, the more important of which were diagnosis and classification, drug therapy, treatment and etiology. A system has been formed in the studies of CPPS, focusing on the diagnosis, drug therapy, and etiology of the disease. However, the research topics are relatively scattered and frequently repeated. Therefore, more attention should be paid to the macrocosmic guidance and rational coordination of the researches on CPPS.

Quality by design in the chiral separation strategy for the determination of enantiomeric impurities: development of a capillary electrophoresis method based on dual cyclodextrin systems for the analysis of levosulpiride.

PubMed

Orlandini, S; Pasquini, B; Del Bubba, M; Pinzauti, S; Furlanetto, S

2015-02-06

Quality by design (QbD) concepts, in accordance with International Conference on Harmonisation Pharmaceutical Development guideline Q8(R2), represent an innovative strategy for the development of analytical methods. In this paper QbD principles have been comprehensively applied in the set-up of a capillary electrophoresis method aimed to quantify enantiomeric impurities. The test compound was the chiral drug substance levosulpiride (S-SUL) and the developed method was intended to be used for routine analysis of the pharmaceutical product. The target of analytical QbD approach is to establish a design space (DS) of critical process parameters (CPPs) where the critical quality attributes (CQAs) of the method have been assured to fulfil the desired requirements with a selected probability. QbD can improve the understanding of the enantioseparation process, including both the electrophoretic behavior of enantiomers and their separation, therefore enabling its control. The CQAs were represented by enantioresolution and analysis time. The scouting phase made it possible to select a separation system made by sulfated-β-cyclodextrin and a neutral cyclodextrin, operating in reverse polarity mode. The type of neutral cyclodextrin was included among other CPPs, both instrumental and related to background electrolyte composition, which were evaluated in a screening phase by an asymmetric screening matrix. Response surface methodology was carried out by a Doehlert design and allowed the contour plots to be drawn, highlighting significant interactions between some of the CPPs. DS was defined by applying Monte-Carlo simulations, and corresponded to the following intervals: sulfated-β-cyclodextrin concentration, 9-12 mM; methyl-β-cyclodextrin concentration, 29-38 mM; Britton-Robinson buffer pH, 3.24-3.50; voltage, 12-14 kV. Robustness of the method was examined by a Plackett-Burman matrix and the obtained results, together with system repeatability data, led to define a method control strategy. The method was validated and was finally applied to determine the enantiomeric purity of S-SUL in pharmaceutical dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway.

PubMed

Kosalková, Katarina; García-Estrada, Carlos; Barreiro, Carlos; Flórez, Martha G; Jami, Mohammad S; Paniagua, Miguel A; Martín, Juan F

2012-01-10

The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway. Using the secretion of bovine chymosin in Aspergillus awamori as a model, we found a drastic increase (40 to 80-fold) in cells grown with casein or casein phosphopeptides (CPPs). CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs), whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase), which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells. In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins.

On the importance of electrostatic interactions between cell penetrating peptides and membranes: a pathway toward tumor cell selectivity?

PubMed

Jobin, Marie-Lise; Alves, Isabel D

2014-12-01

Cell-penetrating peptides (CPPs) are small molecules of major interest due to their ability to efficiently transport cargos across cell membranes in a receptor- and energy-independent way and without being cytotoxic to cells. Since their discovery 20 years ago their potential interest in drug delivery and diagnosis became undeniable. CPPs are being used to deliver inside cells a large variety of cargos such as proteins, DNA, antibodies, imaging agents and nanoparticle drug carriers. Their cellular uptake mechanisms are still debated and may vary depending on their structure, nature and size of cargo they transport and type of cell line targeted. CPPs are generally rich in positively charged residues, thus they are prone to establish electrostatic interactions with anionic membrane components (sugars and lipids). Understanding the molecular basis of CPP membrane interaction and cellular uptake is crucial to improve their in vivo efficiency target-specificity. A great number of studies demonstrated the high potential of CPPs to translocate efficiently therapeutic cargos into cells and some peptides are even in clinical phase studies. Although these molecules seem perfect for a therapeutic or diagnosis purpose, they still possess a small but non negligible drawback: a complete lack of cell type specificity. Tumor cells have recently been shown to over-express certain glycosaminoglycans at the cell membrane surface and to possess a higher amount of anionic lipids in their outer leaflet than healthy cells. Such molecules confer the cell membrane an enhanced anionic character, property that could be used by CPPs to selectively target these cells. Moreover previous studies demonstrate the importance of electrostatic interactions between basic residues in the peptide, especially Arg, and the lipid headgroups and glycosaminoglycans in the cell membrane. Electrostatic interactions put at stake in this process might be one of the keys to resolve the puzzle of CPP cell type specificity. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A gene delivery system for insect cells mediated by arginine-rich cell-penetrating peptides.

PubMed

Chen, Yung-Jen; Liu, Betty Revon; Dai, Yun-Hao; Lee, Cheng-Yi; Chan, Ming-Huan; Chen, Hwei-Hsien; Chiang, Huey-Jenn; Lee, Han-Jung

2012-02-10

Most bioactive macromolecules, such as protein, DNA and RNA, basically cannot permeate into cells freely from outside the plasma membrane. Cell-penetrating peptides (CPPs) are a group of short peptides that possess the ability to traverse the cell membrane and have been considered as candidates for mediating gene and drug delivery into living cells. In this study, we demonstrate that three arginine-rich CPPs (SR9, HR9 and PR9) are able to form stable complexes with plasmid DNA and deliver DNA into insect Sf9 cells in a noncovalent manner. The transferred plasmid DNA containing enhanced green fluorescent protein (EGFP) and red fluorescent protein (RFP) coding regions could be expressed in cells functionally assayed at both the protein and RNA levels. Furthermore, treatment of cells with CPPs and CPP/DNA complexes resulted in a viability of 84-93% indicating these CPPs are not cytotoxic. These results suggest that arginine-rich CPPs appear to be a promising tool for insect transgenesis. Copyright © 2011 Elsevier B.V. All rights reserved.

Harnessing the capacity of cell-penetrating peptides for drug delivery to the central nervous system.

PubMed

Kang, Ting; Gao, Xiaoling; Chen, Jun

2014-01-01

The existence of blood-brain barrier (BBB) represents the most formidable challenge for drug delivery to the central nervous system (CNS). Modern breakthrough in biology offers multiple choices for overcoming this barrier but yields modest outcomes for clinical application due to various problems such as safety concerns, insufficient delivery efficiency and poor penetration. Cell penetrating peptides (CPPs) possessing powerful transmembrane capacity have been shown to be effective transport vectors for bioactive molecules and an attractive alternative to traditional active targeting approaches. However, the non-specificity of CPPs has hindered them from targeting a desired site of action. Promisingly, design of novel CPP-mediated nanoparticulate delivery systems with specific targeting property may extricate CPPs from the dilemma. In this review, both the traditional and novel applications of CPPs-based strategies for CNS drug delivery will be discussed.

A survey of cannabis (marijuana) use and self-reported benefit in men with chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Tripp, Dean A; Nickel, J Curtis; Katz, Laura; Krsmanovic, Adrijana; Ware, Mark A; Santor, Darcy

2014-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a chronic pelvic pain condition largely refractory to treatment. Cannabis (marijuana) use has been reported for a wide variety of chronic pain conditions, but no study has examined prevalence of cannabis use, symptom benefit or side effects, or frequency in CP/CPPS. Participants were recruited from an outpatient CP/CPPS urology clinic (n = 98) and online through the Prostatitis Foundation website (n = 244). Participants completed questionnaires (demographics, CP/CPPS, depression, cannabis). The clinic sample included Canadian patients and the online sample included primarily American patients. Due to differences, groups were examined separately. Almost 50% of respondents reported using cannabis (clinic n = 49; online n = 89). Of the cannabis users, 36.8% of clinic and 75% of online respondents reported that it improved their symptoms. Most of the respondents (from the clinic and online groups) reported that cannabis improved their mood, pain, muscle spasms, and sleep. However, they did not note any improvements for weakness, fatigue, numbness, ambulation, and urination. Overall, the effectiveness of cannabis for CP/CPPS was "somewhat/very effective" (57% clinic; 63% online). There were no differences between side effects or choice of consumption and most reported using cannabis rarely. These are the first estimates in men suffering from CP/CPPS and suggest that while cannabis use is prevalent, its medical use and benefit are unknown. This is an understudied area and the benefit or hazard for cannabis use awaits further study.

Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway

PubMed Central

2012-01-01

Background The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway. Results Using the secretion of bovine chymosin in Aspergillus awamori as a model, we found a drastic increase (40 to 80-fold) in cells grown with casein or casein phosphopeptides (CPPs). CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs), whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase), which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells. Conclusions In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins. PMID:22234238

Therapy-related longitudinal brain perfusion changes in patients with chronic pelvic pain syndrome.

PubMed

Weisstanner, Christian; Mordasini, Livio; Thalmann, George N; Verma, Rajeev K; Rummel, Christian; Federspiel, Andrea; Kessler, Thomas M; Wiest, Roland

2017-08-03

The imaging method most frequently employed to identify brain areas involved in neuronal processing of nociception and brain pain perception is blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Arterial spin labelling (ASL), in contrast, offers advantages when slow varying changes in brain function are investigated. Chronic pelvic pain syndrome (CPPS) is a disorder of, mostly, young males that leads to altered pain perceptions in structures related to the pelvis. We aimed to investigate the potential of ASL to monitor longitudinal cranial blood flow (CBF) changes in patients with CPPS. In a randomised, placebo-controlled, double-blind single centre trial, we investigated treatment effects in CPPS after 12 weeks in patients that underwent sono-electro-magnetic therapy vs placebo. We investigated changes of CBF related to treatment outcome using pseudo-continuous arterial spin labelling (pCASL)-MRI. We observed CBF downregulation in the prefrontal cortex and anterior cingulate cortex and upregulation in the dorsolateral prefrontal cortex in responders. Nonresponders presented with CBF upregulation in the hippocampus. In patients with a history of CPPS of less than 12 months, there were significant correlations between longitudinal CBF changes and the Chronic Prostatitis Symptom Index pain subscore within the joint clusters anterior cingulate cortex and left anterior prefrontal cortex in responders, and the right hippocampus in nonresponders. We demonstrated therapy-related and stimulus-free longitudinal CBF changes in core areas of the pain matrix using ASL. ASL may act as a complementary noninvasive method to functional MRI and single-photon emission computed tomography / positron emission tomography, especially in the longitudinal assessment of pain response in clinical trials.

A common pronociceptive pain modulation profile typifying subgroups of chronic pelvic pain syndromes is interrelated with enhanced clinical pain.

PubMed

Grinberg, Keren; Granot, Michal; Lowenstein, Lior; Abramov, Liora; Weissman-Fogel, Irit

2017-06-01

Provoked vestibulodynia (PVD) and painful bladder syndrome (PBS), subgroups of chronic pelvic pain syndromes (CPPS), are considered to share common biophysiological peripheral mechanisms. In addition, indications of a pronociceptive pain profile coexisting with psychological vulnerability suggest common dysfunctional pain processing and pain modulation in these 2 subgroups of CPPS. We therefore aimed at comparing the pain profile and psychological traits of patients with PVD and PBS to see whether the pain profile contributes to intersubject variability of clinical pain symptoms. Patients with PVD (n = 18) and PBS (n = 21) were compared with healthy controls (n = 20) in their responses to (1) pain psychophysical tests applied to both referred (suprapubis) and remote (hand) body areas and (2) pain-related psychological factors (pain catastrophizing, depression, anxiety, and somatization). We found a similar pronociceptive pain profile in the 2 subgroups of CPPS-enhanced facilitation (ie, hyperalgesia in the referred body area [P < 0.001]) and inefficient inhibition (ie, reduced conditioned pain modulation [P < 0.001] that were associated with both enhanced pain ratings evoked during trigger point examination [P < 0.037]) and higher Brief Pain Inventory ratings (P = 0.002). The latter was also correlated with pain catastrophizing (r = 0.504, P = 0.001) and depression symptoms (r = 0.361, P = 0.024). The findings suggest common mechanisms underlying a dysfunctional nociceptive system in both PVD and PBS. The intersubject variability in the level of dysfunction and its association with disease severity recommends a personalized pain treatment that may alleviate daily pain and dysfunction in patients with CPPS.

[Prostatic inflammation-induced chronic pelvic pain: Roles of substance P and c-fos in the spinal cord].

PubMed

Liu, Ying-jia; Song, Guo-hong; Zhang, Chen

2015-08-01

To explore the possible pain mechanism of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The models of CP/CPPS were established in male Wistar rats by the autoimmune method. The paw withdrawal threshold (PWT) was detected using Von Frey filament. The expressions of the substance P and c-fos in the prostate and spinal L5-S2 segments were determined by immunohistochemistry followed by analysis of their correlation with CP/CPPS. Compared with the control rats, the CP/CPPS models showed significantly decreased PWT (P < 0.05), remarkable prostatic inflammation, enlarged scope of lesions, and obvious interstitial lymphocytic infiltration (P < 0.05). Both the expressions of substance P and c-fos were markedly elevated in the prostate and spinal dorsal horn (L5-S2) of the rat models (P < 0.05), but the expression of substance P in the prostate exhibited no correlation with that in the spinal cord (r = 0.099, P = 0.338), nor did that of c-fos (r = 0.027, P = 0.454). The upregulated expressions of substance P and c-fos in the spinal cord L5-S2 sections may be associated with the pain mechanism of CP/CPPS.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

PubMed

Li, Min; Sander, Sanna; Duan, John; Rosencrance, Susan; Miksinski, Sarah Pope; Yu, Lawrence; Seo, Paul; Rege, Bhagwant

2016-11-01

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

Cell Penetrating Peptides in the Delivery of Biopharmaceuticals

PubMed Central

Munyendo, Were LL; Lv, Huixia; Benza-Ingoula, Habiba; Baraza, Lilechi D.; Zhou, Jianping

2012-01-01

The cell membrane is a highly selective barrier. This limits the cellular uptake of molecules including DNA, oligonucleotides, peptides and proteins used as therapeutic agents. Different approaches have been employed to increase the membrane permeability and intracellular delivery of these therapeutic molecules. One such approach is the use of Cell Penetrating Peptides (CPPs). CPPs represent a new and innovative concept, which bypasses the problem of bioavailability of drugs. The success of CPPs lies in their ability to unlock intracellular and even intranuclear targets for the delivery of agents ranging from peptides to antibodies and drug-loaded nanoparticles. This review highlights the development of cell penetrating peptides for cell-specific delivery strategies involving biomolecules that can be triggered spatially and temporally within a cell transport pathway by change in physiological conditions. The review also discusses conjugations of therapeutic agents to CPPs for enhanced intracellular delivery and bioavailability that are at the clinical stage of development. PMID:24970133

Molecular cloning and analysis of the ergopeptine assembly system in the ergot fungus Claviceps purpurea.

PubMed

Correia, Telmo; Grammel, Nicolas; Ortel, Ingo; Keller, Ullrich; Tudzynski, Paul

2003-12-01

Claviceps purpurea produces the pharmacological important ergopeptines, a class of cyclol-structured alkaloid peptides containing D-lysergic acid. These compounds are assembled from D-lysergic acid and three different amino acids by the nonribosomal peptide synthetase enzymes LPS1 and LPS2. Cloning of alkaloid biosynthesis genes from C. purpurea has revealed a gene cluster including two NRPS genes, cpps 1 and cpps 2. Protein sequence data had assigned earlier cpps1 to encode the trimodular LPS1 assembling the tripeptide portion of ergopeptines. Here, we show by transcriptional analysis, targeted inactivation, analysis of disruption mutants, and heterologous expression that cpps 2 encodes the monomodular LPS2 responsible for D-lysergic acid activation and incorporation into the ergopeptine backbone. The presence of two distinct NRPS subunits catalyzing formation of ergot peptides is the first example of a fungal NRPS system consisting of different NRPS subunits.

Category III Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Insights from The National Institutes of Health Chronic Prostatitis Collaborative Research Network Studies

PubMed Central

Nickel, J. Curtis; Alexander, Richard B.; Anderson, Rodney; Berger, Richard; Comiter, Craig V.; Datta, Nand S.; Fowler, Jackson E.; Krieger, John N.; Landis, J. Richard; Litwin, Mark S.; McNaughton-Collins, Mary; O'Leary, Michael P.; Pontari, Michel A.; Schaeffer, Anthony J.; Shoskes, Daniel A.; White, Paige; Kusek, John; Nyberg, Leroy

2010-01-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains an enigmatic medical condition. Creation of the (NIH) Chronic Prostatitis Collaborative Research Network (CPCRN) funded by the National Institutes of Health has stimulated a renewed interest in the research and clinical aspects of CP/CPPS. Landmark publications of the NIH-CPCRN over the last 10 years document a decade of progress. Insights from these CPCRN studies have improved our management of patients diagnosed with CP/CPPS and offer hope for continued progress. PMID:18765132

[Physiotherapeutic assessment of chronic pelvic pain syndrome : Development of a standardized physiotherapeutic assessment instrument for interprofessional cooperation in patients with chronic pelvic pain syndrome].

PubMed

Klotz, S G R; Ketels, G; Richardsen, B; Löwe, B; Brünahl, C A

2018-04-24

The chronic pelvic pain syndrome (CPPS) can be associated with physiotherapeutic findings. An interprofessional approach is recommended for patients with CPPS; however, no standardized physiotherapeutic assessment and documentation instrument for specific physiotherapeutic assessments exist, which is not only the foundation for physiotherapy but also for interprofessional communication. The aim was the development of a physiotherapeutic assessment instrument for patients with CPPS and therefore, to create a tool for clinical use, research and interprofessional communication. Based on an explorative literature search and an expert consensus, the first version of the instrument was developed as part of a specialized outpatient clinic. This version was applied clinically for 13 months, edited and finalized after another expert consensus. The developed instrument Physical Therapy Assessment for Chronic Pelvic Pain Syndrome (PTA-CPPS) lists external and internal groups of muscles for a systematic assessment of myofascial findings. Functional capacity, breathing movements as well as scars and regions of pain are recorded. A manual for the assessment protocol was developed as accompanying material. The developed instrument provides for the first time a physiotherapeutic assessment tool for patients with CPPS for interprofessional clinical and scientific use.

Molecular imaging analysis of intestinal insulin absorption boosted by cell-penetrating peptides by using positron emission tomography.

PubMed

Kamei, Noriyasu; Morishita, Mariko; Kanayama, Yousuke; Hasegawa, Koki; Nishimura, Mie; Hayashinaka, Emi; Wada, Yasuhiro; Watanabe, Yasuyoshi; Takayama, Kozo

2010-08-17

Molecular imaging technique by use of positron emission tomography (PET) is a noninvasive tool that allows one to quantitatively analyze the function of endogenous molecules and the pharmacokinetics of therapeutic agents in vivo. This technique is expected to be useful for evaluating the effectiveness of diverse drug delivery systems. We demonstrated previously that intestinal insulin absorption is increased significantly by coadministration of cell-penetrating peptides (CPPs), which are taken up effectively by several cells. However, the distribution behavior of insulin whose absorption is increased by CPPs is not clear. We used PET imaging and quantitatively analyzed the intestinal absorption and subsequent distribution of insulin and the effect of CPPs on its absorption and distribution. An unlabeled insulin solution containing tracer insulin, (68)Ga-DOTA-insulin, was administered with or without CPPs into a rat ileal closed loop. PET imaging showed that the CPPs, particularly D-R8 and L-penetratin, significantly increased the (68)Ga-DOTA-insulin level in the liver, kidney, and circulation. After absorption from the intestine, the (68)Ga-DOTA-insulin passed rapidly through the liver and accumulated in the kidney. The increase in the hepatic and renal distribution of (68)Ga-DOTA-insulin by each CPP coadministration was similar manner as that in intestinal absorption, suggesting that the increased accumulation of insulin in the liver and kidney induced by coadministration of CPPs was associated with the increased intestinal absorption of insulin. This is the first study to show that PET imaging enables one to quantitatively analyze the distribution behavior of intestinally absorbed insulin in several organs. This imaging methodology is likely to be useful for developing effective drug delivery systems targeted to specific organs. Copyright 2010 Elsevier B.V. All rights reserved.

The association of personality trait on treatment outcomes in patients with chronic prostatitis/chronic pelvic pain syndrome: an exploratory study.

PubMed

Koh, Jun Sung; Ko, Hyo Jung; Wang, Sheng-Min; Cho, Kang Joon; Kim, Joon Chul; Lee, Soo-Jung; Pae, Chi-Un; Serretti, Alessandro

2014-02-01

This study investigated the association of personality traits with the baseline clinical characteristics and treatment outcomes of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Subjects were evaluated at baseline and at week 12 following routine treatment for CP/CPPS using the Korean version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) to measure the severity of CP/CPPS; the Korean version of the Patient Health Questionnaire-9 (PHQ-9) to assess depression; the Korean version of the Patient Health Questionnaire-15 (PHQ-15) to evaluate somatization; and the Korean version of the EuroQol Questionnaire-5 Dimensions (EQ-5D), specifically the EQ-5D utility index and the EQ-5D visual analog scale (EQ-5D VAS), to assess quality of life (QoL). Personality traits including extraversion, agreeableness, conscientiousness, neuroticism, and openness were determined at baseline using the 44-item Big Five Inventory (BFI). The influence of personality traits on the clinical characteristics and treatment outcomes of patients with CP/CPPS was assessed using relevant statistical analyses. Neuroticism was associated with a significantly poorer treatment response and higher levels of depression and somatization. Extraversion, agreeableness, and conscientiousness had some influence on clinical characteristics but openness did not affect overall symptoms or the treatment response in patients with CP/CPPS. We found that neuroticism may be the most important personality trait associated with treatment response and the severity of depression and somatization in patients with CP/CPPS. However, our exploratory findings should be confirmed by additional studies with adequate power and improved designs. Copyright © 2013 Elsevier Inc. All rights reserved.

Direct effects of casein phosphopeptides on growth and differentiation of in vitro cultured osteoblastic cells (MC3T3-E1).

PubMed

Tulipano, Giovanni; Bulgari, Omar; Chessa, Stefania; Nardone, Alessandro; Cocchi, Daniela; Caroli, Anna

2010-02-25

Casein phosphopeptides (CPPs) obtained by enzymatic hydrolysis in vitro of caseins, have been shown to enhance calcium solubility and to increase the calcification of embryonic rat bones in their diaphyseal area. Little is known about the direct effects of CPPs on cultured osteoblastic cells. Calcium in the microenvironment surrounding bone cells is not only important for the mineralization of the extracellular matrix, but it is believed to provide preosteblasts with a signal that modulates their proliferation and differentiation. The aim of the present study was to investigate the direct effects of four selected casein phosphopeptides on osteoblastic cell (MC3T3-E1 cells) viability and differentiation. The selected peptides have been obtained by chemical synthesis and differed in the number of phosphorylated sites and in the amino acid spacing out two phosphorylated sites, in order to further characterize the relationship between structure and function. The results obtained in this work demonstrated that CPPs may directly affect osteoblast-like cell growth, calcium uptake and ultimately calcium deposition in the extracellular matrix. The effects exerted by distinct CPPs on osteogenesis in vitro can be either stimulatory or inhibitory. Differential short amino acid sequences in their molecules, like the -SpEE- and the -SpTSpEE-motifs, are likely the molecular determinants for their biological activities on osteoblastic cells. Moreover, two genetic variants of CPPs showing one amino acid change in their sequence may profoundly differ in their biological activities. Finally, our data may also suggest important clues about the role of intrinsic phosphorylated peptides derived from endogenous phosphorylated proteins in bone metabolism, apart from extrinsic CPPs. Copyright 2009 Elsevier B.V. All rights reserved.

Synthesis of CuO by Cu-CPPs with the determination of Cu(II) coordination modes from a novel complex of [Cu(terpyOH){sub 2}]·(HBTC)·2H{sub 2}O

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

Wang, Yu, E-mail: wangyu1012@hit.edu.cn; Chen, Gang, E-mail: gchen@hit.edu.cn; Han, Li

2013-10-15

In this study, we investigated the synthesis of CuO microrods by simple calcination of copper-based coordination polymer particles (Cu-CPPs) at high temperature in air. The photocatalytic activity of the CuO microrods was tested by the decomposition of aqueous solution of RhB, which was completely decomposed by irradiation with light. To analyze the relationship of metal ions and ligands in the Cu-CPPs, the single crystal of [Cu(terpyOH){sub 2}]∙(HBTC)∙2H{sub 2}O (1) (terpyOH=4′-hydroxy-2,2′:6′,2″-terpyridine, BTC=1,3,5-benzene tricarboxylate) was first prepared and characterized by X-ray single crystal structural analysis. A variety of hydrogen bonds constructing the 3D complex structure in [Cu(terpyOH){sub 2}]∙(HBTC)∙2H{sub 2}O (1) were observed.more » - Graphical abstract: Demonstrating a general method to synthesize CuO microrods via simple calcination of Cu-CPPs and Cu(II) coordination modes from a novel complex of [Cu(terpyOH){sub 2}]∙(HBTC)·2H{sub 2}O constructed by hydrogen bonding. Display Omitted - Highlights: • The formation of microrods CuO from thermal treatment of Cu-CPPs through an “escape-by-crafty-scheme” strategy has been studied. • Determination of Cu(II) coordination modes in Cu-CPPs from a novel complex of [Cu(terpyOH){sub 2}]∙(HBTC) 2H{sub 2}O. • Invested the behave of hydrogen bonding to construct the 3D complex structure. • Commendable photodegradation performance was observed.« less

The evolving clinical picture of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): A look at 1310 patients over 16 years.

PubMed

Doiron, R Christopher; Tripp, Dean A; Tolls, Victoria; Nickel, J Curtis

2018-06-01

Two decades of increasing understanding of etiopathogenesis and clinical phenotyping produces an impression the clinical face of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is changing. We sought to retrospectively analyze trends in CP/CPPS patients presenting to our clinic for evaluation over a 16-year period. Patients with CP/CPPS presenting to a tertiary clinic were evaluated prospectively from 1998-2014 with Chronic Prostatitis Symptom Index (CPSI) and UPOINT (urinary, psychosocial, organ-specific, infection, neurogenic, and tenderness) categorization. Patients were stratified in four cohorts, based on year of presentation, and we retrospectively analyzed variations in symptom scores and patterns, UPOINT categorization, and treatment modalities amongst cohorts. Mean age of the 1310 CP/CPPS patients was 44.7 years, while mean CPSI pain, urination, and total scores were 10.6, 4.8, and 23.3, respectively. The most prevalent UPOINT domain, urinary (U) (71.8%) was associated with a higher CPSI urination score (6.3), more frequent penile tip pain (37%), dysuria (48%), and more treatment with alpha-blockers (70%). Increase in UPOINT domains was associated with higher CPSI pain, quality of life (QoL), and total scores. Trends over time included increased prevalence of psychosocial (P), organ (O), and tenderness (T) domains, as well as increased use of alpha-blockers, neuromodulation, and phytotherapy as treatment modalities. There was little variation in age, CPSI scores, and pain locations over time. The changing clinical face of CP/CPPS reflects the increased recognition of psychosocial (P domain) and pelvic floor pain (T domain), along with the concomitant use of associated therapies. There was little variation of pain/urinary symptom patterns and QoL.

CiPerGenesis, A Mutagenesis Approach that Produces Small Libraries of Circularly Permuted Proteins Randomly Opened at a Focused Region: Testing on the Green Fluorescent Protein.

PubMed

Gaytán, Paul; Roldán-Salgado, Abigail; Yáñez, Jorge A; Morales-Arrieta, Sandra; Juárez-González, Víctor R

2018-06-12

Circularly permuted proteins (cpPs) represent a novel type of mutant proteins with original termini that are covalently linked through a peptide connector and opened at any other place of the polypeptide backbone to create new ends. cpPs are finding wide applications in biotechnology because their properties may be quite different from those of the parental protein. However, the actual challenge for the creation of successful cpPs is to identify those peptide bonds that can be broken to create new termini and ensure functional and well-folded cpPs. Herein, we describe CiPerGenesis, a combinatorial mutagenesis approach that uses two oligonucleotide libraries to amplify a circularized gene by PCR, starting and ending from a focused target region. This approach creates small libraries of circularly permuted genes that are easily cloned in the correct direction and frame using two different restriction sites encoded in the oligonucleotides. Once expressed, the protein libraries exhibit a unique sequence diversity, comprising cpPs that exhibit ordinary breakpoints between adjacent amino acids localized at the target region as well as cpPs with new termini containing user-defined truncations and repeats of some amino acids. CiPerGenesis was tested at the lid region G134-H148 of green fluorescent protein (GFP), revealing that the most fluorescent variants were those starting at Leu141 and ending at amino acids Tyr145, Tyr143, Glu142, Leu141, Lys140, and H139. Purification and biochemical characterization of some variants suggested a differential expression, solubility and maturation extent of the mutant proteins as the likely cause for the variability in fluorescence intensity observed in colonies.

Cell-penetrating peptides and antimicrobial peptides: how different are they?

PubMed Central

Henriques, Sónia Troeira; Melo, Manuel Nuno; Castanho, Miguel A. R. B.

2006-01-01

Some cationic peptides, referred to as CPPs (cell-penetrating peptides), have the ability to translocate across biological membranes in a non-disruptive way and to overcome the impermeable nature of the cell membrane. They have been successfully used for drug delivery into mammalian cells; however, there is no consensus about the mechanism of cellular uptake. Both endocytic and non-endocytic pathways are supported by experimental evidence. The observation that some AMPs (antimicrobial peptides) can enter host cells without damaging their cytoplasmic membrane, as well as kill pathogenic agents, has also attracted attention. The capacity to translocate across the cell membrane has been reported for some of these AMPs. Like CPPs, AMPs are short and cationic sequences with a high affinity for membranes. Similarities between CPPs and AMPs prompted us to question if these two classes of peptides really belong to unrelated families. In this Review, a critical comparison of the mechanisms that underlie cellular uptake is undertaken. A reflection and a new perspective about CPPs and AMPs are presented. PMID:16956326

Therapeutic effects of Qian-Yu decoction and its three extracts on carrageenan-induced chronic prostatitis/chronic pelvic pain syndrome in rats.

PubMed

Zhang, Keda; Zeng, Xiaobin; Chen, Yonggang; Zhao, Rong; Wang, Hui; Wu, Jinhu

2017-01-25

Qian-Yu decoction (QYD) is a traditional Chinese medicinal recipe composed of Radix astragali (Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P.K. Hsiao, Fabaceae ), Herba epimedii (Epimedium brevicornum Maxim., Berberidaceae), Herba leonuri (Leonurus japonicus Houtt., Lamiaceae), Cortex phellodendri (Phellodendron chinense Schneid., Rutaceae) and Radix achyranthis bidentatae (Achyranthes bidentata Bl., Amaranthaceae). This study aimed to evaluate the therapeutic activity of QYD against carrageenan-induced chronic prostatic/chronic pelvic pain syndrome (CP/CPPS) in rats and further elucidate its effective components. Three types of components, total polysaccharides, total flavonoids and total saponins were separately extracted from QYD. Carrageenan-induced CP/CPPS rats were intragastrically administered with lyophilized product of QYD, individual extracts and all the combined forms of extracts for three weeks. Prostatic index (PI) was determined and histopathological analysis was performed. The levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PEG2) in rat prostate tissues were measured using ELISA. The production of inducible nitric oxide synthase (iNOS) was evaluated by an enzymatic activity assay, and the release of nitric oxide (NO) was determined by a nitrate/nitrite assay. Treatment with QYD significantly ameliorated the histological changes of CP/CPPS rats and reduced the PI by 44.3%, with a marked downregulation of TNF-α (42.8% reduction), IL-1β (45.3%), COX-2 (36.6%), PGE2 (44.2%), iNOS (54.1%) and NO (46.0%). Each of three extracts attenuated the symptom of CP/CPPS, but much more weakly than QYD. The combined administration of three extracts showed efficacy comparable to that of QYD while better than that of any combination of two extracts. A principal component analysis of the six inflammatory mediators as variables indicated that the effects of TS on CP/CPPS were rather different from those of TF and TP, which were similar. QYD can be beneficial in prevention and treatment of CP/CPPS. Polysaccharides, flavonoids and saponins, as the major effective components of QYD, exert a cooperative effect on CP/CPPS.

Chronic prostatitis/chronic pelvic pain syndrome impairs erectile function through increased endothelial dysfunction, oxidative stress, apoptosis, and corporal fibrosis in a rat model.

PubMed

Hu, Y; Niu, X; Wang, G; Huang, J; Liu, M; Peng, B

2016-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an independent risk factor for the development of erectile dysfunction (ED). But the molecular mechanisms underlying the relationship between CP/CPPS and ED are still unclear. The aim of this study was to investigate the effect of CP/CPPS on erectile function in a rat model and the possible mechanisms. A rat model of experimental autoimmune prostatitis (EAP) was established to mimic human CP⁄CPPS. Then twenty 2-month-old male Sprague-Dawley rats were divided into EAP group and control group. Intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured during cavernous nerve electrostimulation, the ratio of max ICP/MAP was calculated. Blood was collected to measure the levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and testosterone, respectively. The expression of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in corpus cavernosum were detected. We also evaluated the smooth muscle/collagen ratio and apoptotic index (AI). The ratio of max ICP/MAP in EAP group were significantly lower than that in control group. The levels of serum CRP, TNF-α, IL-1β, and IL-6 in EAP group were all significantly higher than these in control group. The expression of eNOS and cGMP levels in corpus cavernosum of EAP rats were significantly downregulated. Furthermore, decreased SOD activity and smooth muscle/collagen ratio, increased MDA levels and AI were found in corpus cavernosum of EAP rats. In conclusion, CP/CPPS impaired penile erectile function in a rat model. The declines of eNOS expression and cGMP levels in corpus cavernosum may be an important mechanism of CP/CPPS-induced ED. CP/CPPS also increased oxidative stress, cell apoptosis and decreased smooth muscle/collagen ratio in corpus cavernosum of rats, which were all important for erectile function. © 2016 American Society of Andrology and European Academy of Andrology.

Application of a tablet film coating model to define a process-imposed transition boundary for robust film coating.

PubMed

van den Ban, Sander; Pitt, Kendal G; Whiteman, Marshall

2018-02-01

A scientific understanding of interaction of product, film coat, film coating process, and equipment is important to enable design and operation of industrial scale pharmaceutical film coating processes that are robust and provide the level of control required to consistently deliver quality film coated product. Thermodynamic film coating conditions provided in the tablet film coating process impact film coat formation and subsequent product quality. A thermodynamic film coating model was used to evaluate film coating process performance over a wide range of film coating equipment from pilot to industrial scale (2.5-400 kg). An approximate process-imposed transition boundary, from operating in a dry to a wet environment, was derived, for relative humidity and exhaust temperature, and used to understand the impact of the film coating process on product formulation and process control requirements. This approximate transition boundary may aid in an enhanced understanding of risk to product quality, application of modern Quality by Design (QbD) based product development, technology transfer and scale-up, and support the science-based justification of critical process parameters (CPPs).

A quality by design (QbD) study on enoxaparin sodium loaded polymeric microspheres for colon-specific delivery.

PubMed

Hales, Dana; Vlase, Laurian; Porav, Sebastian Alin; Bodoki, Andreea; Barbu-Tudoran, Lucian; Achim, Marcela; Tomuță, Ioan

2017-03-30

The aim of this study was to apply quality by design (QbD) for pharmaceutical development of enoxaparin sodium microspheres for colon-specific delivery. The Process Parameters (CPPs) and Critical Quality Attributes (CQAs) were identified. A central composite experimental design was used in order to develop the design space of microspheres for colon-specific delivery that have the desired Quality Target Product Profile (QTPP). The CPPs studied were Eudragit® FS-30D/Eudragit® RS-PO ratio, poly(vinyl alcohol) (PVA) concentration and sodium chloride (NaCl) concentration. The encapsulation efficiency increased with NaCl concentration increase, the percentages of enoxaparin sodium reaching 94% for some formulations. Increasing the ratio Eudragit® FS-30D/Eudragit® RS-PO ensured a relatively complete release of enoxaparin sodium in the environment simulating the colonic pH. Based on these results, the optimum conditions were decided and the optimum formulation was prepared. The results obtained for the latter in terms of in vitro enoxaparin sodium release were good, the microparticles releasing only 9.42% enoxaparin sodium in acidic environment and 15.16% in the medium which simulated duodenal pH, but allowing the release of up to 89.24% in the medium which simulated colonic pH. The in vitro release profile of enoxaparin sodium was close to the ideal one, therefore the system was successfully designed using QbD approach. Copyright © 2017 Elsevier B.V. All rights reserved.

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

2016-04-01

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. © 2015 Blackwell Verlag GmbH.

Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.

PubMed

Polackwich, A S; Shoskes, D A

2016-06-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as NIH Category III Prostatitis is a highly prevalent syndrome with significant impact on quality of life. As a heterogeneous syndrome, there exists no 'one size fits all' therapy with level 1 evidence to guide therapy. This often leads to a nihilistic approach to patients and clinical outcomes are poor. In this review, we examine the evidence for CP/CPPS therapies and discuss our technique of clinical phenotyping combined with multimodal therapy. Review of Medline articles with terms 'non-bacterial prostatitis', 'abacterial prostatitis' and 'chronic pelvic pain syndrome'. Many individual therapies have been evaluated in the treatment of CP/CPPS; antibiotics, anti-inflammatory medications (including bioflavonoids), neuromodulators, alpha blockers, pelvic floor physical therapy and cognitive behavior therapy. Each of these has been found to have varying success in alleviating symptoms. UPOINT is a system of clinical phenotyping for CP/CPPS patients that has 6 defined domains, which guide multimodal therapy. It has been validated to correlate with symptom burden and therapy guided by UPOINT leads to significant symptom improvement in 75-84% of patients based on three independent studies. CP/CPPS is a heterogeneous condition and, much like with prostate cancer, optimal therapy can only be achieved by classifying patients into clinically meaningful phenotypic groups (much like TNM) and letting the phenotype drive therapy.

A prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category III prostatitis/chronic pelvic pain syndrome.

PubMed

Kaplan, Steven A; Volpe, Michael A; Te, Alexis E

2004-01-01

This study was designed to assess the safety and efficacy of saw palmetto or finasteride in men with category III prostatitis/chronic pelvic pain syndrome (CP/CPPS). A prospective, randomized, open label, 1-year study was designed to assess the safety and efficacy of saw palmetto and finasteride in the treatment of men diagnosed with CP/CPPS. Patients were randomized to finasteride (5 mg once daily) or saw palmetto (325 mg daily) for 1 year. Patients were evaluated using the National Institutes of Health Chronic Prostatitis Symptom Index, individual domains (pain, urinary symptoms, quality of life and mean pain score) and the American Urological Association Symptom Score at baseline, 3, 6 and 12 months. A total of 64 consecutive men 24 to 58 years old (mean age 43.2) with a diagnosis of CP/CPPS were equally randomized to the 2 treatment arms. All 64 men had previously received antibiotics (duration of 3 to 93 weeks), 52 (82%) had been on alpha-blockade. There were 61, 57 and 56 patients evaluable at 3, 6 and 12 months, respectively. At 1 year mean total National Institutes of Health Chronic Prostatitis Symptom Index score decreased from 23.9 to 18.1 in the finasteride group (p <0.003), and from 24.7 to 24.6 in the saw palmetto arm (p = 0.41). In the finasteride arm the quality of life and pain domains were significantly improved at 1 year; however, urination was not. Adverse events included headache (3 cases) in the saw palmetto group and decreased libido (2 cases) in the finasteride group. At the end of the trial 13 of 32 (41%) and 21 of 32 (66%) opted to continue saw palmetto and finasteride, respectively. CP/CPPS treated with saw palmetto had no appreciable long-term improvement. In contrast, patients treated with finasteride had significant and durable improvement in all various parameters except voiding. Further studies are warranted to ascertain the mechanism and reproducibility of these effects in a placebo controlled trial.

A Portfolio for Optimal Collaboration of Human and Cyber Physical Production Systems in Problem-Solving

ERIC Educational Resources Information Center

Ansari, Fazel; Seidenberg, Ulrich

2016-01-01

This paper discusses the complementarity of human and cyber physical production systems (CPPS). The discourse of complementarity is elaborated by defining five criteria for comparing the characteristics of human and CPPS. Finally, a management portfolio matrix is proposed for examining the feasibility of optimal collaboration between them. The…

New developments in the diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Pontari, Michel; Giusto, Laura

2013-11-01

To describe new developments in the diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome (CPPS). Symptoms in men with chronic prostatitis/CPPS appear to cluster into a group with primarily pelvic or localized disease, and a group with more systemic symptoms. Several other chronic pain conditions can be associated with chronic prostatitis/CPPS, including irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome. Markers of neurologic inflammation and autoimmune disease parallel changes in symptoms after treatment. Treatment options include new alpha-blockers, psychological intervention, and prostate-directed therapy. The areas of acupuncture and pelvic floor physical therapy/myofascial release have received increased recent attention and appear to be good options in these patients. Future therapy may include antibodies to mediators of neurogenic inflammation and even treatment of bacteria in the bowel. The diagnosis of chronic prostatitis/CPPS must include conditions traditionally outside the scope of urologic practice but important for the care of men with chronic pelvic pain. The treatment is best done using multiple simultaneous therapies aimed at the different aspects of the condition.

Discrimination between biologically relevant calcium phosphate phases by surface-analytical techniques

NASA Astrophysics Data System (ADS)

Kleine-Boymann, Matthias; Rohnke, Marcus; Henss, Anja; Peppler, Klaus; Sann, Joachim; Janek, Juergen

2014-08-01

The spatially resolved phase identification of biologically relevant calcium phosphate phases (CPPs) in bone tissue is essential for the elucidation of bone remodeling mechanisms and for the diagnosis of bone diseases. Analytical methods with high spatial resolution for the discrimination between chemically quite close phases are rare. Therefore the applicability of state-of-the-art ToF-SIMS, XPS and EDX as chemically specific techniques was investigated. The eight CPPs hydroxyapatite (HAP), β-tricalcium phosphate (β-TCP), α-tricalcium phosphate (α-TCP), octacalcium phosphate (OCP), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate (DCP), monocalcium phosphate (MCP) and amorphous calcium phosphate (ACP) were either commercial materials in high purity or synthesized by ourselves. The phase purity was proven by XRD analysis. All of the eight CPPs show different mass spectra and the phases can be discriminated by applying the principal component analysis method to the mass spectrometric data. The Ca/P ratios of all phosphates were determined by XPS and EDX. With both methods some CPPs can be distinguished, but the obtained Ca/P ratios deviate systematically from their theoretical values. It is necessary in any case to determine a calibration curve, respectively the ZAF values, from appropriate standards. In XPS also the O(1s)-satellite signals are correlated to the CPPs composition. Angle resolved and long-term XPS measurements of HAP clearly prove that there is no phosphate excess at the surface. Decomposition due to X-ray irradiation has not been observed.

Characterisation of the bacterial community in expressed prostatic secretions from patients with chronic prostatitis/chronic pelvic pain syndrome and infertile men: a preliminary investigation

PubMed Central

Hou, Dong-Sheng; Long, Wen-Min; Shen, Jian; Zhao, Li-Ping; Pang, Xiao-Yan; Xu, Chen

2012-01-01

The expressed prostatic secretions (EPSs) of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), infertile men and normal men were subjected to microbiological study. EPSs were collected from the subjects, which included 26 normal men, 11 infertile patients and 51 CP/CPPS patients. DNA was extracted from each specimen, and the V3 regions of the 16S rRNA genes were amplified using universal bacterial primers. The results showed that the EPS 16S rRNA gene-positive rate in the CP/CPPS and infertile patients was much higher than in the normal men, but without any difference among the three patient groups. The denaturing gradient gel electrophoresis (DGGE) method was used to characterize the EPS bacterial community structure of the prostate fluid from patients with CP/CPPS or infertility issues. Principal component analysis (PCA) and partial least squares (PLS) analyses of PCR-DGGE profiles revealed that the EPS bacterial community structure differed among the three groups. Three bands were identified as the key factors responsible for the discrepancy between CP/CPPS patients and infertile patients (P<0.05). Two bands were identified as priority factors in the discrepancy of category IIIA and category IIIB prostatitis patients (P<0.05). According to this research, the ecological balance of the prostate and low urethra tract, when considered as a microenvironment, might play an important role in the maintenance of a healthy male reproductive tract. PMID:22635162

Comparison of National Institutes of Health-Chronic Prostatitis Symptom Index with International Index of Erectile Function 5 in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Large Cross-Sectional Study in China.

PubMed

Gao, Jingjing; Gao, Pan; Hao, Zongyao; Zhou, Zengrong; Liu, Jihong; Li, Hongjun; Xing, Junping; Zhou, Zhansong; Deng, Chunhua; Deng, Liwen; Wei, Qiang; Zhang, Xiansheng; Zhou, Jun; Fan, Song; Tai, Sheng; Yang, Chen; Shi, Kai; Huang, Yuanyuan; Ye, Zhangqun; Liang, Chaozhao

2015-01-01

The purpose of the study is to evaluate the relationship between NIH-CPSI and IIEF-5 in Chinese men with CP/CPPS. A large cross-sectional and multicenter survey was conducted from July 2012 to January 2014. Men were recruited from urology clinics which were located at the five cities in China. All men participated in the survey by completing a verbal questionnaire (consisted of sociodemographics, past medical history, sexual history, and self-estimated scales). The results showed that 1,280 men completed the survey. Based on the CP/CPPS definition, a total of 801 men were diagnosed as having CP/CPPS. Men with CP/CPPS reported higher scores of NIH-CPSI and lower scores of IIEF-5 than men without CP/CPPS. NIH-CPSI scores were significantly negatively correlated with IIEF-5 scores. The total scores of NIH-CPSI were significantly more strongly correlated with question 5 than other questions of IIEF-5. The total scores of IIEF-5 were significantly more strongly correlated with pain symptoms scores of NIH-CPSI. Strongest correlation was found between QoL impact and question 5 of IIEF-5. The findings suggested that NIH-CPSI scores were significantly negatively correlated with IIEF-5 scores. Strongest correlation was found between QoL impact and question 5 of IIEF-5.

Process characterization and Design Space definition.

PubMed

Hakemeyer, Christian; McKnight, Nathan; St John, Rick; Meier, Steven; Trexler-Schmidt, Melody; Kelley, Brian; Zettl, Frank; Puskeiler, Robert; Kleinjans, Annika; Lim, Fred; Wurth, Christine

2016-09-01

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody (MAb). This chapter describes the tools used for the characterization and validation of MAb manufacturing process under the QbD paradigm. This comprises risk assessments for the identification of potential Critical Process Parameters (pCPPs), statistically designed experimental studies as well as studies assessing the linkage of the unit operations. Outcome of the studies is the classification of process parameters according to their criticality and the definition of appropriate acceptable ranges of operation. The process and product knowledge gained in these studies can lead to the approval of a Design Space. Additionally, the information gained in these studies are used to define the 'impact' which the manufacturing process can have on the variability of the CQAs, which is used to define the testing and monitoring strategy. Copyright © 2016 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Chronic Pelvic Pain: Assessment, Evaluation, and Objectivation

PubMed Central

Pota, Vincenzo; Sansone, Pasquale; Aurilio, Caterina; Pace, Maria Caterina

2017-01-01

Chronic Pelvic Pain (CPP) and Chronic Pelvic Pain Syndrome (CPPS) have a significant impact on men and women of reproductive and nonreproductive age, with a considerable burden on overall quality of life (QoL) and on psychological, functional, and behavioural status. Moreover, diagnostic and therapeutic difficulties are remarkable features in many patients. Therefore evaluation, assessment and objectivation tools are often necessary to properly address each patient and consequently his/her clinical needs. Here we review the different tools for pain assessment, evaluation, and objectivation; specific features regarding CPP/CPPS will be highlighted. Also, recent findings disclosed with neuroimaging investigations will be reviewed as they provide new insights into CPP/CPPS pathophysiology and may serve as a tool for CPP assessment and objectivation. PMID:29359045

In vitro and in vivo delivery of therapeutic proteins using cell penetrating peptides.

PubMed

Bolhassani, Azam; Jafarzade, Behnaz Sadat; Mardani, Golnaz

2017-01-01

The failure of proteins to penetrate mammalian cells or target tumor cells restricts their value as therapeutic tools in a variety of diseases such as cancers. Recently, protein transduction domains (PTDs) or cell penetrating peptides (CPPs) have been shown to promote the delivery of therapeutic proteins or peptides into live cells. The successful delivery of proteins mainly depends on their physicochemical properties. Although, linear cell penetrating peptides are one of the most effective delivery vehicles; but currently, cyclic CPPs has been developed to potently transport bioactive full-length proteins into cells. Up to now, several small protein transduction domains from viral proteins including Tat or VP22 could be fused to other peptides or proteins to entry them in various cell types at a dose-dependent approach. A major disadvantage of PTD-fusion proteins is primary uptake into endosomal vesicles leading to inefficient release of the fusion proteins into the cytosol. Recently, non-covalent complex formation (Chariot) between proteins and CPPs has attracted a special interest to overcome some delivery limitations (e.g., toxicity). Many preclinical and clinical trials of CPP-based delivery are currently under evaluation. Generally, development of more efficient protein transduction domains would significantly increase the potency of protein therapeutics. Moreover, the synergistic or combined effects of CPPs with other delivery systems for protein/peptide drug delivery would promote their therapeutic effects in cancer and other diseases. In this review, we will describe the functions and implications of CPPs for delivering the therapeutic proteins or peptides in preclinical and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats

PubMed Central

Wenzel, Jennifer M.; Su, Zu-In; Shelton, Kerisa; Dominguez, Hiram M.; von Furstenberg, Victoria A.; Ettenberg, Aaron

2013-01-01

Human cocaine users report that the initial “high” produced by cocaine administration is followed by an anxiogenic “crash”. Given that cocaine has such robust and opposing properties, it is likely that both the positive and negative effects of cocaine contribute to an individual’s motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine’s dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug’s negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine’s opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1 mg/kg/0.1 ml) three hours after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine’s immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug’s negative/anxiogenic properties. PMID:24012795

[The role of stress-induced chronic subclinical inflammation in the pathogenesis of the chronic pelvic pain syndrome IIIB in men].

PubMed

Shormanov, I S; Mozhaev, I I; Sokolova, Kh A; Solovev, A S

2017-12-01

This literature review of recent clinical and experimental studies describes the role of oxidative stress in the multifactorial and interdisciplinary pathogenesis of non-inflammatory chronic pelvic pain syndrome IIIB (CPPS-IIIB) in men. The authors outline general biological nature of oxidative stress and its mechanisms. More detailed information is presented on cytokine-mediated chronic subclinical inflammation, one of the key mechanisms of oxidative stress, which is currently being actively studied. It is shown that the imbalance between pro- and anti-inflammatory cytokines observed in patients with CPPS-IIIB can explain some features of the clinical course (in particular, the characteristics of the pain syndrome) and the progression of this disease. In this regard, cytokine profiling of prostatic secretion can provide valuable diagnostic, prognostic and monitoring information in the management of this category of patients. Recently published evidence has demonstrated the essential role of the cytokine-mediated chronic inflammatory response as a mechanism of oxidative stress in the pathogenesis of CPPS-IIIB. Further studies in this area are warranted and in the long term may become a basis for the development of new effective pathogenetic pharmacotherapy of CPPS-IIIB.

A Peptide-based Vector for Efficient Gene Transfer In Vitro and In Vivo

PubMed Central

Lehto, Taavi; Simonson, Oscar E; Mäger, Imre; Ezzat, Kariem; Sork, Helena; Copolovici, Dana-Maria; Viola, Joana R; Zaghloul, Eman M; Lundin, Per; Moreno, Pedro MD; Mäe, Maarja; Oskolkov, Nikita; Suhorutšenko, Julia; Smith, CI Edvard; Andaloussi, Samir EL

2011-01-01

Finding suitable nonviral delivery vehicles for nucleic acid–based therapeutics is a landmark goal in gene therapy. Cell-penetrating peptides (CPPs) are one class of delivery vectors that has been exploited for this purpose. However, since CPPs use endocytosis to enter cells, a large fraction of peptides remain trapped in endosomes. We have previously reported that stearylation of amphipathic CPPs, such as transportan 10 (TP10), dramatically increases transfection of oligonucleotides in vitro partially by promoting endosomal escape. Therefore, we aimed to evaluate whether stearyl-TP10 could be used for the delivery of plasmids as well. Our results demonstrate that stearyl-TP10 forms stable nanoparticles with plasmids that efficiently enter different cell-types in a ubiquitous manner, including primary cells, resulting in significantly higher gene expression levels than when using stearyl-Arg9 or unmodified CPPs. In fact, the transfection efficacy of stearyl-TP10 almost reached the levels of Lipofectamine 2000 (LF2000), however, without any of the observed lipofection-associated toxicities. Most importantly, stearyl-TP10/plasmid nanoparticles are nonimmunogenic, mediate efficient gene delivery in vivo, when administrated intramuscularly (i.m.) or intradermally (i.d.) without any associated toxicity in mice. PMID:21343913

Carbon fiber content measurement in composite

NASA Astrophysics Data System (ADS)

Wang, Qiushi

Carbon fiber reinforced polymers (CFRPs) have been widely used in various structural applications in industries such as aerospace and automotive because of their high specific stiffness and specific strength. Their mechanical properties are strongly influenced by the carbon fiber content in the composites. Measurement of the carbon fiber content in CFRPs is essential for product quality control and process optimization. In this work, a novel carbonization-in-nitrogen method (CIN) is developed to characterize the fiber content in carbon fiber reinforced thermoset and thermoplastic composites. In this method, a carbon fiber composite sample is carbonized in a nitrogen environment at elevated temperatures, alongside a neat resin sample. The carbon fibers are protected from oxidization while the resin (the neat resin and the resin matrix in the composite sample) is carbonized under the nitrogen environment. The residue of the carbonized neat resin sample is used to calibrate the resin carbonization rate and calculate the amount of the resin matrix in the composite sample. The new method has been validated on several thermoset and thermoplastic resin systems and found to yield an accurate measurement of fiber content in carbon fiber polymer composites. In order to further understand the thermal degradation behavior of the high temperature thermoplastic polymer during the carbonization process, the mechanism and the kinetic model of thermal degradation behavior of carbon fiber reinforced poly (phenylene sulfide) (CPPS) are studied using thermogravimetry analysis (TGA). The CPPS is subjected to TGA in an air and nitrogen atmosphere at heating rates from 5 to 40°C min--1. The TGA curves obtained in air are different from those in nitrogen. This demonstrates that weight loss occurs in a single stage in nitrogen but in two stages in air. To elucidate this difference, thermal decomposition kinetics is analyzed by applying the Kissinger, Flynn-Wall-Ozawa, Coat-Redfern and Malek methods. The activation energy (Ea) of the solid-state process is determined to be 202 kJ mol--1 in an oxidative atmosphere using Kissinger's method, which is 10-15 kJ mol--1 more than the results calculated in a nitrogen atmosphere. The value of the activation energy obtained using Ozawa-Flynn methods is in agreement with that using the Kissinger method. Different degradation mechanisms are used to compare with this value. Based on the analytical result, the actual thermal degradation mechanism of the CPPS is a Dn deceleration type. The carbonization temperature range of the CPPS is the same as pure PPS resin.

Cell penetration: scope and limitations by the application of cell-penetrating peptides.

PubMed

Reissmann, Siegmund

2014-10-01

The penetration of polar or badly soluble compounds through a cell membrane into live cells requires mechanical support or chemical helpers. Cell-penetrating peptides (CPPs) are very promising chemical helpers. Because of their low cytotoxicity and final degradation to amino acids, they are particularly favored in in vivo studies and for clinical applications. Clearly, the future of CPP research is bright; however, the required optimization studies for each drug require considerable individualized attention. Thus, CPPs are not the philosopher's stone. As of today, a large number of such transporter peptides with very different sequences have been identified. These have different uptake mechanisms and can transport different cargos. Intracellular concentrations of cargos can reach a low micromole range and are able to influence intracellular reactions. Internalized ribonucleic acids such as small interfering RNA (siRNA) and mimics of RNA such as peptide nucleic acids, morpholino nucleic acids, and triesters of oligonucleotides can influence transcription and translation. Despite the highly efficient internalization of antibodies, enzymes, and other protein factors, as well as siRNA and RNA mimics, the uptake and stabile insertion of DNA into the genome of the host cells remain substantially challenging. This review describes a wide array of differing CPPs, cargos, cell lines, and tissues. The application of CPPs is compared with electroporation, magnetofection, lipofection, viral vectors, dendrimers, and nanoparticles, including commercially available products. The limitations of CPPs include low cell and tissue selectivity of the first generation and the necessity for formation of fusion proteins, conjugates, or noncovalent complexes to different cargos and of cargo release from intracellular vesicles. Furthermore, the noncovalent complexes require a strong molar excess of CPPs, and extensive experimentation is required to determine the most optimal CPP for any given cargo and cell type. Yet to predict which CPP is optimal for any given target remains a complex question. More recently, there have been promising developments: the enhancement of cell specificity using activatable CPPs, specific transport into cell organelles by insertion of corresponding localization sequences, and the transport of drugs through blood-brain barriers, through the conjunctiva of eyes, skin, and into nerve cells. Proteins, siRNA, and mimics of oligonucleotides can be efficiently transported into cells and have been tested for treatment of certain diseases. The recent state of the art in CPP research is discussed together with the overall scope, limitations, and some recommendations for future research directions. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

The role of flower pollen extract in managing patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials.

PubMed

Cai, Tommaso; Verze, Paolo; La Rocca, Roberto; Anceschi, Umberto; De Nunzio, Cosimo; Mirone, Vincenzo

2017-04-21

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still a challenge to manage for all physicians. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic efficacy of flower pollen extract would be helpful for physicians who are considering a phytotherapeutic approach to treating patients with CP/CPPS. A comprehensive search of the PubMed and Embase databases up to June 2016 was performed. This comprehensive analysis included both pre-clinical and clinical trials on the role of flower pollen extract in CP/CPPS patients. Moreover, a meta-analysis of available randomized controlled trials (RCTs) was performed. The NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and Quality of Life related questionnaires (QoL) were the most commonly used tools to evaluate the therapeutic efficacy of pollen extract. Pre-clinical studies demonstrated the anti-inflammatory and anti-proliferative role of pollen extract. 6 clinical, non-controlled studies including 206 patients, and 4 RCTs including 384 patients were conducted. The mean response rate in non-controlled studies was 83.6% (62.2%-96.0%). The meta-analysis revealed that flower pollen extract could significantly improve patients' quality of life [OR 0.52 (0.34-.0.81); p = 0.02]. No significant adverse events were reported. Most of these studies presented encouraging results in terms of variations in NIH-CPSI and QoL scores. These studies suggest that the use of flower pollen extract for the management of CP/CPPS patients is beneficial. Future publications of robust evidence from additional RCTs and longer-term follow-up would provide more support encouraging the use of flower pollen extracts for CP/CPPS patients.

IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP).

PubMed

Murphy, Stephen F; Schaeffer, Anthony J; Done, Joseph; Wong, Larry; Bell-Cohn, Ashlee; Roman, Kenny; Cashy, John; Ohlhausen, Michelle; Thumbikat, Praveen

2015-01-01

Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90-95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17's role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS.

Tumor-targeting delivery of herb-based drugs with cell-penetrating/tumor-targeting peptide-modified nanocarriers

PubMed Central

Kebebe, Dereje; Liu, Yuanyuan; Wu, Yumei; Vilakhamxay, Maikhone; Liu, Zhidong; Li, Jiawei

2018-01-01

Cancer has become one of the leading causes of mortality globally. The major challenges of conventional cancer therapy are the failure of most chemotherapeutic agents to accumulate selectively in tumor cells and their severe systemic side effects. In the past three decades, a number of drug delivery approaches have been discovered to overwhelm the obstacles. Among these, nanocarriers have gained much attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. In order to enhance targeting efficiency further and reduce limitations of nanocarriers, nanoparticle surfaces are functionalized with different ligands. Several kinds of ligand-modified nanomedicines have been reported. Cell-penetrating peptides (CPPs) are promising ligands, attracting the attention of researchers due to their efficiency to transport bioactive molecules intracellularly. However, their lack of specificity and in vivo degradation led to the development of newer types of CPP. Currently, activable CPP and tumor-targeting peptide (TTP)-modified nanocarriers have shown dramatically superior cellular specific uptake, cytotoxicity, and tumor growth inhibition. In this review, we discuss recent advances in tumor-targeting strategies using CPPs and their limitations in tumor delivery systems. Special emphasis is given to activable CPPs and TTPs. Finally, we address the application of CPPs and/or TTPs in the delivery of plant-derived chemotherapeutic agents. PMID:29563797

An automated technique for manufacturing thermoplastic stringers in continuous length

NASA Astrophysics Data System (ADS)

Pantelakis, Sp.; Baxevani, E.; Spelz, U.

In the present work an automated Continuous Compression Moulding Technique for the manufacture of stringers in continuous length is presented. The method combines pultrusion and hot-pressing. The technique is utilized for the production of L-shape stringers which are widely applied in aerospace constructions. The investigation was carried out on carbon reinforced PEEK (C/PEEK), as well as, for comparison, on the thermoplastic composites carbon reinforced polyethersulfon (C/PES), glass and carbon reinforced polyphenylene-sulfide (G/PPS, C/PPS) and Kevlar reinforced Polyamide 6 (K/PA 6). For the materials investigated the optimized process parameters for manufacturing the L-shape stringers were derived experimentally. To achieve this goal, the quality of the produced parts was controlled by using non-destructive testing techniques. Parts providing satisfactory quality were also tested destructively to measure their mechanical properties. The investigation results have shown the suitability of the technique to produce continuous length stringers.

Chronic pelvic pain syndrome: role of a thorough clinical assessment.

PubMed

Quaghebeur, Jörgen; Wyndaele, Jean-Jacques

2015-04-01

Chronic pelvic pain syndrome (CPPS) presents with a variety of symptoms affecting multiple systems. There is no universal treatment that can be given to all patients with CPPS. The results of treatment depend greatly on an accurate diagnosis. A thorough clinical assessment, including a "four-step plan", should include paying special attention to the musculoskeletal system. This assessment is not difficult to perform and provides valuable information on possible muscular problems and neuropathy.

New paradigms in understanding chronic pelvic pain syndrome.

PubMed

Konkle, Katy S; Clemens, J Quentin

2011-08-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male pain condition that is associated with significant discomfort and disability. Despite significant efforts, there remains no definitive etiology or treatment of the spectrum of pelvic symptoms reported by these patients. The purpose of this review is to summarize important clinical and scientific findings related to CP/CPPS from the previous 2 years, and to evaluate their impact on our understanding of, and approach to, the disease.

Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

PubMed Central

Roman, Kenny; Done, Joseph D.; Schaeffer, Anthony J.; Murphy, Stephen F.; Thumbikat, Praveen

2014-01-01

Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine experimental autoimmune prostatitis (EAP). Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia lead to ERK1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS. PMID:24726923

Positioning, telling, and performing a male illness: Chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wood, Nicholas; Qureshi, Annum; Mughal, Fahim

2017-11-01

There is a paucity of illness accounts of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), despite a significant level of prevalence and burden of disease. This qualitative study thus elicited twelve accounts from men suffering with CP/CPPS. Narrative analysis was employed, focusing primarily on narrative content. Three major narrative themes were identified: (1) Medical stories: Blame and shame; (2) The Erratic nature of CP/CPPS; and (3) Ongoing struggles for coping and cures and the Search for meaning. Recommendations were made for health care providers and increasing the internal agency, support and activism of men with this debilitating condition. Statement of contribution What is already known on this subject? One qualitative account of this male illness (CP/CPPS) exists: an IPA study. Five cross-sectional themes: (1) Need for repeated confirmation - disease not life-threatening nor leading inexorably towards cancer; (2) Disturbed sleep and fatigue; (3) Concealing pain and problems - 'normalizing'; (4) Enduring pain by performing activities; and (5) Abrupt mood swings and limited sociality. What does this study add? Narrative analysis adds information as to how this illness is managed and survived over time. It challenges the findings (above) by providing an insider perspective. Novel narrative themes include meaning-making amongst others. Masculine performance and experiences are also crucial to this stigmatized illness. © 2017 The British Psychological Society.

Developing a bright 17 keV x-ray source for probing high-energy-density states of matter at high spatial resolution

NASA Astrophysics Data System (ADS)

Huntington, C. M.; Park, H.-S.; Maddox, B. R.; Barrios, M. A.; Benedetti, R.; Braun, D. G.; Hohenberger, M.; Landen, O. L.; Regan, S. P.; Wehrenberg, C. E.; Remington, B. A.

2015-04-01

A set of experiments were performed on the National Ignition Facility (NIF) to develop and optimize a bright, 17 keV x-ray backlighter probe using laser-irradiated Nb foils. High-resolution one-dimensional imaging was achieved using a 15 μm wide slit in a Ta substrate to aperture the Nb Heα x-rays onto an open-aperture, time integrated camera. To optimize the x-ray source for imaging applications, the effect of laser pulse shape and spatial profile on the target was investigated. Two laser pulse shapes were used—a "prepulse" shape that included a 3 ns, low-intensity laser foot preceding the high-energy 2 ns square main laser drive, and a pulse without the laser foot. The laser spatial profile was varied by the use of continuous phase plates (CPPs) on a pair of shots compared to beams at best focus, without CPPs. A comprehensive set of common diagnostics allowed for a direct comparison of imaging resolution, total x-ray conversion efficiency, and x-ray spectrum between shots. The use of CPPs was seen to reduce the high-energy tail of the x-ray spectrum, whereas the laser pulse shape had little effect on the high-energy tail. The measured imaging resolution was comparably high for all combinations of laser parameters, but a higher x-ray flux was achieved without phase plates. This increased flux was the result of smaller laser spot sizes, which allowed us to arrange the laser focal spots from multiple beams and produce an x-ray source which was more localized behind the slit aperture. Our experiments are a first demonstration of point-projection geometry imaging at NIF at the energies (>10 keV) necessary for imaging denser, higher-Z targets than have previously been investigated.

IL17 Mediates Pelvic Pain in Experimental Autoimmune Prostatitis (EAP)

PubMed Central

Murphy, Stephen F.; Schaeffer, Anthony J.; Done, Joseph; Wong, Larry; Bell-Cohn, Ashlee; Roman, Kenny; Cashy, John; Ohlhausen, Michelle; Thumbikat, Praveen

2015-01-01

Chronic pelvic pain syndrome (CPPS) is the most common form of prostatitis, accounting for 90–95% of all diagnoses. It is a complex multi-symptom syndrome with unknown etiology and limited effective treatments. Previous investigations highlight roles for inflammatory mediators in disease progression by correlating levels of cytokines and chemokines with patient reported symptom scores. It is hypothesized that alteration of adaptive immune mechanisms results in autoimmunity and subsequent development of pain. Mouse models of CPPS have been developed to delineate these immune mechanisms driving pain in humans. Using the experimental autoimmune prostatitis (EAP) in C57BL/6 mice model of CPPS we examined the role of CD4+T-cell subsets in the development and maintenance of prostate pain, by tactile allodynia behavioral testing and flow cytometry. In tandem with increased CD4+IL17A+ T-cells upon EAP induction, prophylactic treatment with an anti-IL17 antibody one-day prior to EAP induction prevented the onset of pelvic pain. Therapeutic blockade of IL17 did not reverse pain symptoms indicating that IL17 is essential for development but not maintenance of chronic pain in EAP. Furthermore we identified a cytokine, IL7, to be associated with increased symptom severity in CPPS patients and is increased in patient prostatic secretions and the prostates of EAP mice. IL7 is fundamental to development of IL17 producing cells and plays a role in maturation of auto-reactive T-cells, it is also associated with autoimmune disorders including multiple sclerosis and type-1 diabetes. More recently a growing body of research has pointed to IL17’s role in development of neuropathic and chronic pain. This report presents novel data on the role of CD4+IL17+ T-cells in development and maintenance of pain in EAP and CPPS. PMID:25933188

Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines.

PubMed

Wierzbicki, Piotr M; Kogut-Wierzbicka, Marzena; Ruczynski, Jaroslaw; Siedlecka-Kroplewska, Kamila; Kaszubowska, Lucyna; Rybarczyk, Agnieszka; Alenowicz, Magdalena; Rekowski, Piotr; Kmiec, Zbigniew

2014-01-01

Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot). HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR). Since up to 10 µM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5-5 µM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs. We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells.

Poly(NIPAm-AMPS) nanoparticles for targeted delivery of anti-inflammatory cell penetrating peptides

NASA Astrophysics Data System (ADS)

Bartlett, Rush Lloyd, II

Inflammatory diseases such as osteoarthritis and rheumatoid arthritis cause $127.8 billion in US healthcare expenditures each year and are the cause of disability for 27% of disabled persons in the United States. Current treatment options rarely halt disease progression and often result in significant unwanted and debilitating side effects. Our laboratory has previously developed a family of cell penetrating peptides (CPPs) which inhibit the activity of mitogen activated protein kinase activate protein kinase 2 (MK2). MK2 mediates the inflammatory response by activating Tristetraprline (TTP). Once activated, TTP rapidly stabilizes AU rich regions of pro-inflammatory cytokine mRNA which allows translation of pro-inflammatory cytokines to occur. Blocking MK2 with our labs CPPs yields a decrease in inflammatory activity but CPPs by are highly non specific and prone to rapid enzymatic degradation in vivo.. In order to increase the potency of MK2 inhibiting CPPs we have developed a novel nanoparticle drug carrier composed of poly(N-isopropylacrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic acid). This drug carrier has been shown to have preliminary efficacy in vitro and ex vivo for suppressing pro-inflammatory cytokine production when releasing CPPs. This thesis will present progress made on three aims: Specific Aim 1) Create and validate a NIPAm based drug delivery system that mimics the binding and release previously observed between cell penetrating peptides and glycosaminoglycans. Specific Aim 2) Engineer degradability into poly(NIPAm-AMPS) nanoparticles to enable more drug to be released and qualify that system in vitro. Specific Aim 3) Validate poly(NIPAm-AMPS) nanoparticles for targeted drug delivery in an ex vivo inflammatory model. Overall we have developed a novel anionic nanoparticle system that is biocompatible and efficient at loading and releasing cell penetrating peptides to inflamed tissue. Once loaded with a CPP the nanoparticle drug complex is capable of targeting diseased tissue and preventing the production of pro-inflammatory cytokines in both in vitro and ex vivo models.

Calcium-containing phosphopeptides pave the secretory pathway for efficient protein traffic and secretion in fungi.

PubMed

Martín, Juan F

2014-09-10

Casein phosphopeptides (CPPs) containing chelated calcium drastically increase the secretion of extracellular homologous and heterologous proteins in filamentous fungi. Casein phosphopeptides released by digestion of alpha - and beta-casein are rich in phosphoserine residues (SerP). They stimulate enzyme secretion in the gastrointestinal tract and enhance the immune response in mammals, and are used as food supplements. It is well known that casein phosphopeptides transport Ca2+ across the membranes and play an important role in Ca2+ homeostasis in the cells. Addition of CPPs drastically increases the production of heterologous proteins in Aspergillus as host for industrial enzyme production. Recent proteomics studies showed that CPPs alter drastically the vesicle-mediated secretory pathway in filamentous fungi, apparently because they change the calcium concentration in organelles that act as calcium reservoirs. In the organelles calcium homeostasis a major role is played by the pmr1 gene, that encodes a Ca2+/Mn2+ transport ATPase, localized in the Golgi complex; this transporter controls the balance between intra-Golgi and cytoplasmic Ca2+ concentrations. A Golgi-located casein kinase (CkiA) governs the ER to Golgi directionality of the movement of secretory proteins by interacting with the COPII coat of secretory vesicles when they reach the Golgi. Mutants defective in the casein-2 kinase CkiA show abnormal targeting of some secretory proteins, including cytoplasmic membrane amino acid transporters that in ckiA mutants are miss-targeted to vacuolar membranes. Interestingly, addition of CPPs increases a glyceraldehyde-3-phpshate dehydrogenase protein that is known to associate with microtubules and act as a vesicle/membrane fusogenic agent. In summary, CPPs alter the protein secretory pathway in fungi adapting it to a deregulated protein traffic through the organelles and vesicles what results in a drastic increase in secretion of heterologous and also of some homologous proteins.

Single-crystal phosphors for high-brightness white LEDs/LDs

NASA Astrophysics Data System (ADS)

Víllora, Encarnación G.; Arjoca, Stelian; Inomata, Daisuke; Shimamura, Kiyoshi

2016-03-01

White light-emitting diodes (wLEDs) are the new environmental friendly sources for general lighting purposes. For applications requiring a high-brightness, current wLEDs present overheating problems, which drastically decrease their emission efficiency, color quality and lifetime. This work gives an overview of the recent investigations on single-crystal phosphors (SCPs), which are proposed as novel alternative to conventional ceramic powder phosphors (CPPs). This totally new approach takes advantage of the superior properties of single-crystals in comparison with ceramic materials. SCPs exhibit an outstanding conversion efficiency and thermal stability up to 300°C. Furthermore, compared with encapsulated CPPs, SCPs possess a superior thermal conductivity, so that generated heat can be released efficiently. The conjunction of all these characteristics results in a low temperature rise of SCPs even under high blue irradiances, where conventional CPPs are overheated or even burned. Therefore, SCPs represent the ideal, long-demanded all-inorganic phosphors for high-brightness white light sources, especially those involving the use of high-density laser-diode beams.

Role of the visual experience-dependent nascent proteome in neuronal plasticity

PubMed Central

Liu, Han-Hsuan; McClatchy, Daniel B; Schiapparelli, Lucio; Shen, Wanhua; Yates, John R

2018-01-01

Experience-dependent synaptic plasticity refines brain circuits during development. To identify novel protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we conducted a quantitative proteomic screen of the nascent proteome in response to visual experience in Xenopus optic tectum using bio-orthogonal metabolic labeling (BONCAT). We identified 83 differentially synthesized candidate plasticity proteins (CPPs). The CPPs form strongly interconnected networks and are annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs revealed the requirement for eukaryotic initiation factor three subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity in tectal neurons and behavioral plasticity in tadpoles. These results demonstrate that the nascent proteome is dynamic in response to visual experience and that de novo synthesis of machinery that regulates RNA splicing and protein translation is required for experience-dependent plasticity. PMID:29412139

Towards quality by design in pharmaceutical manufacturing: modelling and control of air jet mills

NASA Astrophysics Data System (ADS)

Bhonsale, Satyajeet; Telen, Dries; Stokbroekx, Bard; Van Impe, Jan

2017-06-01

Milling is an important step in pharmaceutical manufacturing as it not only determines the final formulation of the drug product, but also influences the bioavailability and dissolution rate of the active pharmaceutical ingredient (API). In this respect, the air jet mill (AJM) is most commonly used in the pharmaceutical industry as it is a non-contaminating and non-degrading self-classifying process capable of delivering narrow particle size distributions (PSD). Keeping the principles of Quality by Design in mind, the Critical Process Parameters (CPPs) of the AJM have been identified to be the pressures at the grinding nozzles, and the feed rate which affect the PSD, surface charge and the morphology of the product (i.e. the Critical Material Attributes (CMAs)). For the purpose of this research, the PSD is considered to be the only relevant CMA. A population balance based model is proposed to simulate the dynamics milling operation by utilizing the concept of breakage functions. This model agrees qualitatively with experimental observations of the air jet mill unit present at Janssen Pharmaceutica but further steps for model validation need to be carried out.

Chinese urologists' practice patterns of diagnosing and treating chronic pelvic pain syndrome: a questionnaire survey.

PubMed

Zhang, Kai; Xu, Ben; Xiao, Yun-xiang; Shang, Xue-jun; Bai, Wen-jun; Wang, Xiao-feng; Liu, Ji-hong; Deng, Chun-hua

2014-08-18

To investigate the application of the Chinese Urological Association (CUA) guidelines on prostatitis and the effects on the clinical practice patterns of diagnosing and treating chronic pelvic pain syndrome (CPPS) among Chinese urologists. We conducted a questionnaire investigation of the CUA guidelines on prostatitis among the urologists from 399 hospitals in 63 cities of China, and performed statistical analyses on all the eligible questionnaires collected. Of the 2 251 questionnaires distributed, 2 046 (90.9%) were eligible, of which 92.5% were from the urologists in tertiary or secondary hospitals, of whom 72.3% had senior or intermediate professional titles, and 90.2% had studied the CUA guidelines. Most respondents agreed that Type III prostatitis was a clinical syndrome, of which the diagnosis should be made after other conditions with similar symptoms had been ruled out and the aim was to relieve pain, alleviate urination symptoms and improve quality of life. Those who had and those who had not studied the CUA guidelines differed in their viewpoints on CPPS as illustrated in the guidelines. In clinical practice, the most common treatment options for CPPS were pharmaceutical therapy (95.0%), life style adjustment (88.9%), and psychotherapy (79.9%), and the most frequently prescribed drugs were phytotherapy (84.5%), α-blockers (79.0%) and antibiotics (64.0%). CUA guidelines on prostatitis has gained a nationwide application and promoted the standardization of the management of CPPS in China.

Investigation of the effect of traditional Chinese medicine on pain and inflammation in chronic nonbacterial prostatitis in rats.

PubMed

Liu, Y-J; Song, G-H; Liu, G T

2016-08-01

According to traditional Chinese medicine, the symptoms of chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS) may be treated using a cocktail of herbs that stimulate blood circulation ('activating blood circulation formula'). We investigated the effect of three doses of this formula on a rat model of CNP/CPPS. Male Wistar rats were injected with a saline extract of male sex accessory glands on days 0 and 30 to induce prostatitis and then treated daily by gavage between days 32 and 60. Treatment with low, medium and high doses of activating blood circulation formula resulted in an almost total rescue of paw withdrawal threshold at day 60, and treatment with the highest dose also significantly decreased prostate inflammation (assessed histopathologically). We further observed elevated serum prostaglandin E2 levels in the CNP/CPPS model which decreased upon high-dose treatment, and increased Cox-2 expression in the prostate and spinal cord dorsal horn which was rescued in both tissues in the high-dose group and in the prostate in the medium-dose group. These results shed light on a possible mechanism by which activating blood circulation therapy may alleviate pain in a rat model of CNP/CPPS by downregulating Cox-2 expression in the spinal cord, thereby raising the pain threshold. Further research will be needed to fully characterise the mechanism by which activating blood circulation therapy produces this therapeutic effect. © 2016 Blackwell Verlag GmbH.

Immunological Mechanisms Underlying Chronic Pelvic Pain and Prostate Inflammation in Chronic Pelvic Pain Syndrome

PubMed Central

Breser, María L.; Salazar, Florencia C.; Rivero, Viginia E.; Motrich, Rubén D.

2017-01-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most common urologic morbidity in men younger than 50 years and is characterized by a diverse range of pain and inflammatory symptoms, both in type and severity, that involve the region of the pelvis, perineum, scrotum, rectum, testes, penis, and lower back. In most patients, pain is accompanied by inflammation in the absence of an invading infectious agent. Since CP/CPPS etiology is still not well established, available therapeutic options for patients are far from satisfactory for either physicians or patients. During the past two decades, chronic inflammation has been deeply explored as the cause of CP/CPPS. In this review article, we summarize the current knowledge regarding immunological mechanisms underlying chronic pelvic pain and prostate inflammation in CP/CPPS. Cumulative evidence obtained from both human disease and animal models indicate that several factors may trigger chronic inflammation in the form of autoimmunity against prostate, fostering chronic prostate recruitment of Th1 cells, and different other leukocytes, including mast cells, which might be the main actors in the consequent development of chronic pelvic pain. Thus, the local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development. Although scientific advances are encouraging, additional studies are urgently needed to establish the relationship between prostatitis development, mast cell recruitment to the prostate, and the precise mechanisms by which they would induce pelvic pain. PMID:28824626

Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design space.

PubMed

Mukharya, Amit; Patel, Paresh U; Shenoy, Dinesh; Chaudhary, Shivang

2013-01-01

Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. Main object of this quality risk management (QRM) study is to provide a sophisticated "robust and rugged" Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. THIS STUDY IS PRINCIPALLY FOCUSING ON THOROUGH MECHANISTIC UNDERSTANDING OF THE FBP BY WHICH IT IS DEVELOPED AND SCALED UP WITH A KNOWLEDGE OF THE CRITICAL RISKS INVOLVED IN MANUFACTURING PROCESS ANALYZED BY RISK ASSESSMENT TOOLS LIKE: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale.

Quality risk management of top spray fluidized bed process for antihypertensive drug formulation with control strategy engendered by Box-behnken experimental design space

PubMed Central

Mukharya, Amit; Patel, Paresh U; Shenoy, Dinesh; Chaudhary, Shivang

2013-01-01

Introduction: Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), flow ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. Materials and Methods: Main object of this quality risk management (QRM) study is to provide a sophisticated “robust and rugged” Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. Results and Conclusion: This study is principally focusing on thorough mechanistic understanding of the FBP by which it is developed and scaled up with a knowledge of the critical risks involved in manufacturing process analyzed by risk assessment tools like: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further refined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale. PMID:23799202

A prospective study on association of prostatic calcifications with sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

PubMed

Zhao, Zhigang; Xuan, Xujun; Zhang, Jingwei; He, Jun; Zeng, Guohua

2014-10-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common debilitating condition of unclear etiology. Sexual dysfunction is an important component of the clinical phenotype of CP/CPPS. Patients often have prostatic calcifications, but a link to sexual dysfunction is unknown. The aim of this study was to evaluate the association of prostatic calcifications with sexual dysfunction in this condition. A total of 358 males with CP/CPPS were consecutively enrolled, and a prospectively maintained database of these patients was analyzed. Calcifications were diagnosed using ultrasound imaging of the prostate. Symptom severity was measured using the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI). Sexual dysfunction was evaluated using the validated 15-item International Index of Erectile Function (IIEF-15) questionnaire and 5-item Premature Ejaculation Diagnostic Tool scales. The variables were compared between patients with prostatic calcifications and those without using the Student's t-test, Wilcoxon unpaired test, or chi-square test. Logistic regression models were developed to explore a possible association between prostatic calcifications and sexual dysfunction. Measurable calcifications in the prostate were found in 175 (48.9%) of the 358 patients. Patients with calcifications were more likely to have higher white blood cell counts or positive bacteria cultures in their prostatic fluid, longer symptoms duration, and lower scores for the total IIEF-15, IIEF-erectile function, and IIEF-intercourse satisfaction domains (P < 0.001 for each). However, the scores for CPSI, premature ejaculation, and IIEF-orgasmic function, IIEF-sexual desire, and IIEF-overall satisfaction domains were identical between men with and without calcifications (P > 0.05 for each). Furthermore, logistic regression analyses revealed that intraprostatic calcification is significantly associated with self-assessed erectile dysfunction (ED) (odds ratio:3.632, 95% confidence interval: 2.405-5.822, P < 0.001). Our results showed that prostatic calcifications are significantly associated with the presence of ED in CP/CPPS males. © 2014 International Society for Sexual Medicine.

Long-term effect of extracorporeal shock wave therapy on the treatment of chronic pelvic pain syndrome due to non bacterial prostatitis.

PubMed

Moayednia, Amir; Haghdani, Saeid; Khosrawi, Saeid; Yousefi, Elham; Vahdatpour, Babak

2014-04-01

There is limited evidence about the chronic pelvic pain syndrome (CPPS) treatment by shockwave therapy, and the aim of this study was to evaluate the effect of extracorporeal shockwave therapy on CPPS due to non bacterial prostatitis in a long-term period. In a follow-up survey, 40 patients with CPPS (that were randomly distributed into the treatment or sham groups were evaluated at 16, 20, and 24 weeks. In the treatment group, patients were treated by extracorporeal shock wave therapy (ESWT) once a week for 4 weeks by a protocol of 3000 impulses, 0.25 mJ/m(2) and 3 Hz of frequency. 0.05 mJ/m(2) were added in each week. In the sham group, the same protocol was applied, but with the probe being turned off. The follow-up assessments were done by visual analog scale for pain and National Institutes of Health-developed Chronic Prostatitis Symptom Index (NIH-CPSI). Data were compared using independent t-test or analysis of variences. Three patients did not complete the study protocol, 37 patients were evlauated (19 patients in treatment and 18 patients in the sham group). At week 24, the mean of pain score, urinary score, quality-of-life and NIH-CPSI score between two groups were not statistically different. Although, ESWT therapy as a safe and effective therapy in CPPS in short-term follow-up has been established, its long-term efficacy was not supported by this study.

Acupuncture versus Sham Acupuncture for Chronic Prostatitis/Chronic Pelvic Pain

PubMed Central

Lee, Shaun Wen Huey; Liong, Men Long; Yuen, Kah Hay; Leong, Wing Seng; Chee, Christopher; Cheah, Phaik Yeong; Choong, Weng Pho; Wu, Yue; Khan, Nurzalina; Choong, Wooi Long; Yap, Hin Wai; Krieger, John N.

2015-01-01

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) afflicts 2–10% of adult men. Available therapies offer little or no proven benefit. Because acupuncture represents an attractive “natural” therapy, we compared the efficacy of acupuncture to sham acupuncture for CP/CPPS Methods Participants met US National Institutes of Health (NIH) consensus criteria for CP/CPPS, aged ≥ 20 years old, with total score ≥ 15 on the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) and symptoms for at least 3 of the preceding 6 months were randomized 1:1 to acupuncture or sham acupuncture. Treatment consisted of twice weekly 30-minute sessions for 10 weeks (20 sessions total), without needle stimulation, herbs or adjuvants. The primary response criterion was a six-point decrease from baseline to week 10 in NIH-CPSI total score (range 0–43). Results Thirty-two (73%) of 44 participants responded in the acupuncture group compared to 21 (47%) of 45 sham group participants (relative risk [RR] 1.81, 95% confidence interval [CI], 1.3–3.1, p=0.02,). Long-term responses 24 weeks after completing therapy without additional treatment occurred in 14 (32%) of 44 acupuncture group participants and in 6 (13%) of 45 sham group participants (RR 2.39, 95% CI, 1.0–5.6, p=0.04). Conclusion After 10 weeks of treatment, acupuncture proved almost twice as likely as sham to improve CP/CPPS symptoms. Participants receiving acupuncture were 2.4 fold more likely to experience long-term benefit than participants receiving sham acupuncture. PMID:18187077

Anti-nanobacterial therapy for men with chronic prostatitis/chronic pelvic pain syndrome and prostatic stones: preliminary experience.

PubMed

Shoskes, Daniel A; Thomas, Kim D; Gomez, Eyda

2005-02-01

Category III chronic prostatitis/chronic pelvic pain syndrome (CPPS) is a common debilitating condition of unclear etiology. Patients often have prostatic calcifications but a link to symptoms is controversial. Nanobacteria are implicated in stone formation in the urinary tract and, therefore, therapy to eliminate nanobacteria and the stones that they produce might have an impact on CPPS symptoms. A total of 16 men with recalcitrant CPPS refractory to multiple prior therapies were treated with comET (Nanobac Life Sciences, Tampa, Florida), which consists of 500 mg tetracycline, a proprietary nutraceutical and an ethylenediaminetetraacetic acid suppository daily. The National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), transrectal ultrasound, and blood and urine tests for nanobacterial antigen were performed at the start and conclusion of 3 months of therapy. One patient was lost to followup. Mean NIH-CPSI total score +/- SD decreased from 25.7 +/- 1.6 to 13.7 +/- 2.0 (p <0.0001). Significant improvement was seen in each subscore domain. A total of 12 patients (80%) had at least 25% improvement on NIH-CPSI and 8 (53%) had at least 50% improvement. Nanobacterial antigen or antibody was found in 60% of serum and 40% of urine samples. In 10 patients who underwent transrectal ultrasound after therapy prostatic stones were decreased in size or resolved in 50%. Therapy designed to eliminate nanobacteria resulted in significant improvement in the symptoms of recalcitrant CPPS in the majority of men, whether due to the treatment of stone producing nanobacteria or through some other mechanism. Prospective placebo controlled trials are warranted.

Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides.

PubMed

de Cogan, Felicity; Hill, Lisa J; Lynch, Aisling; Morgan-Warren, Peter J; Lechner, Judith; Berwick, Matthew R; Peacock, Anna F A; Chen, Mei; Scott, Robert A H; Xu, Heping; Logan, Ann

2017-05-01

To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection. CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV. CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment. CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

Imprinting continuously varying topographical structure onto large-aperture optical surfaces using magnetorheological finishing

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

Menapace, J A; Davis, P J; Dixit, S

2007-03-07

Over the past four years we have advanced Magnetorheological Finishing (MRF) techniques and tools to imprint complex continuously varying topographical structures onto large-aperture (430 x 430 mm) optical surfaces. These optics, known as continuous phase plates (CPPs), are important for high-power laser applications requiring precise manipulation and control of beam-shape, energy distribution, and wavefront profile. MRF's unique deterministic-sub-aperture polishing characteristics make it possible to imprint complex topographical information onto optical surfaces at spatial scale-lengths approaching 1 mm and surface peak-to-valleys as high as 22 {micro}m. During this discussion, we will present the evolution of the MRF imprinting technology and themore » MRF tools designed to manufacture large-aperture 430 x 430 mm CPPs. Our results will show how the MRF removal function impacts and limits imprint fidelity and what must be done to arrive at a high-quality surface. We also present several examples of this imprinting technology for fabrication of phase correction plates and CPPs for use in high-power laser applications.« less

Efficacy of Low-Intensity Extracorporeal Shock Wave Therapy on Men With Chronic Pelvic Pain Syndrome Refractory to 3-As Therapy.

PubMed

Guu, Shiao-Jin; Geng, Jiun-Hung; Chao, I-Ting; Lin, Hui-Tzu; Lee, Yung-Chin; Juan, Yung-Shun; Liu, Chia-Chu; Wang, Chii-Jye; Tsai, Chia-Chun

2018-03-01

Managing patients with chronic pelvic pain syndrome (CPPS) refractory to the traditional 3-As therapy (antibiotics, alpha-blockers, and anti-inflammatories) is a challenging task. Low-intensity extracorporeal shock wave therapy (LI-ESWT) was recently reported to be able to improve pain, urinary symptoms, and even sexual function by inducing neovascularization and anti-inflammation, reducing muscle tone, and influencing nerve impulses. This study evaluates whether combined treatment with LI-ESWT can restore clinical ability and quality of life (QoL) in patients refractory to 3-As therapy. This was an open-label, single-arm prospective study. Patients with CPPS without more than a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score under the maximal dosage of 3-As therapy were enrolled. LI-ESWT treatment consisted of 3,000 shock waves administered once weekly for 4 weeks. The NIH-CPSI, visual analog scale (VAS) score, International Prostate Symptom Score (IPSS), and the five-item version of the International Index of Erectile Function (IIEF-5) were used to evaluate efficacy at 1, 4, and 12 weeks after LI-ESWT. Thirty-three patients were enrolled in this study. After LI-ESWT treatment, 27 of the 33 patients (81.82%) had a successful response to LI-ESWT, with a decrease of 3.29 and 5.97 in the VAS score and total IPSS at the 3-month follow-up. Waist circumference was the only significant predictor of a successful response to LI-ESWT. LI-ESWT can serve as a salvage therapy for patients with CPPS refractory to traditional 3-As therapy. Further studies are needed to determine an adequate therapeutic protocol and important predictors in patients with different CPPS etiologies.

Constant proportion harvest policies: dynamic implications in the Pacific halibut and Atlantic cod fisheries.

PubMed

Yakubu, Abdul-Aziz; Li, Nianpeng; Conrad, Jon M; Zeeman, Mary-Lou

2011-07-01

Overfishing, pollution and other environmental factors have greatly reduced commercially valuable stocks of fish. In a 2006 Science article, a group of ecologists and economists warned that the world may run out of seafood from natural stocks if overfishing continues at current rates. In this paper, we explore the interaction between a constant proportion harvest policy and recruitment dynamics. We examine the discrete-time constant proportion harvest policy discussed in Ang et al. (2009) and then expand the framework to include stock-recruitment functions that are compensatory and overcompensatory, both with and without the Allee effect. We focus on constant proportion policies (CPPs). CPPs have the potential to stabilize complex overcompensatory stock dynamics, with or without the Allee effect, provided the rates of harvest stay below a threshold. If that threshold is exceeded, CPPs are known to result in the sudden collapse of a fish stock when stock recruitment exhibits the Allee effect. In case studies, we analyze CPPs as they might be applied to Gulf of Alaska Pacific halibut fishery and the Georges Bank Atlantic cod fishery based on harvest rates from 1975 to 2007. The best fit models suggest that, under high fishing mortalities, the halibut fishery is vulnerable to sudden population collapse while the cod fishery is vulnerable to steady decline to zero. The models also suggest that CPP with mean harvesting levels from the last 30 years can be effective at preventing collapse in the halibut fishery, but these same policies would lead to steady decline to zero in the Atlantic cod fishery. We observe that the likelihood of collapse in both fisheries increases with increased stochasticity (for example, weather variability) as predicted by models of global climate change. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of acupuncture on clinical symptoms and laboratory indicators for chronic prostatitis/chronic pelvic pain syndrome: a systematic review and meta-analysis.

PubMed

Liu, Bu-Ping; Wang, Yun-Ting; Chen, Si-da

2016-12-01

To systematically review the efficacy and safety of acupuncture for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PubMed, Cochrane library Central, Web of Science, Wang-fang Database, and CNKI were searched from their inception to June 30, 2016. Data of acupuncture for CP/CPPS following randomized controlled trials (RCTs) was included. The data were analyzed using the Cochrane Collaboration Review Manager. The primary data were the National Institute of Health-Chronic Prostatitis Index (NIH-CPSI) score at the end of follow-up. Ten RCTs were enrolled. Acupuncture was superior to the control in NIH-CPSI (MD -3.98, [95 % CI -5.78 to -2.19]; P < 0.0001) and response rate (RR 4.12, [95 % CI 1.67-10.18]; P = 0.002). Acupuncture was superior to sham acupuncture on NIH-CPSI, response rate, pain, urinary, and quality of life (QOL). Standard medication was inferior to acupuncture in terms of NIH-CPSI (MD -3.08, [95 % CI -5.57 to -0.60]; P = 0.02) and response rate (RR 2.03, [95 % CI 1.04-3.97]; P = 0.04), but standard medication was superior to acupuncture on improving urinary symptoms. There was no significant difference in the adverse events. Acupuncture/acupuncture plus standard medication significantly down-regulated IL-1β compared with standard medication in prostatic fluid. Acupuncture treating CP/CPPS is effective and safe. The effects of acupuncture on NIH-CPSI, response rate, pain symptoms, and QOF were superior to the control, but standard medication significantly improved urinary symptoms compared with acupuncture. Acupuncture can decrease the IL-1β in prostatic fluid for CP/CPPS.

Evaluation of cell-penetrating peptides (CPPs) as vehicles for intracellular delivery of antisense peptide nucleic acid (PNA).

PubMed

Bendifallah, Nadia; Rasmussen, Frank Winther; Zachar, Vladimir; Ebbesen, Peter; Nielsen, Peter E; Koppelhus, Uffe

2006-01-01

Cell-penetrating peptides (CPPs) are characterized by their ability to be internalized in mammalian cells. To investigate the relative potency of CPPs as carriers of medicinally relevant cargo, a positive read-out assay based on the ability of a peptide nucleic acid (PNA) oligomer to promote correct expression of a recombinant luciferase gene was employed. Seven different CPPs were included in the study: Transportan, oligo-arginine (R7-9), pTat, Penetratin, KFF, SynB3, and NLS. The CPP-PNA conjugates were synthesized by different conjugation chemistries: continuous synthesis, maleimide coupling, and ester or disulfide linkage. Under serum-free conditions PNA-SS-Transportan-amide (ortho)-PNA was found to be the most potent conjugate, resulting in maximum luciferase signal at a concentration of 1-2 microM. (D-Arg)9-PNA showed optimal efficacy at 5 microM but gave rise to only one-third of the luciferase signal obtained with the Transportan conjugate. The pTat- and KFF-PNA conjugates showed significantly lower efficacy. The penetratin-, SynB3-. and NLS-PNA conjugates showed only minimal or no activity. Serum was found to have a drastic negative impact on CPP-driven cellular uptake. PNA-SS-Transportan-acid (ortho) and (D-Arg)9-PNA were least sensitive to the presence of serum. Both the chemical nature and, in the case of Transportan, the position of the peptide PNA coupling were found to have a major impact on the transport capacity of the peptides. However, no simple relationship between linker type and antisense activity of the conjugates could be deduced from the data.

Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation.

PubMed

Pallagi, Edina; Ambrus, Rita; Szabó-Révész, Piroska; Csóka, Ildikó

2015-08-01

Regulatory science based pharmaceutical development and product manufacturing is highly recommended by the authorities nowadays. The aim of this study was to adapt regulatory science even in the nano-pharmaceutical early development. Authors applied the quality by design (QbD) concept in the early development phase of nano-systems, where the illustration material was meloxicam. The meloxicam nanoparticles produced by co-grinding method for nasal administration were studied according to the QbD policy and the QbD based risk assessment (RA) was performed. The steps were implemented according to the relevant regulatory guidelines (quality target product profile (QTPP) determination, selection of critical quality attributes (CQAs) and critical process parameters (CPPs)) and a special software (Lean QbD Software(®)) was used for the RA, which represents a novelty in this field. The RA was able to predict and identify theoretically the factors (e.g. sample composition, production method parameters, etc.) which have the highest impact on the desired meloxicam-product quality. The results of the practical research justified the theoretical prediction. This method can improve pharmaceutical nano-developments by achieving shorter development time, lower cost, saving human resource efforts and more effective target-orientation. It makes possible focusing the resources on the selected parameters and area during the practical product development. Copyright © 2015 Elsevier B.V. All rights reserved.

Membrane Crossing and Membranotropic Activity of Cell-Penetrating Peptides: Dangerous Liaisons?

PubMed

Walrant, Astrid; Cardon, Sébastien; Burlina, Fabienne; Sagan, Sandrine

2017-12-19

Living organisms have to maintain a stable balance in molecules and ions in the changing environment in which they are living, a process known as homeostasis. At the level of cells, the plasma membrane has a major role in homeostasis, since this hydrophobic film prevents passive diffusion of large and hydrophilic molecules between the extracellular and intracellular milieu. Living organisms have evolved with highly sophisticated transport systems to control exchanges across this barrier: import of nutrients and fuel essential for their survival; recognition of chemical or physical messengers allowing information interchanges with surrounding cells. Besides specialized proteins, endocytosis mechanisms at the level of the lipid bilayer can transport molecules from the outside across the cell membrane, in an energy-dependent manner. The cell membrane is highly heterogeneous in its molecular composition (tens of different lipids, proteins, polysaccharides, and combinations of these) and dynamic with bending, deformation, and elastic properties that depend on the local composition of membrane domains. Many viruses, microorganisms, and toxins exploit the plasma membrane to enter into cells. Chemists develop strategies to target the plasma membrane with molecules capable of circumventing this hydrophobic barrier, in particular to transport and deliver nonpermeable drugs in cells for biotechnological or pharmaceutical purposes. Drug delivery systems are numerous and include lipid-, sugar-, protein-, and peptide-based delivery systems, since these biomolecules generally have good biocompatibility, biodegradability, environmental sustainability, cost effectiveness, and availability. Among those, cell-penetrating peptides (CPPs), reported for the first time in the early 1990s, are attracting major interest not only as potential drug delivery systems but also at the level of fundamental research. It was indeed demonstrated very early that these peptides, which generally correspond to highly cationic sequences, can still cross the cell membrane at 4 °C, a temperature at which all active transport and endocytosis pathways are totally inhibited. Therefore, how these charged hydrophilic peptides cross the hydrophobic membrane barrier is of utmost interest as a pure basic and physicochemical question. In this Account, we focus on cationic cell-penetrating peptides (CPPs) and the way they cross cell membranes. We summarize the history of this field that emerged around 20 years ago. CPPs were indeed first identified as protein-transduction domains from the human immunodeficiency virus (HIV) TAT protein and the Antennapedia homeoprotein, a transcription factor from Drosophila. We highlight our contribution to the elucidation of CPP internalization pathways, in particular translocation, which implies perturbation and reorganization of the lipid bilayer, and endocytosis depending on sulfated glycosaminoglycans. We show a particular role of Trp (indole side chain) and Arg (guanidinium side chain), which are essential amino acids for CPP internalization. Interactions with the cell-surface are not only Coulombic; H-bonds and hydrophobic interactions contribute also significantly to CPP entry. The capacity of CPPs to cross cell membrane is not related to their strength of membrane binding. Finally, we present optimized methods based on mass spectrometry and fluorescence spectroscopy that allow unequivocal quantification of CPPs inside cells or bound to the outer leaflet of the membrane, and discuss some limitations of the technique of flow cytometry that we have recently highlighted.

Electronic transport properties in [n]cycloparaphenylenes molecular devices

NASA Astrophysics Data System (ADS)

Hu, Lizhi; Guo, Yandong; Yan, Xiaohong; Zeng, Hongli; Zhou, Jie

2017-07-01

The electronic transport of [n]cycloparaphenylenes ([n]CPPs) is investigated based on nonequilibrium Green's function formalism in combination with the density-functional theory. Negative differential resistance (NDR) phenomenon is observed. Further analysis shows that the reduction of the transmission peak induced by the bias changing near Fermi energy results in the NDR effect. Replacing the electrode (from carbon chain to Au electrode), doping with N atom and changing the size of the nanohoop (n = 5, 6, 8, 10) have also been studied and the NDR still exists, suggesting the NDR behavior is the intrinsic feature of such [n]CPPs systems, which would be quite useful in future nanoelectronic devices.

Singlet and triplet excitons and charge polarons in cycloparaphenylenes. A density functional theory study

DOE PAGES

Liu, Jin; Adamska, Lyudmyla; Doorn, Stephen K.; ...

2015-05-14

Conformational structure and the electronic properties of various electronic excitations in cycloparaphenylenes (CPPs) are calculated using hybrid Density Functional Theory (DFT). The results demonstrate that wavefunctions of singlet and triplet excitons as well as the positive and negative polarons remain fully delocalized in CPPs. In contrast, these excitations in larger CPP molecules become localized on several phenyl rings, which are locally planarized, while the undeformed ground state geometry is preserved on the rest of the hoop. As evidenced by the measurements of bond-length alternation and dihedral angles, localized regions show stronger hybridization between neighboring bonds and thus enhanced electronic communication.more » This effect is even more significant in the smaller hoops, where phenyl rings have strong quinoid character in the ground state. Thus, upon excitation, electron–phonon coupling leads to the self-trapping of the electronic wavefunction and release of energy from fractions of an eV up to two eVs, depending on the type of excitation and the size of the hoop. The impact of such localization on electronic and optical properties of CPPs is systematically investigated and compared with the available experimental measurements.« less

Bioactive Peptides Isolated from Casein Phosphopeptides Enhance Calcium and Magnesium Uptake in Caco-2 Cell Monolayers.

PubMed

Cao, Yong; Miao, Jianyin; Liu, Guo; Luo, Zhen; Xia, Zumeng; Liu, Fei; Yao, Mingfei; Cao, Xiaoqiong; Sun, Shengwei; Lin, Yanyin; Lan, Yaqi; Xiao, Hang

2017-03-22

The ability of casein phosphopeptides (CPPs) to bind and transport minerals has been previously studied. However, the single bioactive peptides responsible for the effects of CPPs have not been identified. This study was to purify calcium-binding peptides from CPPs and to determine their effects on calcium and magnesium uptake by Caco-2 cell monolayers. Five monomer peptides designated P1 to P5 were isolated and the amino acid sequences were determined using LC-MS/MS. Compared with the CPP-free control, all five monomeric peptides exhibited significant enhancing effects on the uptake of calcium and magnesium (P < 0.05). Interestingly, when calcium and magnesium were presented simultaneously with P5, magnesium was taken up with priority over calcium in the Caco-2 cell monolayers. For example, at 180 min, the amount of transferred magnesium and calcium was 78.4 ± 0.95 μg/well and 2.56 ± 0.64 μg/well, respectively, showing a more than 30-fold difference in the amount of transport caused by P5. These results provide novel insight into the mineral transport activity of phosphopeptides obtained from casein.

Social Determinants of Chronic Prostatitis/Chronic Pelvic Pain Syndrome Related Lifestyle and Behaviors among Urban Men in China: A Case-Control Study

PubMed Central

Chen, Chen; Chen, Liang; Han, Qingrong; Ye, Huarong

2016-01-01

Purpose. In order to find key risk factors of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among urban men in China, an age-matched case-control study was performed from September 2012 to May 2013 in Yichang, Hubei Province, China. Methodology. A total of 279 patients and 558 controls were recruited in this study. Data were collected by a self-administered questionnaire, including demographics, diet and lifestyle, psychological status, and a physical exam. Conditional logistic regression model was used to analyze collected data. Results. Chemical factors exposure, night shift, severity of mood, and poor self-health cognition were entered into the regression model, and result displayed that these four factors had odds ratios of 1.929 (95% CI, 1.321–2.819), 1.456 (95% CI, 1.087–1.949), 1.619 (95% CI, 1.280–2.046), and 1.304 (95% CI, 1.094–1.555), respectively, which suggested that these four factors could significantly affect CP/CPPS. Conclusion. These results suggest that many factors affect CP/CPPS, including biological, social, and psychological factors. PMID:27579305

Purification, Characterization, and Antioxidant Activity of Polysaccharides Isolated from Cortex Periplocae.

PubMed

Wang, Xiaoli; Zhang, Yifei; Liu, Zhikai; Zhao, Mingqin; Liu, Pengfei

2017-10-31

In this study, crude Cortex Periplocae polysaccharides (CCPPs) were extracted with water. CCPPs were decolored with AB-8 resin and deproteinated using papain-Sevage methods. Then, they were further purified and separated through DEAE-52 anion exchange chromatography and Sephadex G-100 gel filtration chromatography, respectively. Three main fractions-CPP1, CPP2, and CPP3, (CPPs)-were obtained. The average molecular weights, monosaccharide analysis, surface morphology, and chemical compositions of the CPPs were investigated by high-performance gel permeation chromatography (HPGPC), gas chromatography-mass spectrometry (GC/MS), UV-vis spectroscopy, Fourier transform infrared (FT-IR) spectrum, and nuclear magnetic resonance (NMR). In addition, the antioxidant activities of these three polysaccharides were investigated. The results indicated that all of the CPPs were composed of rhamnose, arabinose, mannose, glucose, and galactose. These three polysaccharides exhibited antioxidant activities in four assays including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 2,2'-azino-bis(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) radical, reducing power, and total antioxidant activity in vitro. The data indicated that these three polysaccharides could be utilized as potential natural sources of alternative additives in the functional food, cosmetics, and pharmaceutical industries.

The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures.

PubMed

Meloni, Bruno P; Craig, Amanda J; Milech, Nadia; Hopkins, Richard M; Watt, Paul M; Knuckey, Neville W

2014-03-01

Cell-penetrating peptides (CPPs) are small peptides (typically 5-25 amino acids), which are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids, or drugs into cells. However, several recent studies have demonstrated that the TAT CPP has neuroprotective properties. Therefore, in this study, we assessed the TAT and three other CPPs (penetratin, Arg-9, Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose deprivation). Arg-9, penetratin, and TAT-D displayed consistent and high level neuroprotective activity in both the glutamic acid (IC50: 0.78, 3.4, 13.9 μM) and kainic acid (IC50: 0.81, 2.0, 6.2 μM) injury models, while Pep-1 was ineffective. The TAT-D isoform displayed similar efficacy to the TAT-L isoform in the glutamic acid model. Interestingly, Arg-9 was the only CPP that displayed efficacy when washed-out prior to glutamic acid exposure. Neuroprotection following in vitro ischemia was more variable with all peptides providing some level of neuroprotection (IC50; Arg-9: 6.0 μM, TAT-D: 7.1 μM, penetratin/Pep-1: >10 μM). The positive control peptides JNKI-1D-TAT (JNK inhibitory peptide) and/or PYC36L-TAT (AP-1 inhibitory peptide) were neuroprotective in all models. Finally, in a post-glutamic acid treatment experiment, Arg-9 was highly effective when added immediately after, and mildly effective when added 15 min post-insult, while the JNKI-1D-TAT control peptide was ineffective when added post-insult. These findings demonstrate that different CPPs have the ability to inhibit neurodamaging events/pathways associated with excitotoxic and ischemic injuries. More importantly, they highlight the need to interpret neuroprotection studies when using CPPs as delivery agents with caution. On a positive note, the cytoprotective properties of CPPs suggests they are ideal carrier molecules to deliver neuroprotective drugs to the CNS following injury and/or potential neuroprotectants in their own right.

Efficacy of Extracorporeal Shock Wave Therapy for the Treatment of Chronic Pelvic Pain Syndrome: A Randomized, Controlled Trial

PubMed Central

Vahdatpour, Babak; Moayednia, Amir; Emadi, Masoud; Khorami, Mohammad Hatef; Haghdani, Saeid

2013-01-01

Objectives. To investigate the effectiveness of extracorporeal shock wave therapy (ESWT) for symptoms alleviation in chronic pelvic pain syndrome (CPPS). Materials and Methods. 40 patients with CPPS were randomly allocated into either the treatment or sham group. In the first group, patients were treated by ESWT once a week for 4 weeks by a defined protocol. In the sham group, the same protocol was applied but with the probe being turned off. The follow-up assessments were done at 1, 2, 3, and 12 weeks by Visual Analogue Scale (VAS) for pain and NIH-developed Chronic Prostatitis Symptom Index (NIH-CPSI). Results. Pain domain scores at follow-up points in both treatment and sham groups were reduced, more so in the treatment group, which were significant at weeks 2, 3, and 12. Urinary scores became significantly different at weeks 3 and 12. Also, quality of life (QOL) and total NIH-CPSI scores at all four follow-up time points reduced more significantly in the treatment group as compared to the sham group. Noticeably, at week 12 a slight deterioration in all variables was observed compared to the first 3 weeks of the treatment period. Conclusions. our findings confirmed ESWT therapy as a safe and effective method in CPPS in short term. PMID:24000311

Efficacy of extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome: a randomized, controlled trial.

PubMed

Vahdatpour, Babak; Alizadeh, Farshid; Moayednia, Amir; Emadi, Masoud; Khorami, Mohammad Hatef; Haghdani, Saeid

2013-01-01

Objectives. To investigate the effectiveness of extracorporeal shock wave therapy (ESWT) for symptoms alleviation in chronic pelvic pain syndrome (CPPS). Materials and Methods. 40 patients with CPPS were randomly allocated into either the treatment or sham group. In the first group, patients were treated by ESWT once a week for 4 weeks by a defined protocol. In the sham group, the same protocol was applied but with the probe being turned off. The follow-up assessments were done at 1, 2, 3, and 12 weeks by Visual Analogue Scale (VAS) for pain and NIH-developed Chronic Prostatitis Symptom Index (NIH-CPSI). Results. Pain domain scores at follow-up points in both treatment and sham groups were reduced, more so in the treatment group, which were significant at weeks 2, 3, and 12. Urinary scores became significantly different at weeks 3 and 12. Also, quality of life (QOL) and total NIH-CPSI scores at all four follow-up time points reduced more significantly in the treatment group as compared to the sham group. Noticeably, at week 12 a slight deterioration in all variables was observed compared to the first 3 weeks of the treatment period. Conclusions. our findings confirmed ESWT therapy as a safe and effective method in CPPS in short term.

Immune mediators of chronic pelvic pain syndrome

PubMed Central

Murphy, Stephen F.; Schaeffer, Anthony J.; Thumbikat, Praveen

2016-01-01

The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease. PMID:24686526

Contemporary treatment options for chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Ismail, M; Mackenzie, K; Hashim, H

2013-07-01

The prostate gland, about the size a walnut, forms part of the male reproductive system and sits directly underneath the bladder surrounding the urethra. It is a fibromuscular exocrine gland that secretes a complex proteolytic fluid which constitutes one-third of the volume of the seminal fluid. Prostatitis refers to a group of disorders that affect the prostate and cause genitourinary pain, dysuria, urinary frequency and sexual dysfunction. The prevalence of prostatitis in the United States has been estimated to be around 9%, while the worldwide prevalence ranges from 2 to 10%, and 15% of men experience prostatitis-like symptoms at some point in their lives. There are a number of treatments which have been used for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), with only a small amount of high-level evidence. The current recommended treatment for CP/CPPS is predominantly a multimodal approach using a combination of antibiotics, α-blockers, antimuscarinic and anti-inflammatory drugs. The response to treatment and improvement in symptoms is very variable; therefore, as the evidence evolves, it is likely that treatment will become symptom specific rather than a generic, 'one strategy fits all' treatment for CP/CPPS. Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Synthesis, characterization and applications of carboxylated and polyethylene-glycolated bifunctionalized InP/ZnS quantum dots in cellular internalization mediated by cell-penetrating peptides.

PubMed

Liu, Betty R; Winiarz, Jeffrey G; Moon, Jong-Sik; Lo, Shih-Yen; Huang, Yue-Wern; Aronstam, Robert S; Lee, Han-Jung

2013-11-01

Semiconductor nanoparticles, also known as quantum dots (QDs), are widely used in biomedical imaging studies and pharmaceutical research. Cell-penetrating peptides (CPPs) are a group of small peptides that are able to traverse cell membrane and deliver a variety of cargoes into living cells. CPPs deliver QDs into cells with minimal nonspecific absorption and toxic effect. In this study, water-soluble, monodisperse, carboxyl-functionalized indium phosphide (InP)/zinc sulfide (ZnS) QDs coated with polyethylene glycol lipids (designated QInP) were synthesized for the first time. The physicochemical properties (optical absorption, fluorescence and charging state) and cellular internalization of QInP and CPP/QInP complexes were characterized. CPPs noncovalently interact with QInP in vitro to form stable CPP/QInP complexes, which can then efficiently deliver QInP into human A549 cells. The introduction of 500nM of CPP/QInP complexes and QInP at concentrations of less than 1μM did not reduce cell viability. These results indicate that carboxylated and polyethylene-glycolylated (PEGylated) bifunctionalized QInP are biocompatible nanoparticles with potential for use in biomedical imaging studies and drug delivery applications. Copyright © 2013 Elsevier B.V. All rights reserved.

Traps of carnivorous pitcher plants as a habitat: composition of the fluid, biodiversity and mutualistic activities

PubMed Central

Adlassnig, Wolfram; Peroutka, Marianne; Lendl, Thomas

2011-01-01

Background Carnivorous pitcher plants (CPPs) use cone-shaped leaves to trap animals for nutrient supply but are not able to kill all intruders of their traps. Numerous species, ranging from bacteria to vertrebrates, survive and propagate in the otherwise deadly traps. This paper reviews the literature on phytotelmata of CPPs. Pitcher Fluid as a Habitat The volumes of pitchers range from 0·2 mL to 1·5 L. In Nepenthes and Cephalotus, the fluid is secreted by the trap; the other genera collect rain water. The fluid is usually acidic, rich in O2 and contains digestive enzymes. In some taxa, toxins or detergents are found, or the fluid is extremely viscous. In Heliamphora or Sarracenia, the fluid differs little from pure water. Inquiline Diversity Pitcher inquilines comprise bacteria, protozoa, algae, fungi, rotifers, crustaceans, arachnids, insects and amphibia. The dominant groups are protists and Dipteran larvae. The various species of CPPs host different sets of inquilines. Sarracenia purpurea hosts up to 165 species of inquilines, followed by Nepenthes ampullaria with 59 species, compared with only three species from Brocchinia reducta. Reasons for these differences include size, the life span of the pitcher as well as its fluid. Mutualistic Activities Inquilines closely interact with their host. Some live as parasites, but the vast majority are mutualists. Beneficial activities include secretion of enzymes, feeding on the plant's prey and successive excretion of inorganic nutrients, mechanical break up of the prey, removal of excessive prey and assimilation of atmospheric N2. Conclusions There is strong evidence that CPPs influence their phytotelm. Two strategies can be distinguished: (1) Nepenthes and Cephalotus produce acidic, toxic or digestive fluids and host a limited diversity of inquilines. (2) Genera without efficient enzymes such as Sarracenia or Heliamphora host diverse organisms and depend to a large extent on their symbionts for prey utilization. PMID:21159782

Traps of carnivorous pitcher plants as a habitat: composition of the fluid, biodiversity and mutualistic activities.

PubMed

Adlassnig, Wolfram; Peroutka, Marianne; Lendl, Thomas

2011-02-01

Carnivorous pitcher plants (CPPs) use cone-shaped leaves to trap animals for nutrient supply but are not able to kill all intruders of their traps. Numerous species, ranging from bacteria to vertrebrates, survive and propagate in the otherwise deadly traps. This paper reviews the literature on phytotelmata of CPPs. Fluid as a Habitat The volumes of pitchers range from 0·2 mL to 1·5 L. In Nepenthes and Cephalotus, the fluid is secreted by the trap; the other genera collect rain water. The fluid is usually acidic, rich in O(2) and contains digestive enzymes. In some taxa, toxins or detergents are found, or the fluid is extremely viscous. In Heliamphora or Sarracenia, the fluid differs little from pure water. Diversity Pitcher inquilines comprise bacteria, protozoa, algae, fungi, rotifers, crustaceans, arachnids, insects and amphibia. The dominant groups are protists and Dipteran larvae. The various species of CPPs host different sets of inquilines. Sarracenia purpurea hosts up to 165 species of inquilines, followed by Nepenthes ampullaria with 59 species, compared with only three species from Brocchinia reducta. Reasons for these differences include size, the life span of the pitcher as well as its fluid. MUTUALISTIC: Activities Inquilines closely interact with their host. Some live as parasites, but the vast majority are mutualists. Beneficial activities include secretion of enzymes, feeding on the plant's prey and successive excretion of inorganic nutrients, mechanical break up of the prey, removal of excessive prey and assimilation of atmospheric N(2). There is strong evidence that CPPs influence their phytotelm. Two strategies can be distinguished: (1) Nepenthes and Cephalotus produce acidic, toxic or digestive fluids and host a limited diversity of inquilines. (2) Genera without efficient enzymes such as Sarracenia or Heliamphora host diverse organisms and depend to a large extent on their symbionts for prey utilization.

Common Questions About Chronic Prostatitis.

PubMed

Holt, James D; Garrett, W Allan; McCurry, Tyler K; Teichman, Joel M H

2016-02-15

Chronic prostatitis is relatively common, with a lifetime prevalence of 1.8% to 8.2%. Risk factors include conditions that facilitate introduction of bacteria into the urethra and prostate (which also predispose the patient to urinary tract infections) and conditions that can lead to chronic neuropathic pain. Chronic prostatitis must be differentiated from other causes of chronic pelvic pain, such as interstitial cystitis/bladder pain syndrome and pelvic floor dysfunction; prostate and bladder cancers; benign prostatic hyperplasia; urolithiasis; and other causes of dysuria, urinary frequency, and nocturia. The National Institutes of Health divides prostatitis into four syndromes: acute bacterial prostatitis, chronic bacterial prostatitis (CBP), chronic nonbacterial prostatitis (CNP)/chronic pelvic pain syndrome (CPPS), and asymptomatic inflammatory prostatitis. CBP and CNP/CPPS both lead to pelvic pain and lower urinary tract symptoms. CBP presents as recurrent urinary tract infections with the same organism identified on repeated cultures; it responds to a prolonged course of an antibiotic that adequately penetrates the prostate, if the urine culture suggests sensitivity. If four to six weeks of antibiotic therapy is effective but symptoms recur, another course may be prescribed, perhaps in combination with alpha blockers or nonopioid analgesics. CNP/CPPS, accounting for more than 90% of chronic prostatitis cases, presents as prostatic pain lasting at least three months without consistent culture results. Weak evidence supports the use of alpha blockers, pain medications, and a four- to six-week course of antibiotics for the treatment of CNP/CPPS. Patients may also be referred to a psychologist experienced in managing chronic pain. Experts on this condition recommend a combination of treatments tailored to the patient's phenotypic presentation. Urology referral should be considered when appropriate treatment is ineffective. Additional treatments include pelvic floor physical therapy, phytotherapy, and pain management techniques. The UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, tenderness) approach summarizes the various factors that may contribute to presentation and can guide treatment.

Systematic Review of Acupuncture for Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Qin, Zongshi; Wu, Jiani; Zhou, Jing; Liu, Zhishun

2016-01-01

Abstract Acupuncture is a promising therapy for relieving symptoms in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which affects >15% of adult men worldwide. The aim of the study was to assess the effects and safety of the use of acupuncture for CP/CPPS. MEDLINE, EMBASE, CENTRAL, Web of Science, CBM, CNKI, Wang-Fang Database, JCRM, and CiNii were searched from their inception through 30 November 2015. Grey literature databases and websites were also searched. No language limits were applied. Only randomized controlled trials (RCTs) with CP/CPPS treated by acupuncture were included. Two reviewers extracted data and assessed the risk of bias of RCTs using the Cochrane Risk of Bias Tools, respectively. Seven trials were included, involving 471 participants. The result of meta-analysis indicated that compared with sham acupuncture (MD: −6.09 [95%CI: −8.12 to −5.68]) and medicine (Levofloxacinand, Ibuprofen, and Tamsulosin) (MD: −4.57 [95%CI: −7.58 to −1.56]), acupuncture was more effective at decreasing the total NIH-CPSI score. Real acupuncture was superior to sham acupuncture in improving symptoms (pain, voiding) and quality of life (Qof) domain subscores. Compared to sham acupuncture and medicine, acupuncture appears to be more effective at improving the global assessment. Two trials found that there is no significant difference between acupuncture and sham acupuncture in decreasing the IPSS score. Acupuncture failed to show more favorable effects in improving both symptoms and the Qof domain compared with medicine. Overall, current evidence supports acupuncture as an effective treatment for CP/CPPS-induced symptoms, particularly in relieving pain. Based on the meta-analysis, acupuncture is superior to sham acupuncture in improving symptoms and Qof. Acupuncture might be similar to medicine (Levofloxacinand, Ibuprofen, and Tamsulosin) in its long-term effects, but evidence was limited due to high ROB among included trials as well as potential heterogeneity. Acupuncture is associated with rare and slightly adverse events. Protocol registration PROSPERO CRD42015027522. PMID:26986148

Quantitative fluorescence spectroscopy and flow cytometry analyses of cell-penetrating peptides internalization pathways: optimization, pitfalls, comparison with mass spectrometry quantification

NASA Astrophysics Data System (ADS)

Illien, Françoise; Rodriguez, Nicolas; Amoura, Mehdi; Joliot, Alain; Pallerla, Manjula; Cribier, Sophie; Burlina, Fabienne; Sagan, Sandrine

2016-11-01

The mechanism of cell-penetrating peptides entry into cells is unclear, preventing the development of more efficient vectors for biotechnological or therapeutic purposes. Here, we developed a protocol relying on fluorometry to distinguish endocytosis from direct membrane translocation, using Penetratin, TAT and R9. The quantities of internalized CPPs measured by fluorometry in cell lysates converge with those obtained by our previously reported mass spectrometry quantification method. By contrast, flow cytometry quantification faces several limitations due to fluorescence quenching processes that depend on the cell line and occur at peptide/cell ratio >6.108 for CF-Penetratin. The analysis of cellular internalization of a doubly labeled fluorescent and biotinylated Penetratin analogue by the two independent techniques, fluorometry and mass spectrometry, gave consistent results at the quantitative and qualitative levels. Both techniques revealed the use of two alternative translocation and endocytosis pathways, whose relative efficacy depends on cell-surface sugars and peptide concentration. We confirmed that Penetratin translocates at low concentration and uses endocytosis at high μM concentrations. We further demonstrate that the hydrophobic/hydrophilic nature of the N-terminal extremity impacts on the internalization efficiency of CPPs. We expect these results and the associated protocols to help unraveling the translocation pathway to the cytosol of cells.

A design space exploration for control of Critical Quality Attributes of mAb.

PubMed

Bhatia, Hemlata; Read, Erik; Agarabi, Cyrus; Brorson, Kurt; Lute, Scott; Yoon, Seongkyu

2016-10-15

A unique "design space (DSp) exploration strategy," defined as a function of four key scenarios, was successfully integrated and validated to enhance the DSp building exercise, by increasing the accuracy of analyses and interpretation of processed data. The four key scenarios, defining the strategy, were based on cumulative analyses of individual models developed for the Critical Quality Attributes (23 Glycan Profiles) considered for the study. The analyses of the CQA estimates and model performances were interpreted as (1) Inside Specification/Significant Model (2) Inside Specification/Non-significant Model (3) Outside Specification/Significant Model (4) Outside Specification/Non-significant Model. Each scenario was defined and illustrated through individual models of CQA aligning the description. The R(2), Q(2), Model Validity and Model Reproducibility estimates of G2, G2FaGbGN, G0 and G2FaG2, respectively, signified the four scenarios stated above. Through further optimizations, including the estimation of Edge of Failure and Set Point Analysis, wider and accurate DSps were created for each scenario, establishing critical functional relationship between Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs). A DSp provides the optimal region for systematic evaluation, mechanistic understanding and refining of a QbD approach. DSp exploration strategy will aid the critical process of consistently and reproducibly achieving predefined quality of a product throughout its lifecycle. Copyright © 2016 Elsevier B.V. All rights reserved.

Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach.

PubMed

Rose, Fabrice; Wern, Jeanette Erbo; Ingvarsson, Pall Thor; van de Weert, Marco; Andersen, Peter; Follmann, Frank; Foged, Camilla

2015-07-28

The purpose of this study was to design a novel and versatile adjuvant intended for mucosal vaccination based on biodegradable poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with the cationic surfactant dimethyldioctadecylammonium (DDA) bromide and the immunopotentiator trehalose-6,6'-dibehenate (TDB) (CAF01) to tailor humoral and cellular immunity characterized by antibodies and Th1/Th17 responses. Such responses are important for the protection against diseases caused by intracellular bacteria such as Chlamydia trachomatis and Mycobacterium tuberculosis. The hybrid NPs were engineered using an oil-in-water single emulsion method and a quality-by-design approach was adopted to define the optimal operating space (OOS). Four critical process parameters (CPPs) were identified, including the acetone concentration in the water phase, the stabilizer [polyvinylalcohol (PVA)] concentration, the lipid-to-total solid ratio, and the total concentration. The CPPs were linked to critical quality attributes consisting of the particle size, polydispersity index (PDI), zeta-potential, thermotropic phase behavior, yield and stability. A central composite face-centered design was performed followed by multiple linear regression analysis. The size, PDI, enthalpy of the phase transition and yield were successfully modeled, whereas the models for the zeta-potential and the stability were poor. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane structures. The optimal formulation, identified from the OOS, was evaluated in vivo. The hybrid NPs induced antibody and Th1/Th17 immune responses that were similar in quality and magnitude to the response induced by DDA/TDB liposomes, showing that the adjuvant properties of DDA/TDB are maintained in the PLGA hybrid matrix. This study demonstrates the complexity of formulation design for the engineering of a hybrid lipid-polymer nanoparticle adjuvant. Copyright © 2015 Elsevier B.V. All rights reserved.

Recent in vivo advances in cell-penetrating peptide-assisted drug delivery.

PubMed

Kurrikoff, Kaido; Gestin, Maxime; Langel, Ülo

2016-01-01

Delivery of macromolecular drugs is an important field in medical research. However, macromolecules are usually unable to cross the cell membrane without the assistance of a delivery system. Cell penetrating peptides (CPPs) are unique tools to gain access to the cell interior and deliver a bioactive cargo into the cytosol or nucleus. In addition to macromolecular delivery, CPPs have been used to deliver smaller bioactive molecules. Therefore CPPs have become an intensive field of research for medical treatment. In this review, we highlight studies that include CPP in vivo disease models. We review different strategies and approaches that have been used, with specific attention on recent publications. The approaches that have been used include CPP-cargo covalent conjugation strategies and nanoparticle strategies. Various additional strategies have been used to achieve disease targeting, including active targeting, passive targeting, and combined active/passive strategies. As a result, delivery of various types of molecule has been achieved, including small drug molecules, proteins and nucleic acid-based macromolecules (e.g. siRNA, antisense nucleotides and plasmid DNA). Despite recent advances in the field, confusions surrounding CPP internalization mechanisms and intracellular trafficking are hindering the development of new and more efficient vectors. Nevertheless, the recent increase in the number of publications containing in vivo CPP utilization looks promising that the number of clinical trials would also increase in the near future.

Histopathological classification criteria of rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, Xianjin; Zhong, Shan; Xu, Tianyuan; Xia, Leilei; Zhang, Xiaohua; Zhu, Zhaowei; Zhang, Minguang; Shen, Zhoujun

2015-02-01

A variety of murine models of experimental prostatitis that mimic the phenotype of human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been developed. However, there is still a lack of explicit diagnosis criteria about those animal model. Our study is to establish histopathological classification criteria, which will be conducive to evaluate the animal models. We firstly established a rat model of experimental autoimmune prostatitis that is considered a valid model for CP/CPPS. For modelling, male Sprague-Dawley rats were immunized with autologous prostate tissue homogenate supernatant emulsified with complete Freund's adjuvant by subcutaneous injection into abdominal flank and simultaneously immunized with pertussis-diphtheria-tetanus vaccine by intraperitoneal injection. Three immunizations were administered semimonthly. At the 45th day, animals were killed, and prostate tissues were examined for morphology. Histologically, the prostate tissues were characterized by lymphoproliferation, atrophy of acini, and chronic inflammatory cells infiltration in the stromal connective tissue around the acini or ducts. Finally, we built histopathological classification criteria incorporating inflammation locations (mesenchyme, glands, periglandular tissues), ranges (focal, multifocal, diffuse), and grades (grade I-IV). To verify the effectiveness and practicability of the histopathological classification criteria, we conducted the treatment study with one of the alpha blockers, tamsulosin. The histopathological classification criteria of rat model of CP/CPPS will serve for further research of the pathogenesis and treatment strategies of the disease.

η6-Cycloparaphenylene transition metal complexes: synthesis, structure, photophysical properties, and application to the selective monofunctionalization of cycloparaphenylenes.

PubMed

Kubota, Natsumi; Segawa, Yasutomo; Itami, Kenichiro

2015-01-28

The synthesis, structure, photophysical properties, and reactivity of cycloparaphenylenes (CPPs) coordinated to group 6 transition metal fragments are described. The η(6)-coordination of [9]CPP or [12]CPP with M(CO)6 (M = Cr, Mo, W) afforded the corresponding [n]CPP-M(CO)3 complexes (n = 9, 12; M = Cr, Mo, W). In the (1)H NMR spectra of these complexes, characteristic upfield-shifted singlet signals corresponding to the four hydrogen atoms attached to the coordinated C6H4 ring of the CPPs were observed at 5.4-5.9 ppm. The complex [9]CPP-Cr(CO)3 could be successfully isolated in spite of its instability. X-ray crystallographic analysis and computational studies of [9]CPP-Cr(CO)3 revealed that chromium-CPP coordination occurs at the convex surface of [9]CPP both in the solid state and in solution. TD-DFT calculations suggested that the emerging high-wavenumber absorption peak upon coordination of [9]CPP to Cr(CO)3 should be assigned to a weak HOMO-LUMO transition. Moreover, by using the complex [9]CPP-Cr(CO)3, a rapid and highly monoselective CPP functionalization has been achieved. The established one-pot method, consisting of complexation, deprotonation, nucleophilic substitution, and decomplexation steps, yielded silyl-, boryl-, and methoxycarbonyl-substituted CPPs in up to 93% yield relative to reacted starting material.

Birth-death models and coalescent point processes: the shape and probability of reconstructed phylogenies.

PubMed

Lambert, Amaury; Stadler, Tanja

2013-12-01

Forward-in-time models of diversification (i.e., speciation and extinction) produce phylogenetic trees that grow "vertically" as time goes by. Pruning the extinct lineages out of such trees leads to natural models for reconstructed trees (i.e., phylogenies of extant species). Alternatively, reconstructed trees can be modelled by coalescent point processes (CPPs), where trees grow "horizontally" by the sequential addition of vertical edges. Each new edge starts at some random speciation time and ends at the present time; speciation times are drawn from the same distribution independently. CPPs lead to extremely fast computation of tree likelihoods and simulation of reconstructed trees. Their topology always follows the uniform distribution on ranked tree shapes (URT). We characterize which forward-in-time models lead to URT reconstructed trees and among these, which lead to CPP reconstructed trees. We show that for any "asymmetric" diversification model in which speciation rates only depend on time and extinction rates only depend on time and on a non-heritable trait (e.g., age), the reconstructed tree is CPP, even if extant species are incompletely sampled. If rates additionally depend on the number of species, the reconstructed tree is (only) URT (but not CPP). We characterize the common distribution of speciation times in the CPP description, and discuss incomplete species sampling as well as three special model cases in detail: (1) the extinction rate does not depend on a trait; (2) rates do not depend on time; (3) mass extinctions may happen additionally at certain points in the past. Copyright © 2013 Elsevier Inc. All rights reserved.

Cargo self-assembly rescues affinity of cell-penetrating peptides to lipid membranes

NASA Astrophysics Data System (ADS)

Weinberger, Andreas; Walter, Vivien; MacEwan, Sarah R.; Schmatko, Tatiana; Muller, Pierre; Schroder, André P.; Chilkoti, Ashutosh; Marques, Carlos M.

2017-03-01

Although cationic cell-penetrating peptides (CPPs) are able to bind to cell membranes, thus promoting cell internalization by active pathways, attachment of cargo molecules to CPPs invariably reduces their cellular uptake. We show here that CPP binding to lipid bilayers, a simple model of the cell membrane, can be recovered by designing cargo molecules that self-assemble into spherical micelles and increase the local interfacial density of CPP on the surface of the cargo. Experiments performed on model giant unilamellar vesicles under a confocal laser scanning microscope show that a family of thermally responsive elastin-like polypeptides that exhibit temperature-triggered micellization can promote temperature triggered attachment of the micelles to membranes, thus rescuing by self-assembly the cargo-induced loss of the CPP affinity to bio-membranes.

Studies of proteoglycan involvement in CPP-mediated delivery.

PubMed

Wittrup, Anders; Zhang, Si-He; Belting, Mattias

2011-01-01

Cell-penetrating peptides (CPPs) are widely used to deliver macromolecular cargoes to intracellular sites of action. Many CPPs have been demonstrated to rely on cell surface heparan sulfate proteoglycans (HSPGs) for efficient cellular entry and delivery. In this chapter, we describe methods for the study of PG involvement in CPP uptake. We provide descriptions of how to determine whether uptake of a CPP of interest is dependent on PGs. We also provide detailed protocols for the purification of PGs by anion-exchange chromatography as well as the characterization of the HSPG core protein composition of a cell line of interest. Finally, we present methods for modulating the expression level of specific HSPG core proteins as a means to determine the core protein specificity in the uptake of a particular CPP.

Relationship between premature ejaculation and chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Lee, Jun Ho; Lee, Sung Won

2015-03-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common etiology of premature ejaculation (PE). However, the current data are insufficient to explain this relationship and to support routine screening of men with PE. This study aims to evaluate the relationship between PE and CP/CPPS. A cross-sectional study was conducted that included 8,261 men who had participated in a health examination. The Premature Ejaculation Diagnostic Tool (PEDT), the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), and the International Index of Erectile Function-5 (IIEF) were used for assessment of symptoms. A full metabolic work-up and serum testosterone level checks were also performed. We then investigated the relationship using the Spearman correlation test, multiple linear regression, and logistic regression analyses. Associations of PEDT with NIH-CPSI. The mean age was 50.4 ± 5.5 years. In total, 2,205 (24.9%) men had prostatitis-like symptoms (NIH-CPSI pain score of ≥4 and perineal or ejaculatory pain), and 618 (7.0%) men had moderate to severe symptoms (NIH-CPSI pain score of ≥8). Additionally, 2,144 men (24.2%) were classified as demonstrating PE (PEDT > 10). The PEDT score was found to have a significant positive correlation with the NIH-CPSI pain domain score (correlation coefficient = 0.206; P < 0.001). After adjusting for age, metabolic syndrome status, testosterone level, and IIEF score, there was no change in the positive correlation between the NIH-CPSI pain domain score and PEDT score (Beta = 0.175; P < 0.001). After adjusting for age, testosterone level, metabolic syndrome, and IIEF score, the odds ratio (OR) for PE significantly increased with the severity of pelvic pain (mild prostatitis-like symptoms, OR for PE: 1.269, 95% confidence interval: 1.113-1.447; moderate to severe symptoms, OR for PE: 2.134: 95% confidence interval: 1.782-2.557). Our data showed a significant correlation between the PEDT score and the NIH-CPSI score. We suggest routine screening for CP/CPPS in men with PE and PE in men with CP/CPPS. © 2014 International Society for Sexual Medicine.

Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease.

PubMed

Dinca, Ana; Chien, Wei-Ming; Chin, Michael T

2016-02-22

Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects.

Cell-Penetrating Peptide as a Means of Directing the Differentiation of Induced-Pluripotent Stem Cells.

PubMed

Kaitsuka, Taku; Tomizawa, Kazuhito

2015-11-06

Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS) cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies.

Nicotine place preference in the mouse: influences of prior handling, dose and strain and attenuation by nicotinic receptor antagonists.

PubMed

Grabus, Sheri D; Martin, Billy R; Brown, Sharon E; Damaj, M Imad

2006-03-01

Although conditioned place preferences (CPPs) are seen with most abused drugs, nicotine does not always produce a preference in this design. The goals of the present experiment were to (1) examine various factors that could contribute to these inconsistent results and (2) begin to evaluate the specific nicotinic receptors involved in the nicotine CPP. The influences of prior handling, environmental habituation, and injection habituation on a nicotine CPP were first evaluated in ICR mice. Subsequently, various nicotine doses were assessed for their abilities to produce a CPP, and the effectiveness of nicotinic receptor antagonists in attenuating this preference was examined. Finally, nicotine CPPs were assessed in C57BL/6J and DBA/2J mice to examine the influence of strain in this design. Nicotine CPPs were seen in handled/environmentally habituated, but not in unhandled, ICR mice. Habituation to the injection techniques failed to strengthen the preference. In ICR mice, a CPP was seen with one intermediate dose of nicotine. This CPP was attenuated by mecamylamine and dihydro-beta-erythroidine (DHbetaE). A nicotine CPP was also seen in C57BL/6J, but not in DBA/2J, mice. Earlier handling experience and strain are important factors when evaluating a nicotine CPP in the mouse. In addition, certain nicotinic receptors underlie the nicotine CPP, indicating that this model can elucidate underlying mediators of nicotine reward.

Metabolic engineering of the Stevia rebaudiana ent-kaurene biosynthetic pathway in recombinant Escherichia coli.

PubMed

Kong, Min Kyung; Kang, Hyun-Jun; Kim, Jin Ho; Oh, Soon Hwan; Lee, Pyung Cheon

2015-11-20

The ent-kaurene is a dedicated precursor pool and is responsible for synthesizing natural sweeteners such as steviol glycosides. In this study, to produce ent-kaurene in Escherichia coli, we modularly constructed and expressed two ent-kaurene genes encoding ent-copalyl diphosphate synthase (CPPS) and ent-kaurene synthase (KS) from Stevia rebaudiana known as a typical plant producing steviol glycoside. The CPPS and KS from S. rebaudiana were functionally expressed in a heterologous host E. coli. Furthermore, in order to enhance ent-kaurene production in E. coli, six geranylgeranyl diphosphate synthases (GGPPS) from various microorganisms and eight strains of E. coli as host were compared by measuring ent-kaurene production. The highest ent-kaurene production of approximately 41.1mg/L was demonstrated in E. coli strain MG1655 co-expressing synthetic CPPS-KS module and GGPPS from Rhodobacter sphaeroides. The ent-kaurene production was further increased up to 179.6 mg/L by overexpression of the three key enzymes for isoprenoid precursor, 1-deoxyxylulose-5-phosphate synthase (DXS), farnesyl diphosphate synthase (IspA) and isopentenyl diphosphate isomerase (IDI) from E. coli. Finally, the highest titer of ent-kaurene (578 mg/L) with a specific yield of ent-kaurene of 143.5mg/g dry cell weight was obtained by culturing E. coli strain MG1655 co-expressing the ent-kaurene module, DXS, IDI and IspA in 1L bioreactor containing 20 g/L glycerol. Copyright © 2015 Elsevier B.V. All rights reserved.

Translocation of cell-penetrating peptides into Candida fungal pathogens.

PubMed

Gong, Zifan; Karlsson, Amy J

2017-09-01

Cell-penetrating peptides (CPPs) are small peptides capable of crossing cellular membranes while carrying molecular cargo. Although they have been widely studied for their ability to translocate nucleic acids, small molecules, and proteins into mammalian cells, studies of their interaction with fungal cells are limited. In this work, we evaluated the translocation of eleven fluorescently labeled peptides into the important human fungal pathogens Candida albicans and C. glabrata and explored the mechanisms of translocation. Seven of these peptides (cecropin B, penetratin, pVEC, MAP, SynB, (KFF) 3 K, and MPG) exhibited substantial translocation (>80% of cells) into both species in a concentration-dependent manner, and an additional peptide (TP-10) exhibiting strong translocation into only C. glabrata. Vacuoles were involved in translocation and intracellular trafficking of the peptides in the fungal cells and, for some peptides, escape from the vacuoles and localization in the cytosol were correlated to toxicity toward the fungal cells. Endocytosis was involved in the translocation of cecropin B, MAP, SynB, MPG, (KFF) 3 K, and TP-10, and cecropin B, penetratin, pVEC, and MAP caused membrane permeabilization during translocation. These results indicate the involvement of multiple translocation mechanisms for some CPPs. Although high levels of translocation were typically associated with toxicity of the peptides toward the fungal cells, SynB was translocated efficiently into Candida cells at concentrations that led to minimal toxicity. Our work highlights the potential of CPPs in delivering antifungal molecules and other bioactive cargo to Candida pathogens. © 2017 The Protein Society.

Predictors of symptom severity in patients with chronic prostatitis and interstitial cystitis.

PubMed

Clemens, J Quentin; Brown, Sheila O; Kozloff, Lara; Calhoun, Elizabeth A

2006-03-01

Numerous studies have been performed to identify potential risk factors for CP/CPPS and IC. However, few studies have been done to identify predictors of disease severity. A total of 174 men with CP/CPPS and 111 women with IC completed questionnaires to quantify symptom severity and identify demographic, medical and psychosocial characteristics. Symptom severity was assessed with the National Institutes of Health CPSI in men, and the O'Leary-Sant ICSI and problem index in women. Univariate and multivariate analyses were performed to identify characteristics predictive of worse symptoms. The mean National Institutes of Health CPSI score in men was 15.32, and the mean O'Leary-Sant ICSI and problem index in women was 19.17. The most commonly reported comorbidities were allergies, sinusitis, erectile dysfunction and irritable bowel syndrome in men, and allergies, urinary incontinence, sinusitis and irritable bowel syndrome in women. In the 2 sexes self-reported urinary frequency and urgency, worse depression scores and lower education level were independent predictors of worse symptom severity. In men additional independent predictors were self-reported pelvic pain, fibromyalgia and previous heart attack, and in women an additional independent predictor was postmenopausal status. There are several common medical conditions associated with urological pelvic pain syndromes in men and women. Few of them were predictive of symptoms severity in this analysis. Self-reported pelvic pain symptoms, education and depression severity were the factors most strongly predictive of symptom severity in patients with CP/CPPS and IC.

Quality by design approach for optimizing the formulation and physical properties of extemporaneously prepared orodispersible films.

PubMed

Visser, J Carolina; Dohmen, Willem M C; Hinrichs, Wouter L J; Breitkreutz, Jörg; Frijlink, Henderik W; Woerdenbag, Herman J

2015-05-15

The quality by design (QbD) approach was applied for optimizing the formulation of extemporaneously prepared orodispersible films (ODFs) using Design-Expert® Software. The starting formulation was based on earlier experiments and contained the film forming agents hypromellose and carbomer 974P and the plasticizer glycerol (Visser et al., 2015). Trometamol and disodium EDTA were added to stabilize the solution. To optimize this formulation a quality target product profile was established in which critical quality attributes (CQAs) such as mechanical properties and disintegration time were defined and quantified. As critical process parameters (CPP) that were evaluated for their effect on the CQAs the percentage of hypromellose and the percentage of glycerol as well as the drying time were chosen. Response surface methodology (RMS) was used to evaluate the effects of the CPPs on the CQAs of the final product. The main factor affecting tensile strength and Young's modulus was the percentage of glycerol. Elongation at break was mainly influenced by the drying temperature. Disintegration time was found to be sensitive to the percentage of hypromellose. From the results a design space could be created. As long as the formulation and process variables remain within this design space, a product is obtained with desired characteristics and that meets all set quality requirements. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis and evaluation of amphiphilic peptides as nanostructures and drug delivery tools

NASA Astrophysics Data System (ADS)

Sayeh, Naser Ali

Intracellular delivery of cell-impermeable compounds in a variety cells using delivery systems have been extensively studied in recent years. Obtaining desirable cellular uptake levels often requires the administration of high quantities of drugs to achieve the expected intracellular biological effect. Thus, improving the translocation process across the plasma membrane will significantly reduce the quantity of required administered drug and consequently minimize the side effects in most of the cases. Efficient delivery of these molecules to the cells and tissues is a difficult challenge. Compounds with low cellular permeability are commonly considered to be of limited therapeutic value. Over the past few decades, several biomedical carriers, such as polymers, nanospheres, nanocapsules, liposomes, micelles, peptides and dendrimers have been widely used to deliver therapeutic and diagnostic agents to the cells. Biomaterials generated from nano-scale compounds have shown some promising data for delivery of many compounds in a number of diseases, such as viral infections, cancer, and genetic disorders. Although much progress has been achieved in this field, many challenges still remain, such as toxicity and limited stability. Liposomes suffer from poor stability in the bloodstream and leakage during storage. They tend to aggregate and fuse with or leak entrapped drugs, especially highly hydrophilic small molecules. For solid lipid nanoparticles (SLNs), drug expulsion after polymorphic transition during storage, inadequate loading capacity, and relatively high water content of the dispersions have been observed. Poly(lactic-coglycolic acid (PLGA) degrades in the body producing its original monomers of lactic acid and glycolic acid, which are the by-products of various metabolic pathways. However, this acidic microenvironment that occurs during degradation could negatively affect the stability of the loaded compound. Dendrimers can carry drugs as complexes or as conjugates although one limitation lies in the effort of controlling the rate of drug release. The encapsulated or complexed drugs tend to be released rapidly (before reaching the target site) and in the dendrimer--drug conjugates, it is the chemical linkage that controls the drug release. Thus, future studies in this field are urgently required to create more efficient and stable biomaterials. Peptides are considered as efficient vectors for achieving optimal cellular uptake. The potential use of peptides as drug delivery vectors received much attention by the discovery of several cell-penetrating peptides (CPPs). The first CPPs discovered in 1988, that were sequences from HIV-1 encoded TAT protein, TAT (48--60), and penetrated very efficiently through cell membranes of cultured mammalian cells. CPPs are a class of diverse peptides, typically with 8--25 amino acids, and unlike most peptides, they can cross the cellular membrane with more efficiency. CPPs have also shown to undergo self-assembly and generate nanostructures. The generation of self-assembled peptides and nanostructures occur through various types of interactions between functional groups of amino acid residues, such as electrostatic, hydrophobic, and hydrogen bonding. Appropriate design and functionalization of peptides are critical for generating nanostructures. Chemically CPPs are classified into two major groups: linear and cyclic peptides. It has been previously reported that linear peptides containing hydrophilic and hydrophobic amino acids could act as membrane protein stabilizers. These compounds are short hydrophilic or amphiphilic peptides that have positively charged amino acids, such as arginine, lysine or histidine, which can interact with the negative charge phospholipids layer on the cell membrane and translocate the cargo into the cells. Conjugation to cationic linear CPPs, such as TAT, penetratin, or oligoarginine efficiently improves the cellular uptake of large hydrophilic molecules, but the cellular uptake is predominantly via an unproductive endosomal pathway. Therefore, the biological effect is very limited, as the compounds are trapped in these compartments and cannot reach their biological targets in the cytoplasm or the nucleus. Mechanisms that promote endosomal escape or avoid endosomal route are required for improving bioavailability. Highly cationic CPPs preferentially interact with particular cell types, have limited plasma half-life, show toxicity, do not cross multicellular barriers such as vasculature epithelia or the blood-brain barrier, and efficient cargo delivery requires 9-15 arginine residues. Highly cationic CPPs are, therefore not ideal small molecule drug delivery vehicles. Linear CPPs are susceptible to hydrolysis by endogenous peptidases. Conjugation to cationic CPPs, such as TAT, penetratin, or oligoarginine efficiently improves the cellular uptake of large hydrophilic molecules, but the cellular uptake occurs predominantly via an unproductive endosomal pathway. Therefore, the biological effect is very limited, as the compounds are trapped in these compartments and cannot reach their biological targets in the cytoplasm or the nucleus. Mechanisms that promote endosomal escape or avoid endosomal route are required for improving bioavailability. Highly cationic CPPs preferentially interact with particular cell types, have limited plasma half-life, show toxicity, do not cross multicellular barriers such as vasculature epithelia or the blood-brain barrier, and efficient cargo delivery requires 9-15 arginine residues. Highly cationic linear CPPs are, therefore, have not become optimized as small molecule drug delivery vehicles. On the other hand, cyclic peptides containing hydrophilic and hydrophobic amino acids have shown greater potential as drug delivery tools due to their enhanced chemical and enzymatic stability. Parang's laboratory has reported that Amphiphilic Cyclic Peptides (ACPs) containing positively charged arginine and hydrophobic tryptophan residues as potential candidates for drug delivery. Cyclic peptides have several benefits compared to linear peptides, such as rigidness of structure and stability against proteolytic enzymes. The rigidity of the structure can enhance the binding affinity of ligands toward receptors by reducing the freedom of possible structural conformations. Cyclic peptides are also present in nature and have been developed as therapeutics. Cyclosporine, gramicidin S, polymoxin B, and daptomycin are well-known examples of cyclic peptide drugs. Parang's laboratory designed amphiphilic cyclic CPPs containing alternative tryptophan and arginine residues as the positively charged and hydrophobic residues, respectively. The peptides were efficient in improving the cellular delivery of anticancer and antiviral drugs. The cellular uptake mechanism of CPPs into cells is still a matter of some debate. The cellular entry of CPP can be influenced by the type of CPP, the cell line, the nature of the cargo, and the conditions of incubation. As described above, linear CPPs pass through the plasma membrane mostly via an energy-independent or endocytosis pathway. Moreover, the cellular delivery of CPP-conjugated molecules also occurs through endosomal pathway and a strong enzymatic degradation and an inadequate cytoplasmic release of intact molecules from the conjugates are expected, thus leading to an inefficient transfer into the cytoplasm. The best strategy to overcome this issue is to designing CPP that by pass the endosomal uptake or by increasing the escape rate from the endosome to improve the intracellular delivery of CPP-attached molecules. Parang laboratory has reported the cellular uptake of a number of cyclic peptides independent of endocytotic pathway. The extraordinary ability of cyclic peptides containing tryptophan and arginine, [WR]4 and [WR] 5 to spontaneously translocate across bilayers independent of an energy source is distinctly different from the behavior of the well-known, highly cationic CPPs, such as TAT and Arg9, which do not translocate across phospholipid bilayers, and enter cells mostly by active endocytosis. Alternatively, researchers have found that an effective cellular delivery vector can be improved developed by conjugating a CPP with a fatty acid chain. Amphiphilic peptides have also become a subject of major interest as potent antibacterial agents. Antimicrobial peptides (AMPs) are produced naturally by bacteria and are considered as the first line of host defense protecting living organisms from microorganisms. Various types of AMPs has been discovered, such as defensins, cecropins, magainins and cathelicidins, with significant different structures and bioactivity profiles. The mechanism of actions for these peptides were reported as effectors and regulators of the innate immune system by increasing production and release of chemokine, and enhancing wound healing and angiogenesis. They were able to suppress biofilm formation and induce the dissolution of existing biofilms. Thus, design of new AMPs and more cost effective sequences with highly activity are urgently needed. Although a number of cyclic peptides were discovered and reported as efficient cellular delivery agents or antimicrobial agent, a more systematic investigation is required to identify design rules for optimal entrapment, drug loading, and stability. The balance of many small forces determines the overall morphology, size, and functionality of the structures. A deeper understanding of these factors is required for guiding future research, and for customizing cyclic peptides for drug loading and cellular delivery applications. Thus, additional amphiphilic cyclic and linear peptides were designed with variable electrostatic and hydrophobic residues to optimize drug encapsulation. The diversity in ring size, amino acid number, position and sequences, number of rings, net charge, and hydrophobicity of side chains in cyclic peptides will allow us to explore requirements for generating peptides with optimized drug encapsulation and to establish correlations between the structure of peptides with their drug entrapment properties. Thus, the general objective of this dissertation was to design and evaluate additional cyclic or amphiphilic peptides as nanostructures, compare their efficiency in delivery of small molecules with the previously reported cyclic peptides containing tryptophan and arginine residues. This dissertation consists of three chapters. Chapter 1. MANUSCRIPT (published in Current Organic Chemistry 2014). The objective of this work was to design amphiphilic linear and cyclic peptides containing hydrophobic tryptophan W residues that were linked through a triazole ring to positively charged arginine R and lysine (K) residues. The peptides were synthesized through click chemistry between hydrophobic peptides containing alkyne and positively charged peptides containing azide groups. Characterization of their structures like solubility, CD, TEM, cytotoxicity were investigated. The conjugates were showed minimal cytotoxicity at two cell lines. The secondary structures of both peptides were similar to a distorted α-helix as shown by CD spectroscopy. TEM imaging also showed that linear-linear (WG(triazole-KR-NH2))3 and cyclic-linear [WG(triazole-KR-NH2)]3 peptides formed nano-sized structures. Chapter 2. MANUSCRIPT I (Submitted to Journal of Molecular Modeling). In this work, we investigated the structural and dynamical aspects of cyclic-linear peptide ([WG(triazole-KR-NH2)] 3 and linear-linear peptide (WG(triazole-KR-NH2))3) formed nanostructures compared to a drug delivery system with [WR]4. While [WR]4 was found to be an efficient molecular transporter for small molecule drugs, such as lamivudine and dasatinib, cyclic-linear peptide ([WG(triazole-KR-NH2)]3 was inefficient. Molecular modeling was used to explain the differential behavior of these peptides. We showed how the morphology of these systems can affect the drug delivery efficiency. The result of this work provided insights about optimizing the amphiphilic cyclic-linear trizaolyl peptides can be used to design compounds with more efficient drug delivery capabilities. Chapter 3. MANUSCRIPT II. The objective of this Chapter was to synthesize a different series of amphiphilic peptides for different objectives. First, the amphiphilic trizaolyl peptides in Chapter I were systematically modified by increasing the number of arginine and tryptophan sequence in cyclic and linear peptides. The rationale for the modification was to enhance the possibility of interaction with the cell membrane and therefore improving the cellular uptake process. Moreover, a new class of amphiphilic peptides consist of tryptophan and glutamic acid were conjugated with a peptide containing arginine and lysine residues using Fmoc chemistry. These peptides have an amide bond that generates more flexibility compared to a triazole ring. The chemical and biological properties will be evaluated in future and compared with amphiphilic triazolyl peptides. Finally, additional fatty acids with different length chains were conjugated with positively charged peptides to be evaluated as antibacterial agents. Stearic acid (C16) and myristic acid (C14) were conjugated with a peptides consisting of arginine azide and lysine amino acids to enhance the antibacterial activity. In summary, the work in this dissertation provided insights about the synthesis and characterization of a new class of amphiphilic triazolyl peptides as drug delivery carriers and amphiphilic peptides as antibacterial agents. Molecular modeling was used to explain why triazolyl peptides were unable to enhance the delivery of small molecule drugs compared to the previously synthesized cyclic peptides [WR]4 (Chapter 2) Modification of synthesized peptides in Chapter 1, by addition of more positively charged amino acids or reducing the rigidity by incorporating amide bonds instead of triazoly groups can be used to improve the cell penetrating properties. Finally, we conjugated amphiphilic peptides with different fatty acids (Chapter 3) to investigate their application as antibacterial agents.

Range-expanding pests and pathogens in a warming world.

PubMed

Bebber, Daniel Patrick

2015-01-01

Crop pests and pathogens (CPPs) present a growing threat to food security and ecosystem management. The interactions between plants and their natural enemies are influenced by environmental conditions and thus global warming and climate change could affect CPP ranges and impact. Observations of changing CPP distributions over the twentieth century suggest that growing agricultural production and trade have been most important in disseminating CPPs, but there is some evidence for a latitudinal bias in range shifts that indicates a global warming signal. Species distribution models using climatic variables as drivers suggest that ranges will shift latitudinally in the future. The rapid spread of the Colorado potato beetle across Eurasia illustrates the importance of evolutionary adaptation, host distribution, and migration patterns in affecting the predictions of climate-based species distribution models. Understanding species range shifts in the framework of ecological niche theory may help to direct future research needs.

Synthesis of cell-penetrating peptides and their application in neurobiology.

PubMed

Dietz, Gunnar P H; Bähr, Mathias

2007-01-01

Short basic amino acid sequences, often called cell-penetrating peptides (CPPs), allow the delivery of proteins and other molecules into cells and across the blood-brain barrier (BBB). Although the ability of basic proteins to facilitate such trafficking is known for a long time, only the application of genetic methods and overexpression of fusion proteins in Escherichia coli has lead to a wide application of CPP in many research areas, including signal transduction, cancer, angiogenesis, apoptosis, bone development, cardioprotection, cell cycle, neurobiology, and many others. For the neuroscientist, CPPs are particularly attractive, as a number of articles in the last 5 years have reported their use for neuronal rescue in a number of models for neurodegenerative diseases in vitro and in vivo in rats, mice, or gerbils. Here, we give a detailed description of the protein purification methodology and applications in neuroscience.

Design of experiments (DoE) in pharmaceutical development.

PubMed

N Politis, Stavros; Colombo, Paolo; Colombo, Gaia; M Rekkas, Dimitrios

2017-06-01

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming's profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology. The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies. Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP). This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.

GFP-complementation assay to detect functional CPP and protein delivery into living cells

PubMed Central

Milech, Nadia; Longville, Brooke AC; Cunningham, Paula T; Scobie, Marie N; Bogdawa, Heique M; Winslow, Scott; Anastasas, Mark; Connor, Theresa; Ong, Ferrer; Stone, Shane R; Kerfoot, Maria; Heinrich, Tatjana; Kroeger, Karen M; Tan, Yew-Foon; Hoffmann, Katrin; Thomas, Wayne R; Watt, Paul M; Hopkins, Richard M

2015-01-01

Efficient cargo uptake is essential for cell-penetrating peptide (CPP) therapeutics, which deliver widely diverse cargoes by exploiting natural cell processes to penetrate the cell’s membranes. Yet most current CPP activity assays are hampered by limitations in assessing uptake, including confounding effects of conjugated fluorophores or ligands, indirect read-outs requiring secondary processing, and difficulty in discriminating internalization from endosomally trapped cargo. Split-complementation Endosomal Escape (SEE) provides the first direct assay visualizing true cytoplasmic-delivery of proteins at biologically relevant concentrations. The SEE assay has minimal background, is amenable to high-throughput processes, and adaptable to different transient and stable cell lines. This split-GFP-based platform can be useful to study transduction mechanisms, cellular imaging, and characterizing novel CPPs as pharmaceutical delivery agents in the treatment of disease. PMID:26671759

Methanolic Extract of Morinda citrifolia L. (Noni) Unripe Fruit Attenuates Ethanol-Induced Conditioned Place Preferences in Mice

PubMed Central

Khan, Yasmin; Pandy, Vijayapandi

2016-01-01

Phytotherapy is an emerging field successfully utilized to treat various chronic diseases including alcohol dependence. In the present study, we examined the effect of the standardized methanolic extract of Morinda citrifolia Linn. unripe fruit (MMC), on compulsive ethanol-seeking behavior using the mouse conditioned place preference (CPP) test. CPP was established by injections of ethanol (2 g/kg, i.p.) in a 12-day conditioning schedule in mice. The effect of MMC and the reference drug, acamprosate (ACAM), on the reinforcing properties of ethanol in mice was studied by the oral administration of MMC (1, 3, and 5 g/kg) and ACAM (300 mg/kg) 60 min prior to the final CPP test postconditioning. Furthermore, CPPs weakened with repeated testing in the absence of ethanol over the next 12 days (extinction), during which the treatment groups received MMC (1, 3, and 5 g/kg, p.o.) or ACAM (300 mg/kg, p.o.). Finally, a priming injection of a low dose of ethanol (0.4 g/kg, i.p.) in the home cage (Reinstatement) was sufficient to reinstate CPPs, an effect that was challenged by the administration of MMC or ACAM. MMC (3 and 5 g/kg, p.o.) and ACAM (300 mg/kg, p.o.) significantly reversed the establishment of ethanol-induced CPPs and effectively facilitated the extinction of ethanol CPP. In light of these findings, it has been suggested that M. citrifolia unripe fruit could be utilized for novel drug development to combat alcohol dependence. PMID:27729866

Methanolic Extract of Morinda citrifolia L. (Noni) Unripe Fruit Attenuates Ethanol-Induced Conditioned Place Preferences in Mice.

PubMed

Khan, Yasmin; Pandy, Vijayapandi

2016-01-01

Phytotherapy is an emerging field successfully utilized to treat various chronic diseases including alcohol dependence. In the present study, we examined the effect of the standardized methanolic extract of Morinda citrifolia Linn. unripe fruit (MMC), on compulsive ethanol-seeking behavior using the mouse conditioned place preference (CPP) test. CPP was established by injections of ethanol (2 g/kg, i.p.) in a 12-day conditioning schedule in mice. The effect of MMC and the reference drug, acamprosate (ACAM), on the reinforcing properties of ethanol in mice was studied by the oral administration of MMC (1, 3, and 5 g/kg) and ACAM (300 mg/kg) 60 min prior to the final CPP test postconditioning. Furthermore, CPPs weakened with repeated testing in the absence of ethanol over the next 12 days (extinction), during which the treatment groups received MMC (1, 3, and 5 g/kg, p.o.) or ACAM (300 mg/kg, p.o.). Finally, a priming injection of a low dose of ethanol (0.4 g/kg, i.p.) in the home cage (Reinstatement) was sufficient to reinstate CPPs, an effect that was challenged by the administration of MMC or ACAM. MMC (3 and 5 g/kg, p.o.) and ACAM (300 mg/kg, p.o.) significantly reversed the establishment of ethanol-induced CPPs and effectively facilitated the extinction of ethanol CPP. In light of these findings, it has been suggested that M. citrifolia unripe fruit could be utilized for novel drug development to combat alcohol dependence.

COMPARISON OF BASELINE UROLOGIC SYMPTOMS IN MEN AND WOMEN IN THE MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN (MAPP) RESEARCH COHORT

PubMed Central

Clemens, J. Quentin; Clauw, Daniel J.; Kreder, Karl; Krieger, John N.; Kusek, John W.; Lai, H. Henry; Rodriguez, Larissa; Williams, David A.; Hou, Xiaoling; Stephens, Alisa; Landis, J Richard

2015-01-01

INTRODUCTION The clinical features of interstitial cystitis/ bladder pain syndrome (IC/BPS) are similar to those of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, no studies have directly compared the characteristics of these syndromes in men and women. METHODS The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network recruited 191 men and 233 women with IC/BPS or CP/CPPS. Baseline data included demographics, the Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), the Genitourinary Pain Index (GUPI), the American Urological Association Symptom Index (AUASI), Likert scales to assess urinary urgency, frequency, pain and overall symptom severity, and a single question about the most bothersome pelvic symptom. RESULTS After adjustment for age, income and symptom duration, measures of pain severity were similar across genders. Mean scores for the ICSI, ICPI and AUASI were significantly higher in women than men, reflecting more bladder-focused symptoms in women. The most bothersome single symptom in both men and women was pain in the pubic/bladder area (34% of men, 58% of women). The characteristics of the men and women in the MAPP cohort were similar to those reported in other research cohorts of IC/BPS and CP/CPPS. CONCLUSIONS Our findings indicate that pain severity is similar in both sexes, and that bladder-focused symptoms (urgency, suprapubic pain, frequency) are more common in women. However, a substantial proportion of men also report these types of bladder symptoms. PMID:25463989

Chronic prostatitis and comorbid non-urological overlapping pain conditions: A co-twin control study.

PubMed

Gasperi, Marianna; Krieger, John N; Forsberg, Christopher; Goldberg, Jack; Buchwald, Dedra; Afari, Niloofar

2017-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by pain and voiding symptoms in the absence of an obvious infection or other cause. CP/CPPS frequently occurs with non-urological chronic overlapping pain conditions (COPCs) of unknown etiology. We conducted a co-twin control study in men discordant for chronic prostatitis (CP), an overarching diagnosis of which approximately 90% is CP/CPPS. The primary aim was to investigate the contribution of familial factors, including shared genetic and common environmental factors, to the comorbidity of CP and COPCs. Data from 6824 male twins in the Vietnam Era Twin Registry were examined to evaluate the association between self-reported lifetime physician diagnosis of CP with COPCs including fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorder, tension headaches, and migraine headaches. Random effects logistic regression models were used and within-pair analyses evaluated confounding effects of familial factors on the associations. There were significant associations between CP and all 6 examined COPCs. After adjusting for shared familial influences in within twin pair analyses, the associations for all COPCs diminished but remained significant. Familial confounding was strongest for the association of CP with fibromyalgia and temporomandibular disorder and smallest for irritable bowel syndrome. CP and COPCs are highly comorbid. These associations can be partially explained by familial factors. The mechanisms underlying these relationships are likely diverse and multifactorial. Future longitudinal research can help to further elucidate specific genetic and environmental mechanisms and determine potentially causal relationships between CP and its comorbidities. Published by Elsevier Inc.

Calcium absorption is not increased by caseinophosphopeptides.

PubMed

Teucher, Birgit; Majsak-Newman, Gosia; Dainty, Jack R; McDonagh, David; FitzGerald, Richard J; Fairweather-Tait, Susan J

2006-07-01

One of the suggested health benefits of caseinophosphopeptides (CPPs) is their ability to enhance calcium absorption. This possibility is based on the assumption that they resist proteolysis in the upper gastrointestinal tract and maintain calcium in a soluble form at alkaline pH in the distal ileum. The effects of CPP-enriched preparations (containing candidate functional food ingredients) on calcium absorption from a calcium lactate drink were tested. A randomized crossover trial was undertaken in 15 adults in whom we measured the absorption of calcium from a calcium lactate drink (drink A: 400 mg Ca as lactate) and 2 preparations enriched with forms of CPP (1.7 g each; drinks B and C). Both drinks B and C contained 400 mg Ca as calcium lactate plus approximately 100 mg CPP-derived calcium). Each volunteer received the 3 drinks in random order. Absorption was measured by the dual-label calcium stable-isotope technique. The quantity of calcium absorbed was significantly lower from drink A (103 mg) than from drink B (117 mg; P = 0.012) or drink C (121 mg; P = 0.002), which indicated a positive effect of the CPPs. However, because the CPP preparations contributed additional calcium besides that found in the calcium lactate (drink A), fractional absorption of calcium from drink B (23%) was slightly but significantly (P = 0.015) lower than that from drink A (26%). The differences in calcium absorption are unlikely to have any biological significance. CPPs are unsuitable as candidate ingredients for functional foods that are designed to deliver improved calcium nutrition.

A phase II, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of Curcumina and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III.

PubMed

Morgia, Giuseppe; Russo, Giorgio Ivan; Urzì, Daniele; Privitera, Salvatore; Castelli, Tommaso; Favilla, Vincenzo; Cimino, Sebastiano

2017-06-30

The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underling the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Curcumin and Calendula extract in patients with CP/CPPS III. From June 2015 to January 2016 we enrolled 60 consecutive patients affected by CP/CPPS III in our institution. Patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 15 point and diagnosed with NIH category III. Patients were then allocated to receive placebo (Group A) or treatment (Group B). Treatment consisted of rectal suppositories of Curcumin extract 350 mg (95%) and Calendula extract 80 mg (1 suppository/die for 1 month). Patients of Group B received 1 suppository/die for 1 month of placebo. The primary endpoint of the study was the reduction of NIH-CPSI. The secondary outcomes were the change of peak flow, IIEF-5, VAS score and of premature ejaculation diagnostic tool (PEDT). A total of 48 patients concluded the study protocol. The median age of the all cohort was 32.0 years, the median NIH-CPSI was 20.5, the median IIEF-5 was 18.5, the median PEDT was 11.0, the median VAS score was 7.5 and the median peak flow was 14.0. After 3 months of therapy in group A we observed a significant improvement of NIH-CPSI (-5.5; p < 0.01), IIEF-5 (+ 3.5; p < 0.01), PEDT (-6.5; p < 0.01), peak flow (+2.8; p < 0.01) and VAS (-6.5; p < 0.01) with significant differences over placebo group (all p-value significant). In this phase II clinical trial we showed the clinical efficacy of the treatment with Curcumin and Calendula in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. These results should be confirmed in further studies with greater sample size.

Sono-electro-magnetic therapy for treating chronic pelvic pain syndrome in men: a randomized, placebo-controlled, double-blind trial.

PubMed

Kessler, Thomas M; Mordasini, Livio; Weisstanner, Christian; Jüni, Peter; da Costa, Bruno R; Wiest, Roland; Thalmann, George N

2014-01-01

To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. ClinicalTrials.gov NCT00688506.

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium

PubMed Central

Xia, Tian; Hamilton, Raymond F.; Bonner, James C.; Crandall, Edward D.; Elder, Alison; Fazlollahi, Farnoosh; Girtsman, Teri A.; Kim, Kwang; Mitra, Somenath; Ntim, Susana A.; Orr, Galya; Tagmount, Mani; Taylor, Alexia J.; Telesca, Donatello; Tolic, Ana; Vulpe, Christopher D.; Walker, Andrea J.; Wang, Xiang; Witzmann, Frank A.; Wu, Nianqiang; Xie, Yumei; Zink, Jeffery I.; Nel, Andre

2013-01-01

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells. Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β. Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity. PMID:23649538

Pregabalin for the Treatment of Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Pontari, Michel A.; Krieger, John N.; Litwin, Mark S.; White, Paige C.; Anderson, Rodney U.; McNaughton-Collins, Mary; Nickel, J. Curtis; Shoskes, Daniel A.; Alexander, Richard B.; O'Leary, Michael; Zeitlin, Scott; Chuai, Shannon; Landis, J. Richard; Cen, Liyi; Propert, Kathleen J.; Kusek, John W.; Nyberg, Leroy M.; Schaeffer, Anthony J.

2013-01-01

Background Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic. Methods This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006–2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed. Results Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIHCPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo (P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and sub-scores (P < .05), a higher Global Response Assessment response rate (31.2% and 18.9%; P = .02), and improvement in total McGill Pain Questionnaire score (P = .01). Results for the other outcomes did not differ between groups. Conclusion Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS. Trial Registration clinicaltrials.gov Identifier: NCT00371033 PMID:20876412

Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Adaptive Double-blind, Randomized Controlled Trial.

PubMed

Wagenlehner, Florian M E; van Till, J W Olivier; Houbiers, Jos G A; Martina, Reynaldo V; Cerneus, Dirk P; Melis, Joost H J M; Majek, Antoni; Vjaters, Egils; Urban, Michael; Ramonas, Henrikas; Shoskes, Daniel A; Nickel, J Curtis

2017-05-01

To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. In this adaptive, randomized, double-blind, placebo-controlled study, adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150, or 300 mg twice daily, or 300 mg once daily), or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions, and analysis of the efficacy variables. The study was stopped for futility at preplanned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25 mg group showed the largest reduction of the primary end point National Institutes of Health Chronic Prostatitis Symptom Index total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9, 2.6]). Micturition outcomes improved compared with placebo in all ASP3652 groups; for example, in the 300 mg twice daily group, voiding frequency decreased by -1.10 (95% CI: -2.0, -0.2) voids/24 hours vs placebo. Safety outcomes were comparable across the treatment groups. ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, the results indicate that FAAH inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this. Copyright © 2017 Elsevier Inc. All rights reserved.

Network Meta-Analysis of the Efficacy of Acupuncture, Alpha-blockers and Antibiotics on Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Qin, Zongshi; Wu, Jiani; Tian, Jinhui; Zhou, Jing; Liu, Yali; Liu, Zhishun

2016-01-01

Alpha-blockers and antibiotics are most commonly used to treat chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in clinical practice. Currently, increasing evidence also suggests acupuncture as an effective strategy. This network meta-analysis intended to assess the comparative efficacy and safety of acupuncture, alpha-blockers and antibiotics for CP/CPPS. Twelve trials involving 1203 participants were included. Based on decreases in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, a network meta-analysis indicated that electro-acupuncture (standard mean difference [SMD]: 4.29; 95% credible interval [CrI], 1.96–6.65), acupuncture (SMD: 3.69; 95% CrI, 0.27–7.17), alpha-blockers (SMD: 1.85; 95% CrI, 1.07–2.64), antibiotics (SMD: 2.66; 95% CrI, 1.57–3.76), and dual therapy (SMD: 3.20; 95% CrI, 1.95–4.42) are superior to placebo in decreasing this score. Additionally, electro-acupuncture (SMD: 2.44; 95% CrI, 0.08–4.83) and dual therapy (SMD: 1.35; 95% CrI, 0.07–2.62) were more effective than alpha-blockers in decreasing the total NIH-CPSI total score. Other network meta-analyses did not show significant differences between interventions other placebo. The incidence of adverse events of acupuncture was relatively rare (5.4%) compared with placebo (17.1%), alpha-blockers (24.9%), antibiotics (31%) and dual therapy (48.6%). Overall, rank tests and safety analyses indicate that electro-acupuncture/acupuncture may be recommended for the treatment of CP/CPPS. PMID:27759111

A novel murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) induced by immunization with a spermine binding protein (p25) peptide

PubMed Central

Altuntas, Cengiz Z.; Veizi, Elias; Izgi, Kenan; Bicer, Fuat; Ozer, Ahmet; Grimberg, Kerry O.; Bakhautdin, Bakytzhan; Sakalar, Cagri; Tasdemir, Cemal; Tuohy, Vincent K.

2013-01-01

The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poorly understood. Inflammatory and autoimmune mechanisms may play a role. We developed a murine model of experimental autoimmune prostatitis (EAP) that mimics the human phenotype of CP/CPPS. Eight-week-old mice were immunized subcutaneously with prostate-specific peptides in an emulsion of complete Freund's adjuvant. Mice were euthanized 10 days after immunization, and lymph node cells were isolated and assessed for recall proliferation to each peptide. P25 99–118 was the most immunogenic peptide. T-cell and B-cell immunity and serum levels of C-reactive protein and nitrate/nitrite levels were evaluated over a 9-wk period. Morphometric studies of prostate, 24-h micturition frequencies, and urine volume per void were evaluated. Tactile referred hyperalgesia was measured using von Frey filaments to the pelvic region. The unpaired Student's t-test was used to analyze differences between EAP and control groups. Prostates from p25 99–118-immunized mice demonstrated elevated gene expression levels of TNF-α, IL-17A, IFN-γ, and IL-1β, not observed in control mice. Compared with controls, p25 99–118-immunized mice had significantly higher micturition frequency and decreased urine output per void, and they demonstrated elevated pelvic pain response. p25 99–118 immunization of male SWXJ mice induced prostate-specific autoimmunity characterized by prostate-confined inflammation, increased micturition frequency, and pelvic pain. This autoimmune prostatitis model provides a useful tool for exploring the pathophysiology and new treatments. PMID:23344231

The heparin-binding domain of HB-EGF as an efficient cell-penetrating peptide for drug delivery.

PubMed

Luo, Zhao; Cao, Xue-Wei; Li, Chen; Wu, Miao-Dan; Yang, Xu-Zhong; Zhao, Jian; Wang, Fu-Jun

2016-11-01

Cell-penetrating peptides (CPPs) have been shown to be potential drug carriers for cancer therapy. The inherently low immunogenicity and cytotoxicity of human-derived CPPs make them more suitable for intracellular drug delivery compared to other delivery vehicles. In this work, the protein transduction ability of a novel CPP (termed HBP) derived from the heparin-binding domain of HB-EGF was evaluated. Our data shows, for the first time, that HBP possesses similar properties to typical CPPs and is a potent drug delivery vector for improving the antitumor activity of impermeable MAP30. The intrinsic bioactivities of recombinant MAP30-HBP were well preserved compared to those of free MAP30. Furthermore, HBP conjugated to the C-terminus of MAP30 promoted the cellular uptake of recombinant MAP30-HBP. Moreover, the fusion of HBP to MAP30 gave rise to significantly enhanced cytotoxic effects in all of the tumor cell lines tested. In HeLa cells, this cytotoxicity was mainly caused by the induction of cell apoptosis. Further investigation revealed that HBP enhanced MAP30-induced apoptosis through the activation of the mitochondrial- and death receptor-mediated signaling pathways. In addition, the MAP30-HBP fusion protein caused more HeLa cells to become arrested in S phase compared to MAP30 alone. These results highlight the MAP30-HBP fusion protein as a promising drug candidate for cancer therapy and demonstrate HBP, a novel CPP derived from human HB-EGF, as a new potential vector for antitumor drug delivery. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Impact of data base structure in a successful in vitro-in vivo correlation for pharmaceutical products.

PubMed

Roudier, B; Davit, B; Schütz, H; Cardot, J-M

2015-01-01

The in vitro-in vivo correlation (IVIVC) (Food and Drug Administration 1997) aims to predict performances in vivo of a pharmaceutical formulation based on its in vitro characteristics. It is a complex process that (i) incorporates in a gradual and incremental way a large amount of information and (ii) requires information from different properties (formulation, analytical, clinical) and associated dedicated treatments (statistics, modeling, simulation). These results in many studies that are initiated and integrated into the specifications (quality target product profile, QTPP). This latter defines the appropriate experimental designs (quality by design, QbD) (Food and Drug Administration 2011, 2012) whose main objectives are determination (i) of key factors of development and manufacturing (critical process parameters, CPPs) and (ii) of critical points of physicochemical nature relating to active ingredients (API) and critical quality attribute (CQA) which may have implications in terms of efficiency, safety, and inoffensiveness for the patient, due to their non-inclusion. These processes generate a very large amount of data that is necessary to structure. In this context, the storage of information in a database (DB) and the management of this database (database management system, DBMS) become an important issue for the management of projects and IVIVC and more generally for development of new pharmaceutical forms. This article describes the implementation of a prototype object-oriented database (OODB) considered as a tool, which is helpful for decision taking, responding in a structured and consistent way to the issues of project management of IVIVC (including bioequivalence and bioavailability) (Food and Drug Administration 2003) necessary for the implementation of QTPP.

Clinical pharmacology of antiepileptic drug use: "clinical pearls about the perils of patty".

PubMed

Schraeder, P L; Lathers, C M

1995-12-01

This Clinical Pharmacology Problem Solving (CPPS) Unit is for use with fourth- or fifth-year pharmacy students and third- or fourth-year medical students during conferences held when they are taking either a rotation in Neurology or Clinical Pharmacology. It may also be used for house staff teaching of residents in Neurology, Pediatrics, Internal Medicine, and Family Practice and fellows in Clinical Pharmacology. This material was prepared for a Teaching Clinic in Clinical Pharmacology taught by Claire M. Lathers, PhD, FCP, Hugh J. Burford, PhD, FCP, and Cedric M. Smith, MD, FCP, and sponsored by the American College of Clinical Pharmacology, September 19-20, 1992, Washington, DC. This workbook includes: (1) an introduction to the Clinical Pharmacology Problem Solving (CPPS) Unit; (2) the learning objectives of the clinical simulation; (3) a pretest; (4) four clinical episodes occurring over many years in the life of a patient; (5) answers to the pretest; (6) a posttest; (7) answers to the posttest.

Improvement of a stability-indicating method by Quality-by-Design versus Quality-by-Testing: a case of a learning process.

PubMed

Hubert, C; Lebrun, P; Houari, S; Ziemons, E; Rozet, E; Hubert, Ph

2014-01-01

The understanding of the method is a major concern when developing a stability-indicating method and even more so when dealing with impurity assays from complex matrices. In the presented case study, a Quality-by-Design approach was applied in order to optimize a routinely used method. An analytical issue occurring at the last stage of a long-term stability study involving unexpected impurities perturbing the monitoring of characterized impurities needed to be resolved. A compliant Quality-by-Design (QbD) methodology based on a Design of Experiments (DoE) approach was evaluated within the framework of a Liquid Chromatography (LC) method. This approach allows the investigation of Critical Process Parameters (CPPs), which have an impact on Critical Quality Attributes (CQAs) and, consequently, on LC selectivity. Using polynomial regression response modeling as well as Monte Carlo simulations for error propagation, Design Space (DS) was computed in order to determine robust working conditions for the developed stability-indicating method. This QbD compliant development was conducted in two phases allowing the use of the Design Space knowledge acquired during the first phase to define the experimental domain of the second phase, which constitutes a learning process. The selected working condition was then fully validated using accuracy profiles based on statistical tolerance intervals in order to evaluate the reliability of the results generated by this LC/ESI-MS stability-indicating method. A comparison was made between the traditional Quality-by-Testing (QbT) approach and the QbD strategy, highlighting the benefit of this QbD strategy in the case of an unexpected impurities issue. On this basis, the advantages of a systematic use of the QbD methodology were discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of nanostructured lipid carriers containing salicyclic acid for dermal use based on the Quality by Design method.

PubMed

Kovács, A; Berkó, Sz; Csányi, E; Csóka, I

2017-03-01

The aim of our present work was to evaluate the applicability of the Quality by Design (QbD) methodology in the development and optimalization of nanostructured lipid carriers containing salicyclic acid (NLC SA). Within the Quality by Design methology, special emphasis is layed on the adaptation of the initial risk assessment step in order to properly identify the critical material attributes and critical process parameters in formulation development. NLC SA products were formulated by the ultrasonication method using Compritol 888 ATO as solid lipid, Miglyol 812 as liquid lipid and Cremophor RH 60® as surfactant. LeanQbD Software and StatSoft. Inc. Statistica for Windows 11 were employed to indentify the risks. Three highly critical quality attributes (CQAs) for NLC SA were identified, namely particle size, particle size distribution and aggregation. Five attributes of medium influence were identified, including dissolution rate, dissolution efficiency, pH, lipid solubility of the active pharmaceutical ingredient (API) and entrapment efficiency. Three critical material attributes (CMA) and critical process parameters (CPP) were identified: surfactant concentration, solid lipid/liquid lipid ratio and ultrasonication time. The CMAs and CPPs are considered as independent variables and the CQAs are defined as dependent variables. The 2 3 factorial design was used to evaluate the role of the independent and dependent variables. Based on our experiments, an optimal formulation can be obtained when the surfactant concentration is set to 5%, the solid lipid/liquid lipid ratio is 7:3 and ultrasonication time is 20min. The optimal NLC SA showed narrow size distribution (0.857±0.014) with a mean particle size of 114±2.64nm. The NLC SA product showed a significantly higher in vitro drug release compared to the micro-particle reference preparation containing salicylic acid (MP SA). Copyright © 2016 Elsevier B.V. All rights reserved.

Cell penetrating peptides: a comparative transport analysis for 474 sequence motifs.

PubMed

Ramaker, Katrin; Henkel, Maik; Krause, Thorsten; Röckendorf, Niels; Frey, Andreas

2018-11-01

Delivering reagents into cells is a key demand in molecular medicine. The vehicle of choice is often cell penetrating peptides (CPPs), which can ferry conjugated cargo across membranes. Although numerous peptides have been shown to promote such uptake events, there has been no comprehensive comparison of individual performance under standardized conditions. We have devised a method to rapidly analyze the ability of a multitude of CPP conjugates to carry a model cargo into HeLa cells. Sequence information for 474 CPPs was collected from literature sources, and the respective peptides were synthesized and modified with carboxyfluorescein (FAM) as model cargo. All candidates were evaluated in an identical uptake test, and transport was quantified using cellular fluorescence intensities. Substantial differences in the ability to carry the fluorophore into the cells were observed, with transport performance differing by a factor of 70 between the best CPP investigated and cargo alone. Strong correlations were observed between uptake efficiency and both sequence length and the presence of positive net charge. A compilation of the 20 top performers with regard to cargo delivery performance and cell compatibility is provided.

Spray dried amikacin powder for inhalation in cystic fibrosis patients: a quality by design approach for product construction.

PubMed

Belotti, Silvia; Rossi, Alessandra; Colombo, Paolo; Bettini, Ruggero; Rekkas, Dimitrios; Politis, Stavros; Colombo, Gaia; Balducci, Anna Giulia; Buttini, Francesca

2014-08-25

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement. Copyright © 2014 Elsevier B.V. All rights reserved.

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium

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

Xia, Tian; Hamilton, Raymond F.; Bonner, James C.

2013-06-01

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different speciesmore » (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells. Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μ g/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β. Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity.« less

The Urinary Microbiome Differs Significantly Between Patients With Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Controls as Well as Between Patients With Different Clinical Phenotypes.

PubMed

Shoskes, Daniel A; Altemus, Jessica; Polackwich, Alan S; Tucky, Barbara; Wang, Hannah; Eng, Charis

2016-06-01

To study the urinary microbiome of patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) compared with controls. We identified 25 patients with CP/CPPS and 25 men who were either asymptomatic or only had urinary symptoms. Midstream urine was collected. Symptom severity was measured with the National Institutes of Health Chronic Prostatitis Symptom Index and clinical phenotype with UPOINT. Total DNA was extracted from the urine pellet and bacterial-specific 16Sr-DNA-capture identified by MiSeq sequencing. Taxonomic and functional bioinformatic analyses used principal coordinate analysis (PCoA)/MacQIIME, LEfSe, and PiCRUSt algorithms. Patients and controls were similar ages (52.3 vs 57.0 years, P = .27). For patients, median duration was 48 months, mean Chronic Prostatitis Symptom Index was 26.0, and mean UPOINT domains was 3.6. Weighted 3D UniFrac PCoA revealed tighter clustering of controls distinct from the wider clustering of cases (P = .001; α-diversity P = .005). Seventeen clades were overrepresented in patients, for example, Clostridia, and 5 were underrepresented, eg, Bacilli, resulting in predicted perturbations in functional pathways. PiCRUSt inferred differentially regulated pathways between cases and controls that may be of relevance including sporulation, chemotaxis, and pyruvate metabolism. PCoA-derived microbiomic differences were noted for neurologic/systemic domains (P = .06), whereas LEfSe identified differences associated with each of the 6 clinical features. Urinary microbiomes from patients with CP/CPPS have significantly higher alpha(phylogenetic) diversity which cluster differently from controls, and higher counts of Clostridia compared with controls, resulting in predicted perturbations of functional pathways which could suggest metabolite-specific targeted treatment. Several measures of severity and clinical phenotype have significant microbiome differences. Copyright © 2016 Elsevier Inc. All rights reserved.

Establishment of a rat model of chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) induced by immunization with a novel peptide T2.

PubMed

Ihsan, Awais Ullah; Khan, Farhan Ullah; Nawaz, Waqas; Khan, Muhammad Zahid; Yang, Mengqi; Zhou, Xiaohui

2017-07-01

The exact etiological mechanism of Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unclear however autoimmunity is the most valid theory. We developed a rat model of Chronic Prostatitis/chronic pelvic pain syndrome by using a novel peptide (T2) isolated from TRPM8. This model might be beneficial in elucidating mechanisms involved in the pathogenesis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). 40 male Sprague-Dawley rats with an average weight of 180-220g were equally distributed into five groups. The normal control group was injected with normal saline (.9% NACL), the CFA group with CFA, AL(OH)3 group was given AL(OH)3 injection, T2 group using a novel peptide T2 and T2+AL(OH)3+CFA group was injected with T2+AL(OH)3+CFA. Dosing to all rat groups were injected subcutaneously. Hematoxylin and eosin staining and Immunohistochemistry were used to investigate inflammatory cell infiltration and IL-1β in the prostate tissue respectively. ELISA technique was used to measure the serum level of CRP and TNF-α. T-test was used to analyze the results. Maximum infiltration of inflammatory cells and the highest level of IL-1β in the prostate tissue was observed in T2+AL(OH)3+CFA group as revealed by histopathology and Immunohistochemistry, respectively. Furthermore, T2+AL(OH)3+CFA group attained the peak value of serum TNF-α and CRP as determined by ELISA technique. Our results demonstrated that T2 in combination with AL(OH)3 and CFA induced severe Prostatitis in rats. We believe that our present model will be highly beneficial for investigation of the pathophysiology of Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups.

PubMed

Thomas, Christian; Sill, Martin; Ruland, Vincent; Witten, Anika; Hartung, Stefan; Kordes, Uwe; Jeibmann, Astrid; Beschorner, Rudi; Keyvani, Kathy; Bergmann, Markus; Mittelbronn, Michel; Pietsch, Torsten; Felsberg, Jörg; Monoranu, Camelia M; Varlet, Pascale; Hauser, Peter; Olar, Adriana; Grundy, Richard G; Wolff, Johannes E; Korshunov, Andrey; Jones, David T; Bewerunge-Hudler, Melanie; Hovestadt, Volker; von Deimling, Andreas; Pfister, Stefan M; Paulus, Werner; Capper, David; Hasselblatt, Martin

2016-06-01

Choroid plexus tumors are intraventricular neoplasms derived from the choroid plexus epithelium. A better knowledge of molecular factors involved in choroid plexus tumor biology may aid in identifying patients at risk for recurrence. Methylation profiles were examined in 29 choroid plexus papillomas (CPPs, WHO grade I), 32 atypical choroid plexus papillomas (aCPPs, WHO grade II), and 31 choroid plexus carcinomas (CPCs, WHO grade III) by Illumina Infinium HumanMethylation450 Bead Chip Array. Unsupervised hierarchical clustering identified 3 subgroups: methylation cluster 1 (pediatric CPP and aCPP of mainly supratentorial location), methylation cluster 2 (adult CPP and aCPP of mainly infratentorial location), and methylation cluster 3 (pediatric CPP, aCPP, and CPC of supratentorial location). In methylation cluster 3, progression-free survival (PFS) accounted for a mean of 72 months (CI, 55-89 mo), whereas only 1 of 42 tumors of methylation clusters 1 and 2 progressed (P< .001). On stratification of outcome data according to WHO grade, all CPCs clustered within cluster 3 and were associated with shorter overall survival (mean, 105 mo [CI, 81-128 mo]) and PFS (mean, 55 mo [CI, 36-73 mo]). The aCPP of methylation cluster 3 also progressed frequently (mean, 69 mo [CI, 44-93 mo]), whereas no tumor progression was observed in aCPP of methylation clusters 1 and 2 (P< .05). Only 1 of 29 CPPs recurred. Methylation profiling of choroid plexus tumors reveals 3 distinct subgroups (ie, pediatric low-risk choroid plexus tumors [cluster 1], adult low-risk choroid plexus tumors [cluster 2], and pediatric high-risk choroid plexus tumors [cluster 3]) and may provide useful prognostic information in addition to histopathology. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

IL-17 is not essential for inflammation and chronic pelvic pain development in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Motrich, Ruben D; Breser, María L; Sánchez, Leonardo R; Godoy, Gloria J; Prinz, Immo; Rivero, Virginia E

2016-03-01

Pain and inflammation in the absence of infection are hallmarks in chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients. The etiology of CP/CPPS is unclear, and autoimmunity has been proposed as a cause. Experimental autoimmune prostatitis (EAP) models have long been used for studying CP/CPPS. Herein, we studied prostate inflammation induction and chronic pelvic pain development in EAP using IL-12p40-KO, IL-4-KO, IL-17-KO, and wild-type (C57BL/6) mice. Prostate antigen (PAg) immunization in C57BL/6 mice induced specific Th1 and Th17 immune responses and severe prostate inflammation and cell infiltration, mainly composed of CD4 T cells and macrophages. Moreover, chronic pelvic pain was evidenced by increased allodynia responses. In immunized IL-17-KO mice, the presence of a prominent PAg-specific Th1 immune response caused similar prostate inflammation and chronic pelvic pain. Furthermore, markedly high PAg-specific Th1 immune responses, exacerbated prostate inflammation, and chronic pelvic pain were detected in immunized IL-4-KO mice. Conversely, immunized IL-12p40-KO mice developed PAg-specific Th2 immune responses, characterized by high IL-4 secretion and neither infiltration nor damage in the prostate. As observed in wild-type control animals, IL12p40-KO mice did not evidence tactile allodynia responses. Our results suggest that, as in patients, chronic pelvic pain is a consequence of prostate inflammation. After PAg immunization, a Th1-associated immune response develops and induces prostate inflammation and chronic pelvic pain. The absence of Th1 or Th2 cytokines, respectively, diminishes or enhances EAP susceptibility. In addition, IL-17 showed not to be essential for pathology induction and chronic pelvic pain development.

How Membrane-Active Peptides Get into Lipid Membranes.

PubMed

Sani, Marc-Antoine; Separovic, Frances

2016-06-21

The structure-function relationship for a family of antimicrobial peptides (AMPs) from the skin of Australian tree frogs is discussed and compared with that of peptide toxins from bee and Australian scorpion venoms. Although these membrane-active peptides induce a similar cellular fate by disrupting the lipid bilayer integrity, their lytic activity is achieved via different modes of action, which are investigated in relation to amino acid sequence, secondary structure, and membrane lipid composition. In order to better understand what structural features govern the interaction between peptides and lipid membranes, cell-penetrating peptides (CPPs), which translocate through the membrane without compromising its integrity, are also discussed. AMPs possess membrane lytic activities that are naturally designed to target the cellular membrane of pathogens or competitors. They are extremely diverse in amino acid composition and often show specificity against a particular strain of microbe. Since our antibiotic arsenal is declining precariously in the face of the rise in multiantibiotic resistance, AMPs increasingly are seen as a promising alternative. In an effort to understand their molecular mechanism, biophysical studies of a myriad of AMPs have been reported, yet no unifying mechanism has emerged, rendering difficult the rational design of drug leads. Similarly, a wide variety of cytotoxic peptides are found in venoms, the best known being melittin, yet again, predicting their activity based on a particular amino acid composition or secondary structure remains elusive. A common feature of these membrane-active peptides is their preference for the lipid environment. Indeed, they are mainly unstructured in solution and, in the presence of lipid membranes, quickly adsorb onto the surface, change their secondary structure, eventually insert into the hydrophobic core of the membrane bilayer, and finally disrupt the bilayer integrity. These steps define the molecular mechanism by which these membrane-active peptides lyse membranes. The last class of membrane-active peptides discussed are the CPPs, which translocate across the lipid bilayer without inducing severe disruption and have potential as drug vehicles. CPPs are typically highly charged and can show antimicrobial activity by targeting an intracellular target rather than via a direct membrane lytic mechanism. A critical aspect in the structure-function relationship of membrane-active peptides is their specific activity relative to the lipid membrane composition of the cell target. Cell membranes have a wide diversity of lipids, and those of eukaryotic and prokaryotic species differ greatly in composition and structure. The activity of AMPs from Australian tree frogs, toxins, and CPPs has been investigated within various lipid systems to assess whether a relationship between peptide and membrane composition could be identified. NMR spectroscopy techniques are being used to gain atomistic details of how these membrane-active peptides interact with model membranes and cells, and in particular, competitive assays demonstrate the difference between affinity and activity for a specific lipid environment. Overall, the interactions between these relatively small sized peptides and various lipid bilayers give insight into how these peptides function at the membrane interface.

α-blockers, antibiotics and anti-inflammatories have a role in the management of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Thakkinstian, Ammarin; Attia, John; Anothaisintawee, Thunyarat; Nickel, J Curtis

2012-10-01

Study Type - Therapy (systematic review) Level of Evidence 1a. What's known on the subject? and What does the study add? Individual clinical trials evaluating antibiotics, anti-inflammatories and α-blockers for the treatment of chronic prostatitis/chronic pelvic pain syndrome have shown only modest or even no benefits for patients compared with placebo, yet we continue to use these agents in selected patients with some success in clinical practice. This network meta-analysis of current evidence from all available randomized placebo-controlled trials with similar inclusion criteria and outcome measures shows that these '3-As' of chronic prostatitis/chronic pelvic pain syndrome treatment (antibiotics, anti-inflammatories and α-blockers) do offer benefits to some patients, particularly if we use them strategically in selected individuals. To provide an updated network meta-analysis mapping α-blockers, antibiotics and anti-inflammatories (the 3-As) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). • To use the results of this meta-analysis to comment on the role of the 3-As in clinical practice. We updated a previous review including only randomized controlled studies employing the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) as one of the outcomes to compare treatment effects in CP/CPPS patients. • A longitudinal mixed regression model (network meta-analysis) was applied to indirectly assess multiple treatment comparisons (i.e. α-blockers, antibiotics, anti-inflammatory/immune modulation therapies, α-blockers plus antibiotics, and placebo). Nineteen studies (1669 subjects) were eligible for analysis. • α-blockers, antibiotics and anti-inflammatory/immune modulation therapies were associated with significant improvement in symptoms when compared with placebo, with mean differences of total CPSI of -10.8 (95% CI -13.2 to -8.3; P < 0.001), -9.7 (95% CI -14.2 to -5.3; P < 0.001) and -1.7 (95% CI -3.2 to -0.2; P= 0.032) respectively, while α-blockers plus antibiotics resulted in the greatest CPSI difference (-13.6, 95% CI -16.7 to -10.6; P < 0.001). • With respect to responder analysis compared with placebo, anti-inflammatories showed the greatest response rates (risk ratio 1.7, 95% CI 1.4-2.1; P < 0.001) followed by α-blockers (risk ratio 1.4, 95% CI 1.1-1.8; P= 0.013) and antibiotics (risk ratio 1.2, 95% CI 0.7-1.9; P= 0.527). α-blockers, antibiotics and/or anti-inflammatory/immune modulation therapy appear to be beneficial for some patients with CP/CPPS. • The magnitude of effect and the disconnect between mean CPSI decrease and response rates compared with placebo suggest that directed multimodal therapy, rather than mono-therapy, with these agents should be considered for optimal management of CP/CPPS. © 2012 BJU INTERNATIONAL.

JPRS Report, Environmental Issues

DTIC Science & Technology

1991-06-26

been coordinated by the National Environ- mental Policy Commission [Comision Nacional de Politica Ambiental ]. The first step was the creation of a...May 91 [Text] Santiago, 30 May (EFE)—The Permanent South Pacific Commission (CPPS), which comprises Colombia, Chile, Ecuador , and Peru, has lodged a...decisions. We are adopting measures that will create the State Secretariat for the Environment [Secretaria de Estado del Medio Ambiente ], which will be

Nanoparticle transport across in vitro olfactory cell monolayers.

PubMed

Gartziandia, Oihane; Egusquiaguirre, Susana Patricia; Bianco, John; Pedraz, José Luis; Igartua, Manoli; Hernandez, Rosa Maria; Préat, Véronique; Beloqui, Ana

2016-02-29

Drug access to the CNS is hindered by the presence of the blood-brain barrier (BBB), and the intranasal route has risen as a non-invasive route to transport drugs directly from nose-to-brain avoiding the BBB. In addition, nanoparticles (NPs) have been described as efficient shuttles for direct nose-to-brain delivery of drugs. Nevertheless, there are few studies describing NP nose-to-brain transport. Thus, the aim of this work was (i) to develop, characterize and validate in vitro olfactory cell monolayers and (ii) to study the transport of polymeric- and lipid-based NPs across these monolayers in order to estimate NP access into the brain using cell penetrating peptide (CPPs) moieties: Tat and Penetratin (Pen). All tested poly(d,l-lactide-co-glycolide) (PLGA) and nanostructured lipid carrier (NLC) formulations were stable in transport buffer and biocompatible with the olfactory mucosa cells. Nevertheless, 0.7% of PLGA NPs was able to cross the olfactory cell monolayers, whereas 8% and 22% of NLC and chitosan-coated NLC (CS-NLC) were transported across them, respectively. Moreover, the incorporation of CPPs to NLC surface significantly increased their transport, reaching 46% of transported NPs. We conclude that CPP-CS-NLC represent a promising brain shuttle via nose-to-brain for drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficient Cargo Delivery into Adult Brain Tissue Using Short Cell-Penetrating Peptides.

PubMed

Kizil, Caghan; Iltzsche, Anne; Thomas, Alvin Kuriakose; Bhattarai, Prabesh; Zhang, Yixin; Brand, Michael

2015-01-01

Zebrafish brains can regenerate lost neurons upon neurogenic activity of the radial glial progenitor cells (RGCs) that reside at the ventricular region. Understanding the molecular events underlying this ability is of great interest for translational studies of regenerative medicine. Therefore, functional analyses of gene function in RGCs and neurons are essential. Using cerebroventricular microinjection (CVMI), RGCs can be targeted efficiently but the penetration capacity of the injected molecules reduces dramatically in deeper parts of the brain tissue, such as the parenchymal regions that contain the neurons. In this report, we tested the penetration efficiency of five known cell-penetrating peptides (CPPs) and identified two- polyR and Trans - that efficiently penetrate the brain tissue without overt toxicity in a dose-dependent manner as determined by TUNEL staining and L-Plastin immunohistochemistry. We also found that polyR peptide can help carry plasmid DNA several cell diameters into the brain tissue after a series of coupling reactions using DBCO-PEG4-maleimide-based Michael's addition and azide-mediated copper-free click reaction. Combined with the advantages of CVMI, such as rapidness, reproducibility, and ability to be used in adult animals, CPPs improve the applicability of the CVMI technique to deeper parts of the central nervous system tissues.

Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells

PubMed Central

Liu, Betty R.; Huang, Yue-Wern; Aronstam, Robert S.; Lee, Han-Jung

2016-01-01

Cell-penetrating peptides (CPPs) have been shown to deliver cargos, including protein, DNA, RNA, and nanomaterials, in fully active forms into live cells. Most of the CPP sequences in use today are based on non-native proteins that may be immunogenic. Here we demonstrate that the L5a CPP (RRWQW) from bovine lactoferricin (LFcin), stably and noncovalently complexed with plasmid DNA and prepared at an optimal nitrogen/phosphate ratio of 12, is able to efficiently enter into human lung cancer A549 cells. The L5a CPP delivered a plasmid containing the enhanced green fluorescent protein (EGFP) coding sequence that was subsequently expressed in cells, as revealed by real-time PCR and fluorescent microscopy at the mRNA and protein levels, respectively. Treatment with calcium chloride increased the level of gene expression, without affecting CPP-mediated transfection efficiency. Zeta-potential analysis revealed that positively electrostatic interactions of CPP/DNA complexes correlated with CPP-mediated transport. The L5a and L5a/DNA complexes were not cytotoxic. This biomimetic LFcin L5a represents one of the shortest effective CPPs and could be a promising lead peptide with less immunogenic for DNA delivery in gene therapy. PMID:26942714

Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells.

PubMed

Liu, Betty R; Huang, Yue-Wern; Aronstam, Robert S; Lee, Han-Jung

2016-01-01

Cell-penetrating peptides (CPPs) have been shown to deliver cargos, including protein, DNA, RNA, and nanomaterials, in fully active forms into live cells. Most of the CPP sequences in use today are based on non-native proteins that may be immunogenic. Here we demonstrate that the L5a CPP (RRWQW) from bovine lactoferricin (LFcin), stably and noncovalently complexed with plasmid DNA and prepared at an optimal nitrogen/phosphate ratio of 12, is able to efficiently enter into human lung cancer A549 cells. The L5a CPP delivered a plasmid containing the enhanced green fluorescent protein (EGFP) coding sequence that was subsequently expressed in cells, as revealed by real-time PCR and fluorescent microscopy at the mRNA and protein levels, respectively. Treatment with calcium chloride increased the level of gene expression, without affecting CPP-mediated transfection efficiency. Zeta-potential analysis revealed that positively electrostatic interactions of CPP/DNA complexes correlated with CPP-mediated transport. The L5a and L5a/DNA complexes were not cytotoxic. This biomimetic LFcin L5a represents one of the shortest effective CPPs and could be a promising lead peptide with less immunogenic for DNA delivery in gene therapy.

Intelligent "Peptide-Gathering Mechanical Arm" Tames Wild "Trojan-Horse" Peptides for the Controlled Delivery of Cancer Nanotherapeutics.

PubMed

Shi, Nian-Qiu; Li, Yan; Zhang, Yong; Shen, Nan; Qi, Ling; Wang, Shu-Ran; Qi, Xian-Rong

2017-12-06

Cell-penetrating peptides (CPPs), also called "Trojan-Horse" peptides, have been used for facilitating intracellular delivery of numerous diverse cargoes and even nanocarriers. However, the lack of targeting specificity ("wildness" or nonselectivity) of CPP-nanocarriers remains an intractable challenge for many in vivo applications. In this work, we used an intelligent "peptide-gathering mechanical arm" (Int PMA) to curb CPPs' wildness and enhance the selectivity of R 9 -liposome-based cargo delivery for tumor targeting. The peptide NGR, serving as a cell-targeting peptide for anchoring, and peptide PLGLAG, serving as a substrate peptide for deanchoring, were embedded in the Int PMA motif. The Int PMA construct was designed to be sensitive to tumor microenvironmental stimuli, including aminopeptidase N (CD13) and matrix metalloproteinases (MMP-2/9). Moreover, Int PMA could be specifically recognized by tumor tissues via CD13-mediated anchoring and released for cell entry by MMP-2/9-mediated deanchoring. To test the Int PMA design, a series of experiments were conducted in vitro and in vivo. Functional conjugates Int PMA-R 9 -poly(ethylene glycol) (PEG) 2000 -distearoylphosphatidyl-ethanolamine (DSPE) and R 9 -PEG 2000 -DSPE were synthesized by Michael addition reaction and were characterized by thin-layer chromatography and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. The Int PMA-R 9 -modified doxorubicin-loaded liposomes (Int PMA-R 9 -Lip-DOX) exhibited a proper particle diameter (approximately 155 nm) with in vitro sustained release characteristics. Cleavage assay showed that Int PMA-R 9 peptide molecules could be cleaved by MMP-2/9 for completion of deanchoring. Flow cytometry and confocal microscopy studies indicated that Int PMA-R 9 -Lip-DOX can respond to both endogenous and exogenous stimuli in the presence/absence of excess MMP-2/9 and MMP-2/9 inhibitor (GM6001) and effectively function under competitive receptor-binding conditions. Moreover, Int PMA-R 9 -Lip-DOX generated more significant subcellular dispersions that were especially evident within endoplasmic reticulum (ER) and Golgi apparatus. Notably, Int PMA-R 9 -Lip-DOX could induce enhanced apoptosis, during which caspase 3/7 might be activated. In addition, Int PMA-R 9 -Lip-DOX displayed enhanced in vitro and in vivo antitumor efficacy versus "wild" R 9 -Lip-DOX. On the basis of investigations at the molecular level, cellular level, and animals' level, the control of Int PMA was effective and promoted selective delivery of R 9 -liposome cargo to the target site and reduced nonspecific uptake. This Int PMA-controlled strategy based on aminopeptidase-guided anchoring and protease-triggered deanchoring effectively curbed the wildness of CPPs and bolstered their effectiveness for in vivo delivery of nanotherapeutics. The specific nanocarrier delivery system used here could be adapted using a variety of intelligent designs based on combinations of multifunctional peptides that would specifically and preferentially bind to tumors versus nontumor tissues for tumor-localized accumulation in vivo. Thus, CPPs have a strong advantage for the development of intelligent nanomedicines for targeted tumor therapy.

Poly-arginine and arginine-rich peptides are neuroprotective in stroke models

PubMed Central

Meloni, Bruno P; Brookes, Laura M; Clark, Vince W; Cross, Jane L; Edwards, Adam B; Anderton, Ryan S; Hopkins, Richard M; Hoffmann, Katrin; Knuckey, Neville W

2015-01-01

Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs. PMID:25669902

31P Solid-state NMR based monitoring of permeation of cell penetrating peptides into skin

PubMed Central

Desai, Pinaki R.; Cormier, Ashley R.; Shah, Punit P.; Patlolla, Ram R.; Paravastu, Anant K.; Singh, Mandip

2013-01-01

The main objective of the current study was to investigate penetration of cell penetrating peptides (CPPs: TAT, R8, R11 and YKA) through skin intercellular lipids using 31P magic angle spinning (MAS) solid-state NMR. In vitro skin permeation studies were performed on rat skin, sections (0–60, 61–120 and 121–180 µm) were collected and analyzed for 31P NMR signal. The concentration dependent shift of 0, 25, 50, 100 and 200 mg/ml of TAT on skin layers, diffusion of TAT, R8, R11 and YKA in the skin and time dependent permeation of R11 was measured on various skin sections using 31P solid-state NMR. Further, CPPs and CPP-tagged fluorescent dye encapsulate liposomes (FLip) in skin layers were tagged using confocal microscopy. The change in 31P NMR chemical shift was found to depend monotonically on the amount of CPP applied on skin, with saturation behavior above 100 mg/ml CPP concentration. R11 and TAT caused more shift in solid-state NMR peaks compared to other peptides. Furthermore, NMR spectra showed R11 penetration up to 180 µm within 30 min. The results of the solid-state NMR study were in agreement with confocal microscopy studies. Thus, 31P solid-state NMR can be used to track CPP penetration into different skin layers. PMID:23702274

Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo

PubMed Central

EL Andaloussi, Samir; Lehto, Taavi; Mäger, Imre; Rosenthal-Aizman, Katri; Oprea, Iulian I.; Simonson, Oscar E.; Sork, Helena; Ezzat, Kariem; Copolovici, Dana M.; Kurrikoff, Kaido; Viola, Joana R.; Zaghloul, Eman M.; Sillard, Rannar; Johansson, Henrik J.; Said Hassane, Fatouma; Guterstam, Peter; Suhorutšenko, Julia; Moreno, Pedro M. D.; Oskolkov, Nikita; Hälldin, Jonas; Tedebark, Ulf; Metspalu, Andres; Lebleu, Bernard; Lehtiö, Janne; Smith, C. I. Edvard; Langel, Ülo

2011-01-01

While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential. PMID:21245043

Evidence of structural invariance across three groups of Meehlian schizotypes

PubMed Central

Chan, Raymond CK; Gooding, Diane C; Shi, Hai-song; Geng, Fu-lei; Xie, Dong-jie; Yang, Zhuo-Ya; Liu, Wen-hua; Wang, Yi; Yan, Chao; Shi, Chuan; Lui, Simon SY; Cheung, Eric FC

2016-01-01

According to Meehl’s model of schizotypy, there is a latent personality organization associated with the diathesis for schizophrenia that can be identified in several ways. We sought to examine the structural invariance of four Chapman psychosis–proneness scales (CPPS) across three groups of putative schizotypes, namely, clinically-, biologically-, and psychometrically-identified schizotypes. We examined the factor structure of the Perceptual Aberration (PER), Magical Ideation (MIS), Revised Social Anhedonia (RSAS), and Revised Physical Anhedonia (RPAS) scales in 196 schizophrenia patients, 197 non-psychotic first-degree relatives, and 1,724 non-clinical young adults. The confirmatory factor analyses indicated that the best-fitting model was one in which there is a two-factor model with negative schizotypy (RSAS and RPAS) and positive schizotypy (PER and MIS). All three samples fit the model well, with Comparative Fit Indices>0.95 and Tucker Lewis Indices>0.90. The root mean square error of approximations were all small (P values⩽0.01). We also observed that for both anhedonia scales, the groups’ mean scale scores varied in the hypothesized direction, as predicted by Meehl’s model of schizotypy. All three Chinese samples, namely, the patients (clinical schizotypes), relatives (biologically-identified schizotypes), and non-clinical young adults (containing psychometrically-identified schizotypes) showed the same factorial structure. This finding supports the suitability of the CPPS for cross-cultural and/or genetic investigations of schizotypy. PMID:27336057

The coalescent of a sample from a binary branching process.

PubMed

Lambert, Amaury

2018-04-25

At time 0, start a time-continuous binary branching process, where particles give birth to a single particle independently (at a possibly time-dependent rate) and die independently (at a possibly time-dependent and age-dependent rate). A particular case is the classical birth-death process. Stop this process at time T>0. It is known that the tree spanned by the N tips alive at time T of the tree thus obtained (called a reduced tree or coalescent tree) is a coalescent point process (CPP), which basically means that the depths of interior nodes are independent and identically distributed (iid). Now select each of the N tips independently with probability y (Bernoulli sample). It is known that the tree generated by the selected tips, which we will call the Bernoulli sampled CPP, is again a CPP. Now instead, select exactly k tips uniformly at random among the N tips (a k-sample). We show that the tree generated by the selected tips is a mixture of Bernoulli sampled CPPs with the same parent CPP, over some explicit distribution of the sampling probability y. An immediate consequence is that the genealogy of a k-sample can be obtained by the realization of k random variables, first the random sampling probability Y and then the k-1 node depths which are iid conditional on Y=y. Copyright © 2018. Published by Elsevier Inc.

Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care.

PubMed

Koblizek, Vladimir; Chlumsky, Jan; Zindr, Vladimir; Neumannova, Katerina; Zatloukal, Jakub; Zak, Jaroslav; Sedlak, Vratislav; Kocianova, Jana; Zatloukal, Jaromir; Hejduk, Karel; Pracharova, Sarka

2013-06-01

COPD is a global concern. Currently, several sets of guidelines, statements and strategies to managing COPD exist around the world. The Czech Pneumological and Phthisiological Society (CPPS) has commissioned an Expert group to draft recommended guidelines for the management of stable COPD. Subsequent revisions were further discussed at the National Consensus Conference (NCC). Reviewers' comments contributed to the establishment of the document's final version. The hallmark of the novel approach to COPD is the integrated evaluation of the patient's lung functions, symptoms, exacerbations and identifications of clinical phenotype(s). The CPPS defines 6 clinically relevant phenotypes: frequent exacerbator, COPD-asthma overlap, COPD-bronchiectasis overlap, emphysematic phenotype, bronchitic phenotype and pulmonary cachexia phenotype. Treatment recommendations can be divided into four steps. 1(st) step = Risk exposure elimination: reduction of smoking and environmental tobacco smoke (ETS), decrease of home and occupational exposure risks. 2(nd) step = Standard treatment: inhaled bronchodilators, regular physical activity, pulmonary rehabilitation, education, inhalation training, comorbidity treatment, vaccination. 3(rd) step = Phenotype-specific therapy: PDE4i, ICS+LABA, LVRS, BVR, AAT augmentation, physiotherapy, mucolytic, ABT. 4(th) step = Care for respiratory insufficiency and terminal COPD: LTOT, lung transplantation, high intensity-NIV and palliative care. Optimal treatment of COPD patients requires an individualised, multidisciplinary approach to the patient's symptoms, clinical phenotypes, needs and wishes. The new Czech COPD guideline reflects and covers these requirements.

Cell-penetrating peptide-morpholino conjugates alter pre-mRNA splicing of DMD (Duchenne muscular dystrophy) and inhibit murine coronavirus replication in vivo.

PubMed

Moulton, H M; Fletcher, S; Neuman, B W; McClorey, G; Stein, D A; Abes, S; Wilton, S D; Buchmeier, M J; Lebleu, B; Iversen, P L

2007-08-01

The cellular uptake of PMOs (phosphorodiamidate morpholino oligomers) can be enhanced by their conjugation to arginine-rich CPPs (cell-penetrating peptides). Here, we discuss our recent findings regarding (R-Ahx-R)(4)AhxB (Ahx is 6-aminohexanoic acid and B is beta-alanine) CPP-PMO conjugates in DMD (Duchenne muscular dystrophy) and murine coronavirus research. An (R-Ahx-R)(4)AhxB-PMO conjugate was the most effective compound in inducing the correction of mutant dystrophin transcripts in myoblasts derived from a canine model of DMD. Similarly, normal levels of dystrophin expression were restored in the diaphragms of mdx mice, with treatment starting at the neonatal stage, and protein was still detecTable 22 weeks after the last dose of an (R-Ahx-R)(4)AhxB-PMO conjugate. Effects of length, linkage and carbohydrate modification of this CPP on the delivery of a PMO were investigated in a coronavirus mouse model. An (R-Ahx-R)(4)AhxB-PMO conjugate effectively inhibited viral replication, in comparison with other peptides conjugated to the same PMO. Shortening the CPP length, modifying it with a mannosylated serine moiety or replacing it with the R(9)F(2) CPP significantly decreased the efficacy of the resulting PPMO (CPP-PMO conjugate). We attribute the success of this CPP to its stability in serum and its capacity to transport PMO to RNA targets in a manner superior to that of poly-arginine CPPs.

Interactions between Membranes and "Metaphilic" Polypeptide Architectures with Diverse Side-Chain Populations.

PubMed

Lee, Michelle W; Han, Ming; Bossa, Guilherme Volpe; Snell, Carly; Song, Ziyuan; Tang, Haoyu; Yin, Lichen; Cheng, Jianjun; May, Sylvio; Luijten, Erik; Wong, Gerard C L

2017-03-28

At physiological conditions, most proteins or peptides can fold into relatively stable structures that present on their molecular surfaces specific chemical patterns partially smeared out by thermal fluctuations. These nanoscopically defined patterns of charge, hydrogen bonding, and/or hydrophobicity, along with their elasticity and shape stability (folded proteins have Young's moduli of ∼1 × 10 8 Pa), largely determine and limit the interactions of these molecules, such as molecular recognition and allosteric regulation. In this work, we show that the membrane-permeating activity of antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) can be significantly enhanced using prototypical peptides with "molten" surfaces: metaphilic peptides with quasi-liquid surfaces and adaptable shapes. These metaphilic peptides have a bottlebrush-like architecture consisting of a rigid helical core decorated with mobile side chains that are terminated by cationic or hydrophobic groups. Computer simulations show that these flexible side chains can undergo significant rearrangement in response to different environments, giving rise to adaptable surface chemistry of the peptide. This quality makes it possible to control their hydrophobicity over a broad range while maintaining water solubility, unlike many AMPs and CPPs. Thus, we are able to show how the activity of these peptides is amplified by hydrophobicity and cationic charge, and rationalize these results using a quantitative mean-field theory. Computer simulations show that the shape-changing properties of the peptides and the resultant adaptive presentation of chemistry play a key enabling role in their interactions with membranes.

Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development.

PubMed

Iliou, Katerina; Malenović, Anđelija; Loukas, Yannis L; Dotsikas, Yannis

2018-02-05

A novel Liquid Chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the quantitative determination of two potential genotoxic impurities (PGIs) in rabeprazole active pharmaceutical ingredient (API). In order to overcome the analytical challenges in the trace analysis of PGIs, a development procedure supported by Quality-by-Design (QbD) principles was evaluated. The efficient separation between rabeprazole and the two PGIs in the shortest analysis time was set as the defined analytical target profile (ATP) and to this purpose utilization of a switching valve allowed the flow to be sent to waste when rabeprazole was eluted. The selected critical quality attributes (CQAs) were the separation criterion s between the critical peak pair and the capacity factor k of the last eluted compound. The effect of the following critical process parameters (CPPs) on the CQAs was studied: %ACN content, the pH and the concentration of the buffer salt in the mobile phase, as well as the stationary phase of the analytical column. D-Optimal design was implemented to set the plan of experiments with UV detector. In order to define the design space, Monte Carlo simulations with 5000 iterations were performed. Acceptance criteria were met for C 8 column (50×4mm, 5μm) , and the region having probability π≥95% to achieve satisfactory values of all defined CQAs was computed. The working point was selected with the mobile phase consisting ‎of ACN, ammonium formate 11mM at a ratio 31/69v/v with pH=6,8 for the water phase. The LC protocol was transferred to LC-MS/MS and validated according to ICH guidelines. Copyright © 2017 Elsevier B.V. All rights reserved.

Impregnation quality of shredded semipreg after compression moulding

NASA Astrophysics Data System (ADS)

Vincent, G.; Balakrishnan, V.; de Bruijn, T. A.; Wijskamp, S.; Abdul Rasheed, M. I.

2017-10-01

Manufacturing of thermoplastic composites (TPC) inherently generates scrap, mainly in the form of offcuts or rejected parts. The growth of TPC over recent decades has now reached a point where developing specific recycling solutions for TPC waste has become crucial. While looking at the various steps during which scrap is produced, the nesting of semipreg or prepreg appears to be critical. This work aims to develop a route for recycling semipreg offcuts, comprising shredding and compression moulding. This article focuses on an experimental study of the compression moulding step of carbon fibres reinforced PPS (C/PPS) to investigate the uniformity and impregnation quality of plates. These plates were realised in a picture frame while varying both the fibre volume content between 30% and 50% and the processing parameters. Visual inspection and cross-sectional microscopy were performed to assess the quality of each plate. As a first step, the influence of the type of added matrix (film, powder, pellets) and the type of pre-impregnation (film, powder) was studied. Stacking of polymer powder with shredded powder-coated semipreg gave the best impregnation quality. It was also shown that longer dwell time at melt leads to better consolidation quality. However, the difficulty in obtaining good impregnation comes from the disentangled shredded material, which is composed of three forms: semipreg flakes, dry bundles and pieces of matrix. When dry bundles reach the mould surfaces during the filling of the mould or when they are packed together, the consolidation cycle hardly impregnates them and they remain dry afterwards. Furthermore, large local variations of fibre fraction were noticed, resulting from a random mould filling. Therefore, the recycling solution for shredded semipreg is feasible when the fibre fraction is reduced but improvements on the part variability still have to be made.

Nonviral Vectors for Gene Delivery

NASA Astrophysics Data System (ADS)

Baoum, Abdulgader Ahmed

2011-12-01

The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,L-lactide- co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (˜200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. On the other hand, a more simple method to synthesize 50-200 nm complexes capable of high transfection efficiency or high gene knockdown was also explored. Positively charged CPPs were complexed with pDNA or siRNA, which resulted in 'loose' (˜1 micron) particles. These were then condensed into small nanoparticles by using calcium, which formed "soft" crosslinks by interacting with both phosphates on nucleic acids and amines on CPPs. An optimal amount of CaCl2 produced stable, ˜100 nm complexes that exhibited higher transfection efficiency and gene silencing than PEI polyplexes. CPPs also displayed negligible cytotoxicity up to 5 mg/mL. Biophysical studies of the pDNA structure within complexes suggested that pDNA within CPP complexes (condensed with calcium) had similar structure, but enhanced thermal stability compared to PEI complexes. Thus, CPP complexes emerged as simple, attractive candidates for future studies on nonviral gene delivery in vivo.

Non-pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Franco, Juan Va; Turk, Tarek; Jung, Jae Hung; Xiao, Yu-Tian; Iakhno, Stanislav; Garrote, Virginia; Vietto, Valeria

2018-01-26

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder in which the two main clinical features are pelvic pain and lower urinary tract symptoms. There are currently many approaches for its management, using both pharmacological and non-pharmacological interventions. The National Institute of Health - Chronic Prostatitis Symptom Index (NIH-CPSI) score is a validated measure commonly used to measure CP/CPPS symptoms. To assess the effects of non-pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was August 2017. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available non-pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence (QoE) according to the GRADE methods. We included 38 unique studies with 3290 men with CP/CPPS across 23 comparisons.1. Acupuncture: (three studies, 204 participants) based on short-term follow-up, acupuncture reduces prostatitis symptoms in an appreciable number of participants compared with sham procedure (mean difference (MD) in total NIH-CPSI score -5.79, 95% confidence interval (CI) -7.32 to -4.26, high QoE). Acupuncture likely results in little to no difference in adverse events (moderate QoE). It probably also decreases prostatitis symptoms compared with standard medical therapy in an appreciable number of participants (MD -6.05, 95% CI -7.87 to -4.24, two studies, 78 participants, moderate QoE).2. Circumcision: (one study, 713 participants) based on short-term follow-up, early circumcision probably decreases prostatitis symptoms slightly (NIH-CPSI score MD -3.00, 95% CI -3.82 to -2.18, moderate QoE) and may not be associated with a greater incidence of adverse events compared with control (a waiting list to be circumcised, low QoE).3. Electromagnetic chair: (two studies, 57 participants) based on short-term follow-up, we are uncertain of the effects of the use of an electromagnetic chair on prostatitis symptoms. It may be associated with a greater incidence of adverse events compared with sham procedure (low to very low QoE).4. Lifestyle modifications: (one study, 100 participants) based on short-term follow-up, lifestyle modifications may be associated with a greater improvement in prostatitis symptoms in an appreciable number of participants compared with control (risk ratio (RR) for improvement in NIH-CPSI scores 3.90, 95% CI 2.20 to 6.92, very low QoE). We found no information regarding adverse events.5. Physical activity: (one study, 85 participants) based on short-term follow-up, a physical activity programme may cause a small reduction in prostatitis symptoms compared with control (NIH-CPSI score MD -2.50, 95% CI -4.69 to -0.31, low QoE). We found no information regarding adverse events.6. Prostatic massage: (two studies, 115 participants) based on short-term follow-up, we are uncertain whether the prostatic massage reduces or increases prostatitis symptoms compared with control (very low QoE). We found no information regarding adverse events.7. Extracorporeal shockwave therapy: (three studies, 157 participants) based on short-term follow-up, extracorporeal shockwave therapy reduces prostatitis symptoms compared with control (NIH-CPSI score MD -6.18, 95% CI -7.46 to -4.89, high QoE). These results may not be sustained at medium-term follow-up (low QoE). This treatment may not be associated with a greater incidence of adverse events (low QoE).8. Transrectal thermotherapy compared to medical therapy: (two studies, 237 participants) based on short-term follow-up, transrectal thermotherapy alone or in combination with medical therapy may decrease prostatitis symptoms slightly when compared with medical therapy alone (NIH-CPSI score MD -2.50, 95% CI -3.82 to -1.18, low QoE). One included study reported that participants may experience transient adverse events.9. Other interventions: there is uncertainty about the effects of other interventions included in this review. We found no information regarding psychological support or prostatic surgery. Some of the interventions can decrease prostatitis symptoms in an appreciable number without a greater incidence of adverse events. The QoE was mostly low. Future clinical trials should include a full report of their methods including adequate masking, consistent assessment of all patient-important outcomes including potential treatment-related adverse events and appropriate sample sizes.

Nose-to-Brain Delivery of Peptide Drugs Enhanced by Coadministration of Cell-penetrating Peptides: Therapeutic Potential for Dementia.

PubMed

Kamei, Noriyasu

2017-01-01

Recent reports suggest that peptide drugs such as insulin have the potential to serve as therapeutics in neurodegenerative diseases such as Alzheimer's disease. However, the transport of these drugs to the therapeutic target, the brain, is significantly hindered by the blood-brain barrier (BBB). Intranasal administration appears to be an ideal solution for drug delivery to the brain, bypassing the BBB, however the entry of peptide drugs into neuronal and epithelial cells in the olfactory mucosa remains low. In this study, we therefore examined whether intranasal coadministration of cell-penetrating peptides (CPPs) could improve nose-to-brain drug transport. In both mice and rats, we found that direct transport of insulin into the brain was significantly facilitated when coadministered with amphipathic CPP penetratin, and eventually insulin reached the deeper regions of the brain such as the hippocampus. In the mouse line senescence-accelerated mouse prone-8 (SAMP8), spatial learning tests demonstrated that long-term intranasal coadministration of insulin with penetratin improved mild memory loss in the early stages of dementia. In contrast, the severe cognitive dysfunction in the aged SAMP8 mice was preserved despite intranasal coadministration of insulin with penetratin. The immunohistological examination of the hippocampus suggested that enhanced nose-to-brain delivery of insulin had a partial neuroprotective effect but unexpectedly increased amyloid β plaque deposition. In conclusion, intranasal coadministration of insulin with CPPs has the potential to serve as a therapeutic for mild cognitive dysfunction. To identify suitable pharmacotherapy for dementia with severe pathology, further studies of nose-to-brain delivery of molecularly appropriate biopharmaceuticals are necessary.

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

PubMed

Abes, Saïd; Moulton, Hong M; Clair, Philippe; Prevot, Paul; Youngblood, Derek S; Wu, Rebecca P; Iversen, Patrick L; Lebleu, Bernard

2006-12-01

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.

Generation of GFP Native Protein for Detection of Its Intracellular Uptake by Cell-Penetrating Peptides.

PubMed

Kadkhodayan, S; Sadat, S M; Irani, S; Fotouhi, F; Bolhassani, A

2016-01-01

Different types of lipid- and polymer-based vectors have been developed to deliver proteins into cells, but these methods showed relatively poor efficiency. Recently, a group of short, highly basic peptides known as cell-penetrating peptides (CPPs) were used to carry polypeptides and proteins into cells. In this study, expression and purification of GFP protein was performed using the prokaryotic pET expression system. We used two amphipathic CPPs (Pep-1 and CADY-2) as a novel delivery system to transfer the GFP protein into cells. The morphological features of the CPP/GFP complexes were studied by scanning electron microscopy (SEM), Zetasizer, and SDS-PAGE. The efficiency of GFP transfection using Pep-1 and CADY-2 peptides and TurboFect reagent was compared with FITC-antibody protein control delivered by these transfection vehicles in the HEK-293T cell line. SEM data confirmed formation of discrete nanoparticles with a diameter of below 300 nm. Moreover, formation of the complexes was detected using SDS-PAGE as two individual bands, indicating non-covalent interaction. The size and homogeneity of Pep-1/GFP and CADY-2/GFP complexes were dependent on the ratio of peptide/cargo formulations, and responsible for their biological efficiency. The cells transfected by Pep-1/GFP and CADY-2/GFP complexes at a molar ratio of 20 : 1 demonstrated spreading green regions using fluorescent microscopy. Flow cytometry results showed that the transfection efficiency of Pep-based nanoparticles was similar to CADY-based nanoparticles and comparable with TurboFect-protein complexes. These data open an efficient way for future therapeutic purposes.

A standard for terminology in chronic pelvic pain syndromes: A report from the chronic pelvic pain working group of the international continence society.

PubMed

Doggweiler, Regula; Whitmore, Kristene E; Meijlink, Jane M; Drake, Marcus J; Frawley, Helena; Nordling, Jørgen; Hanno, Philip; Fraser, Matthew O; Homma, Yukio; Garrido, Gustavo; Gomes, Mario J; Elneil, Sohier; van de Merwe, Joop P; Lin, Alex T L; Tomoe, Hikaru

2017-04-01

Terms used in the field of chronic pelvic pain (CPP) are poorly defined and often confusing. An International Continence Society (ICS) Standard for Terminology in chronic pelvic pain syndromes (CPPS) has been developed with the aim of improving diagnosis and treatment of patients affected by chronic pelvic pain syndromes. The standard aims to facilitate research, enhance therapy development and support healthcare delivery, for healthcare providers, and patients. This document looks at the whole person and all the domains (organ systems) in a systematic way. A dedicated working group (WG) was instituted by the ICS Standardisation Steering Committee according to published procedures. The WG extracted information from existing relevant guidelines, consensus documents, and scientific publications. Medline and other databases were searched in relation to each chronic pelvic pain domain from 1980 to 2014. Existing ICS Standards for terminology were utilized where appropriate to ensure transparency, accessibility, flexibility, and evolution. Consensus was based on majority agreement. The multidisciplinary CPPS Standard reports updated consensus terminology in nine domains; lower urinary tract, female genital, male genital, gastrointestinal, musculoskeletal, neurological aspects, psychological aspects, sexual aspects, and comorbidities. Each is described in terms of symptoms, signs and further evaluation. The document presents preferred terms and definitions for symptoms, signs, and evaluation (diagnostic work-up) of female and male patients with chronic pelvic pain syndromes, serving as a platform for ongoing development in this field. Neurourol. Urodynam. 36:984-1008, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Live Cell Genomics: RNA Exon-Specific RNA-Binding Protein Isolation.

PubMed

Bell, Thomas J; Eberwine, James

2015-01-01

RNA-binding proteins (RBPs) are essential regulatory proteins that control all modes of RNA processing and regulation. New experimental approaches to isolate these indispensable proteins under in vivo conditions are needed to advance the field of RBP biology. Historically, in vitro biochemical approaches to isolate RBP complexes have been useful and productive, but biological relevance of the identified RBP complexes can be imprecise or erroneous. Here we review an inventive experimental to isolate RBPs under the in vivo conditions. The method is called peptide nucleic acid (PNA)-assisted identification of RBP (PAIR) technology and it uses cell-penetrating peptides (CPPs) to deliver photo-activatible RBP-capture molecule to the cytoplasm of the live cells. The PAIR methodology provides two significant advantages over the most commonly used approaches: (1) it overcomes the in vitro limitation of standard biochemical approaches and (2) the PAIR RBP-capture molecule is highly selective and adaptable which allows investigators to isolate exon-specific RBP complexes. Most importantly, the in vivo capture conditions and selectivity of the RBP-capture molecule yield biologically accurate and relevant RBP data.

Applications of laser ultrasound NDT methods on composite structures in aerospace industry

NASA Astrophysics Data System (ADS)

Kalms, Michael; Focke, Oliver; v. Kopylow, Christoph

2008-09-01

Composite materials are used more and more in aircraft production. Main composite types are Carbon Fiber Reinforced Plastics (CFRP), Glass Fiber Reinforced Plastics (GFRP) and metal-aluminium laminates (e. g. Glass Fiber Aluminium Reinforced GLARE©). Typical parts made of CFRP material are flaps, vertical and horizontal tail planes, center wing boxes, rear pressure bulkheads, ribs and stringers. These composite parts require adequate nondestructive testing (NDT) methods. Flaws to be detected are delaminations and debondings, porosity and foreign body inclusion. Manual ultrasonic testing with single element transducers is still the most applied method for composite parts with small and medium size. The extension of the conventional ultrasound technique for nondestructive testing with the laser ultrasound method brings new possibilities into the production processes for example the inspection of complex CFRP-components and the possibilities of online observation under remote control. In this paper we describe the principle of laser ultrasound with respect to the demands of nondestructive testing especially of small complex CFRP and C/PPS parts. We report applications of laser-based ultrasound options with generated types of guided and bulk waves on modern aircraft materials.

Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by fluorescence correlation spectroscopy.

PubMed

Vasconcelos, Luís; Lehto, Tõnis; Madani, Fatemeh; Radoi, Vlad; Hällbrink, Mattias; Vukojević, Vladana; Langel, Ülo

2018-02-01

Peptides able to translocate cell membranes while carrying macromolecular cargo, as cell-penetrating peptides (CPPs), can contribute to the field of drug delivery by enabling the transport of otherwise membrane impermeable molecules. Formation of non-covalent complexes between amphipathic peptides and oligonucleotides is driven by electrostatic and hydrophobic interactions. Here we investigate and quantify the coexistence of distinct molecular species in multiple equilibria, namely peptide monomer, peptide self-aggregates and peptide/oligonucleotide complexes. As a model for the complexes, we used a stearylated peptide from the PepFect family, PF14 and siRNA. PF14 has a cationic part and a lipid part, resembling some characteristics of cationic lipids. Fluorescence correlation spectroscopy (FCS) and fluorescence cross-correlation spectroscopy (FCCS) were used to detect distinct molecular entities in solution and at the plasma membrane of live cells. For that, we labeled the peptide with carboxyrhodamine 6G and the siRNA with Cyanine 5. We were able to detect fluorescent entities with diffusional properties characteristic of the peptide monomer as well as of peptide aggregates and peptide/oligonucleotide complexes. Strategies to avoid peptide adsorption to solid surfaces and self-aggregation were developed and allowed successful FCS measurements in solution and at the plasma membrane. The ratio between the detected molecular species was found to vary with pH, peptide concentration and the proximity to the plasma membrane. The present results suggest that the diverse cellular uptake mechanisms, often reported for amphipathic CPPs, might result from the synergistic effect of peptide monomers, self-aggregates and cargo complexes, distributed unevenly at the plasma membrane. Copyright © 2017 Elsevier B.V. All rights reserved.

Chronic bacterial prostatitis and chronic pelvic pain syndrome.

PubMed

Bowen, Diana K; Dielubanza, Elodi; Schaeffer, Anthony J

2015-08-27

Chronic prostatitis can cause pain and urinary symptoms, and can occur either with an active infection (chronic bacterial prostatitis [CBP]) or with only pain and no evidence of bacterial causation (chronic pelvic pain syndrome [CPPS]). Bacterial prostatitis is characterised by recurrent urinary tract infections or infection in the prostate with the same bacterial strain, which often results from urinary tract instrumentation. However, the cause and natural history of CPPS are unknown and not associated with active infection. We conducted a systematic overview and aimed to answer the following clinical questions: What are the effects of treatments for chronic bacterial prostatitis? What are the effects of treatments for chronic pelvic pain syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). At this update, searching of electronic databases retrieved 131 studies. After deduplication and removal of conference abstracts, 67 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 51 studies and the further review of 16 full publications. Of the 16 full articles evaluated, three systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for 14 PICO combinations. In this systematic overview, we categorised the efficacy for 12 interventions based on information relating to the effectiveness and safety of 5 alpha-reductase inhibitors, allopurinol, alpha-blockers, local injections of antimicrobial drugs, mepartricin, non-steroidal anti-inflammatory drugs (NSAIDs), oral antimicrobial drugs, pentosan polysulfate, quercetin, sitz baths, transurethral microwave thermotherapy (TUMT), and transurethral resection of the prostate (TURP).

Therapeutic effect of melittin on a rat model of chronic prostatitis induced by Complete Freund's Adjuvant.

PubMed

Lin, Li; Zhu, Bao-Ping; Cai, Liang

2017-06-01

The present study was aimed to establish a model of chronic prostatitis in rat with the use of intraprostatic injection of Complete Freund's Adjuvant, and to examine the anti-inflammatory and analgesic effects of melittin on the newly-developed chronic prostatic pain model. Adult male Sprague-Dawley rats were injected with Complete Freund's Adjuvant (CFA) into the prostate. Twelve days after model rats of the treatment group were injected melittin into the prostate, while those of the control group received sterile saline injection. The nociceptive effects of CFA were evaluated by using a behavior approach (i.e. mechanical pain threshold measurement) on the day of CFA injection and 6, 12, and 18days after CFA injection. After the in-live study was done, the prostate was collected for histological examination of inflammatory cell infiltration. Levels of cyclooxygenase (COX)-2 in prostate and glial fibrillary acidic protein (GFAP) in spinal cord were determined using immunohistochemistry. Rats of the sham control group received intraprostatic injection of sterile saline and were studied using the same methods RESULTS: Intraprostatic CFA injection induced local allodynia that lasted over at least 2 weeks. The pain behavior of rat was associated with increases in inflammatory cell infiltration into the prostate. Levels of COX-2 in prostate and GFAP in spinal cord were also elevated. Treatment with melittin significantly raised pain threshold, decreased inflammatory infiltrates, and suppressed COX-2 and GFAP expression. Intraprostatic injection of CFA induced neurogenic prostatitis and prostatic pain. The established model will be useful to the study of CP/CPPS pathogenesis. Melittin demonstrated profound anti-inflammatory and analgesic effects on the chronic prostatic pain model, suggesting melittin may hold promise as a novel therapeutic for treatment of CP/CPPS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evidence for an ergot alkaloid gene cluster in Claviceps purpurea.

PubMed

Tudzynski, P; Hölter, K; Correia, T; Arntz, C; Grammel, N; Keller, U

1999-02-01

A gene (cpd1) coding for the dimethylallyltryptophan synthase (DMATS) that catalyzes the first specific step in the biosynthesis of ergot alkaloids, was cloned from a strain of Claviceps purpurea that produces alkaloids in axenic culture. The derived gene product (CPD1) shows only 70% similarity to the corresponding gene previously isolated from Claviceps strain ATCC 26245, which is likely to be an isolate of C. fusiformis. Therefore, the related cpd1 most probably represents the first C. purpurea gene coding for an enzymatic step of the alkaloid biosynthetic pathway to be cloned. Analysis of the 3'-flanking region of cpd1 revealed a second, closely linked ergot alkaloid biosynthetic gene named cpps1, which codes for a 356-kDa polypeptide showing significant similarity to fungal modular peptide synthetases. The protein contains three amino acid-activating modules, and in the second module a sequence is found which matches that of an internal peptide (17 amino acids in length) obtained from a tryptic digest of lysergyl peptide synthetase 1 (LPS1) of C. purpurea, thus confirming that cpps1 encodes LPS1. LPS1 activates the three amino acids of the peptide portion of ergot peptide alkaloids during D-lysergyl peptide assembly. Chromosome walking revealed the presence of additional genes upstream of cpd1 which are probably also involved in ergot alkaloid biosynthesis: cpox1 probably codes for an FAD-dependent oxidoreductase (which could represent the chanoclavine cyclase), and a second putative oxidoreductase gene, cpox2, is closely linked to it in inverse orientation. RT-PCR experiments confirm that all four genes are expressed under conditions of peptide alkaloid biosynthesis. These results strongly suggest that at least some genes of ergot alkaloid biosynthesis in C. purpurea are clustered, opening the way for a detailed molecular genetic analysis of the pathway.

Direct cytosolic delivery of cargoes in vivo by a chimera consisting of D- and L-arginine residues.

PubMed

Ma, Yan; Gong, Cheng; Ma, Yilong; Fan, Fengkai; Luo, Meijie; Yang, Fei; Zhang, Yu-Hui

2012-09-10

The ability of cell-penetrating peptides (CPPs) to deliver a range of membrane-impermeable molecules into living cells makes them attractive potential vehicles for therapeutics. However, in vivo, the efficiency of CPP delivery to the cytosol remains unsatisfactory owing to endosomal entrapment and/or systemic toxicity, which severely restrict their bioavailability and efficacy in in vivo applications. In this study, we developed a series of novel chimeras consisting of various numbers of d- and l-arginine residues and investigated their cellular uptake behaviors and systemic toxicities. We demonstrated that the intracellular distribution, uptake efficiency, and systemic toxicity of these oligoarginines were all significantly affected by the number of d-arginine residues in the peptide sequence. We also found that a hybrid peptide, (rR)(3)R(2), possessed low systemic toxicity, high uptake efficiency, and, remarkably, achieved efficient cytosolic delivery not only in cultured cells but also in living tissue cells in mice after intravenous injection, implying that this heterogeneous motif might have promising applications in the delivery of cargoes of small sizes directed to cytosolic targets in vivo. Our studies into the uptake mechanism of (rR)(3)R(2) indicate that its cellular uptake was not affected by pharmacological or physical inhibitors of endocytosis but by the elimination of the membrane potential, suggesting that (rR)(3)R(2) does not enter the cells via endocytosis but rather through direct membrane translocation driven by the membrane potential. The results here might provide useful guidelines for the design and application of CPPs in drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

Perceptual structure of adductor spasmodic dysphonia and its acoustic correlates.

PubMed

Cannito, Michael P; Doiuchi, Maki; Murry, Thomas; Woodson, Gayle E

2012-11-01

To examine the perceptual structure of voice attributes in adductor spasmodic dysphonia (ADSD) before and after botulinum toxin treatment and identify acoustic correlates of underlying perceptual factors. Reliability of perceptual judgments is considered in detail. Pre- and posttreatment trial with comparison to healthy controls, using single-blind randomized listener judgments of voice qualities, as well as retrospective comparison with acoustic measurements. Oral readings were recorded from 42 ADSD speakers before and after treatment as well as from their age- and sex-matched controls. Experienced judges listened to speech samples and rated attributes of overall voice quality, breathiness, roughness, and brokenness, using computer-implemented visual analog scaling. Data were adjusted for regression to the mean and submitted to principal components factor analysis. Acoustic waveforms, extracted from the reading samples, were analyzed and measurements correlated with perceptual factor scores. Four reliable perceptual variables of ADSD voice were effectively reduced to two underlying factors that corresponded to hyperadduction, most strongly associated with roughness, and hypoadduction, most strongly associated with breathiness. After treatment, the hyperadduction factor improved, whereas the hypoadduction factor worsened. Statistically significant (P<0.01) correlations were observed between perceived roughness and four acoustic measures, whereas breathiness correlated with aperiodicity and cepstral peak prominence (CPPs). This study supported a two-factor model of ADSD, suggesting perceptual characterization by both hyperadduction and hypoadduction before and after treatment. Responses of the factors to treatment were consistent with previous research. Correlations among perceptual and acoustic variables suggested that multiple acoustic features contributed to the overall impression of roughness. Although CPPs appears to be a partial correlate of perceived breathiness, a physical basis of this percept remained less clear. Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Rational Design of Porous Conjugated Polymers and Roles of Residual Palladium for Photocatalytic Hydrogen Production

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

Li, Lianwei; Cai, Zhengxu; Wu, Qinghe

Developing high efficient photocatalyts for splitting water into oxygen and hydrogen is one of the biggest chemical challenges in solar energy utilization. In this paper, we report our effort in rationally designing conjugated porous polymer (CPP) photocatalysts for photocatalytic hydrogen production (PHP) from water. A series of CPP photocatalysts with different chromophore components and bipyridyl (bpy) contents were synthesized and found to evolve hydrogen photocatalytically from water. The PHP activity of bpy-containing CPPs can be greatly enhanced due to the improved light absorption, better wettability, higher crystallinity and the improved charge separation process. Moreover, the CPP photocatalyst made of strongmore » and fully conjugated donor chromo-phore DBD shows the highest hydrogen production rate ~ 33 μmol/h. The results indicate that copolymerization between a strong donor and weak acceptor is a useful strategy for the devel-opment of efficient photocatalysts. This study clarifies that the residual palladium in the CPP networks plays a key role for the catalytic performance. The PHP activity of CPP photocatalyst can be further enhanced to 164 μmol/h with an apparent quantum yield of 1.8% at 350 nm by loading 2 wt% of extra platinum cocat-alyst.« less

Mitochondrial transit peptide exhibits cell penetration ability and efficiently delivers macromolecules to mitochondria.

PubMed

Jain, Aastha; Chugh, Archana

2016-09-01

Mitochondrial malfunction under various circumstances can lead to a variety of disorders. Effective targeting of macromolecules (drugs) is important for restoration of mitochondrial function and treatment of related disorders. We have designed a novel cell-penetrating mitochondrial transit peptide (CpMTP) for delivery of macromolecules to mitochondria. Comparison between properties of cell-penetrating peptides (CPPs) and mitochondrial signal sequences enabled prediction of peptides with dual ability for cellular translocation and mitochondrial localization. Among the predicted peptides, CpMTP translocates across HeLa cells and shows successful delivery of noncovalently conjugated cargo molecules to mitochondria. CpMTP may have applications in transduction and transfection of mitochondria for therapeutics. © 2016 Federation of European Biochemical Societies.

The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide.

PubMed

Michiue, Hiroyuki; Sakurai, Yoshinori; Kondo, Natsuko; Kitamatsu, Mizuki; Bin, Feng; Nakajima, Kiichiro; Hirota, Yuki; Kawabata, Shinji; Nishiki, Tei-ichi; Ohmori, Iori; Tomizawa, Kazuhito; Miyatake, Shin-ichi; Ono, Koji; Matsui, Hideki

2014-03-01

New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting. Copyright © 2013 Elsevier Ltd. All rights reserved.

CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis

PubMed Central

Quick, Marsha L.; Mukherjee, Soumi; Rudick, Charles N.; Done, Joseph D.; Schaeffer, Anthony J.

2012-01-01

Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2- to 3-fold, CCL8 by 15-fold, CCL12 by 12- to 13-fold, and CXCL9 by 2- to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1- to 2-fold), CCL3 (2- to 3-fold) and CCL11 (2- to 3-fold); and at 30 days, CCL12 (20- to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4+ T cells at day 20, and CD4+ and CD8+ T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2- and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP. PMID:22814670

Enhanced Cellular Uptake of Short Polyarginine Peptides through Fatty Acylation and Cyclization

PubMed Central

2015-01-01

Many of the reported arginine-rich cell-penetrating peptides (CPPs) for the enhanced delivery of drugs are linear peptides composed of more than seven arginine residues to retain the cell penetration properties. Herein, we synthesized a class of nine polyarginine peptides containing 5 and 6 arginines, namely, R5 and R6. We further explored the effect of acylation with long chain fatty acids (i.e., octanoic acid, dodecanoic acid, and hexadecanoic acid) and cyclization on the cell penetrating properties of the peptides. The fluorescence-labeled acylated cyclic peptide dodecanoyl-[R5] and linear peptide dodecanoyl-(R5) showed approximately 13.7- and 10.2-fold higher cellular uptake than that of control 5,6-carboxyfluorescein, respectively. The mechanism of the peptide internalization into cells was found to be energy-dependent endocytosis. Dodecanoyl-[R5] and dodecanoyl-[R6] enhanced the intracellular uptake of a fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI) in human ovarian cancer cells (SK-OV-3) by 3.4-fold and 5.5-fold, respectively, as shown by flow cytometry. The cellular uptake of F′-GpYEEI in the presence of hexadecanoyl-[R5] was 9.3- and 6.0-fold higher than that in the presence of octanoyl-[R5] and dodecanoyl-[R5], respectively. Dodecanoyl-[R5] enhanced the cellular uptake of the phosphopeptide by 1.4–2.5-fold higher than the corresponding linear peptide dodecanoyl-(R5) and those of representative CPPs, such as hepta-arginine (CR7) and TAT peptide. These results showed that a combination of acylation by long chain fatty acids and cyclization on short arginine-containing peptides can improve their cell-penetrating property, possibly through efficient interaction of rigid positively charged R and hydrophobic dodecanoyl moiety with the corresponding residues in the cell membrane phospholipids. PMID:24978295

Design of aromatic-containing cell-penetrating peptide mimics with structurally modified π electronics.

PubMed

deRonde, Brittany M; Birke, Alexander; Tew, Gregory N

2015-02-09

Cell-penetrating peptides (CPPs) and their synthetic mimics (CPPMs) represent a class of molecules that facilitate the intracellular delivery of various cargo. Previous studies indicated that the presence of aromatic functionalities improved CPPM activity. Given that aromatic functionalities play prominent roles in membrane biology and participate in various π interactions, we explored whether these interactions could be optimized for improved CPPM activity. CPPMs were synthesized by ring-opening metathesis polymerization by using monomers that contained aromatic rings substituted with electron-donating and electron-withdrawing groups and covered an electrostatic potential range from -29.69 to +15.57 kcal mol(-1) . These groups altered the quadrupole moments of the aromatic systems and were used to test if such structural modifications changed CPPM activity. CPPMs were added to dye-loaded vesicles and the release of carboxyfluorescein was monitored as a function of polymer concentration. Changes in the effective polymer concentration to release 50% of the dye (effective concentration, EC50 ) were monitored. Results from this assay showed that the strength of the electron-donating and electron-withdrawing groups incorporated in the CPPMs did not alter polymer EC50 values or activity. This suggests that other design parameters may have a stronger impact on CPPM activity. In addition, these results indicate that a wide range of aromatic groups can be incorporated without negatively impacting polymer activity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cell Penetrating Peptides and Cationic Antibacterial Peptides

PubMed Central

Rodriguez Plaza, Jonathan G.; Morales-Nava, Rosmarbel; Diener, Christian; Schreiber, Gabriele; Gonzalez, Zyanya D.; Lara Ortiz, Maria Teresa; Ortega Blake, Ivan; Pantoja, Omar; Volkmer, Rudolf; Klipp, Edda; Herrmann, Andreas; Del Rio, Gabriel

2014-01-01

Cell penetrating peptides (CPP) and cationic antibacterial peptides (CAP) have similar physicochemical properties and yet it is not understood how such similar peptides display different activities. To address this question, we used Iztli peptide 1 (IP-1) because it has both CPP and CAP activities. Combining experimental and computational modeling of the internalization of IP-1, we show it is not internalized by receptor-mediated endocytosis, yet it permeates into many different cell types, including fungi and human cells. We also show that IP-1 makes pores in the presence of high electrical potential at the membrane, such as those found in bacteria and mitochondria. These results provide the basis to understand the functional redundancy of CPPs and CAPs. PMID:24706763

Modulation of Endosomal Escape of IRQ-PEGylated Nano-carrier

NASA Astrophysics Data System (ADS)

Mudhakir, Diky; Akita, Hidetaka; Harashima, Hideyoshi

2011-12-01

The novel IRQ peptide is one of cell penetrating peptides (CPPs) that has ability to induce endosomal escape. It has been demonstrated that IRQ ligand had ability to facilitate an escape of liposomes encapsulating siRNA from the endosomes presumably by fusion-independent mechanism [1,2]. In the present study, we attempted to modulate the intracellular trafficking of IRQ-modified nano-carrier in term of escaping process by changing the lipid composition. The peptide was attached to the terminal end of maleimide group of polyethylene glycol-modified liposomes (IRQ-PEG-Lip). The liposomes were composed of DOTAP, DOPE and cholesterol and it was labeled by water soluble sulpho-rhodamine B (Sr-B). The escape of PEG-coated liposomes was then observed by confocal laser scanning microscope after the endosomes were stained with Lysosensor. The results exhibited that IRQ-PEG-Lip was escaped from endosomal compartment after 1 h transfection when 40% of DOPE was incorporated into the nanostructure comparing to that of PEG-Lip. These results are consistent with the previous results that the IRQ facilitates endosomal escape via independent-mechanism. However, IRQ-PEG-Lip were then completely co-localized in the acidic compartment when density of DOPE was reduced approximately 20%. These results indicated that the utilizing of DOPE is important for the escape process even in the presence of hydrophilic PEG polymer. In conclusion, the regulation of endosomal escape ability of the PEGylated-IRQ nano-carrier was induced by fusion-independent manner as well as fusogenic lipid.

Cell penetrating peptide-modified poly(lactic-co-glycolic acid) nanoparticles with enhanced cell internalization.

PubMed

Steinbach, Jill M; Seo, Young-Eun; Saltzman, W Mark

2016-01-01

The surface modification of nanoparticles (NPs) can enhance the intracellular delivery of drugs, proteins, and genetic agents. Here we studied the effect of different surface ligands, including cell penetrating peptides (CPPs), on the cell binding and internalization of poly(lactic-co-glycolic) (PLGA) NPs. Relative to unmodified NPs, we observed that surface-modified NPs greatly enhanced cell internalization. Using one CPP, MPG (unabbreviated notation), that achieved the highest degree of internalization at both low and high surface modification densities, we evaluated the effect of two different NP surface chemistries on cell internalization. After 2h, avidin-MPG NPs enhanced cellular internalization by 5 to 26-fold relative to DSPE-MPG NP formulations. Yet, despite a 5-fold increase in MPG density on DSPE compared to Avidin NPs, both formulations resulted in similar internalization levels (48 and 64-fold, respectively) after 24h. Regardless of surface modification, all NPs were internalized through an energy-dependent, clathrin-mediated process, and became dispersed throughout the cell. Overall both Avidin- and DSPE-CPP modified NPs significantly increased internalization and offer promising delivery options for applications in which internalization presents challenges to efficacious delivery. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Enrichment of naturally occurring radionuclides and trace elements in Yatagan and Yenikoy coal-fired thermal power plants, Turkey.

PubMed

Ozden, Banu; Guler, Erkan; Vaasma, Taavi; Horvath, Maria; Kiisk, Madis; Kovacs, Tibor

2018-08-01

Coal, residues and waste produced by the combustion of the coal contain naturally occurring radionuclides such as 238 U, 226 Ra, 210 Pb, 232 Th and 40 K and trace elements such as Cd, Cr, Pb, Ni and Zn. In this work, coal and its combustion residues collected from Yatagan and Yenikoy coal fired thermal power plants (CPPs) in Turkey were studied to determine the concentrations of natural radionuclides and trace elements, and their enrichments factors to better understand the radionuclide concentration processes within the combustion system. In addition, the utilization of coal fly ash as a secondary raw material in building industry was also studied in terms of radiological aspects. Fly ash samples were taken at different stages along the emission control system of the thermal power plants. Activity concentrations of naturally occurring radionuclides were determined with Canberra Broad Energy Germanium (BEGe) detector BE3830-P and ORTEC Soloist PIPS type semiconductor detector. The particle size distribution and trace elements contents were determined in various ash fractions by the laser scattering particle size distribution analyzer and inductively coupled plasma (ICP-OES). From the obtained data, natural radionuclides tend to condense on fly ash with and the activity concentrations increase as the temperature drop in CPPs. Measured 210 Pb and 210 Po concentration varied between 186 ± 20-1153 ± 44 Bq kg -1 , and 56 ± 5-1174 ± 45 Bq kg -1 , respectively. The highest 210 Pb and 210 Po activity concentrations were determined in fly ash taken from the temporary storage point as 1153 ± 44 Bq kg -1 and 1174 ± 45 Bq kg -1 , respectively. There were significant differences in the activity concentrations of some natural radionuclide and trace elements (Pb and Zn) contents in ash fractions among the sampling point inside both of the plants (ANOVA, p < 0.001). Coal and ash sample analysis showed an increase activity concentration and enrichment factors towards the electrostatic precipitators for both of the power plants. The enrichment factors for Zn follow a similar trend as Pb, increasing in value towards the end of the emission control system. The calculated activity indexes were above 1.0 value for both of the power plants, assuming the utilization of fly ash at 100%. It can be concluded that the reuse of fly ash as a secondary raw material may not be hazardous depending on the percentage of utilization of ash. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical study of duloxetine hydrochloride combined with doxazosin for the treatment of pain disorder in chronic prostatitis/chronic pelvic pain syndrome: An observational study.

PubMed

Zhang, Mingxin; Li, Hanzhong; Ji, Zhigang; Dong, Dexin; Yan, Su

2017-03-01

To explore the safety and efficacy of the selective 5-serotonin and norepinephrine reuptake inhibitor duloxetine hydrochloride and alpha-adrenergic receptor blocker (alpha-blocker) doxazosin mesylate-controlled tablets in the treatment of pain disorder in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).In all, 150 patients were enrolled and 126 patients completed the study (41 patients in the doxazosin group, 41 patients in the sertraline group, and 44 patients in the duloxetine group). This was an open randomized 6-month study. CP/CPPS patients who met the diagnostic criteria were randomized into 3 groups. The patients in the duloxetine group received doxazosin 4 mg + duloxetine 30 mg once a day, and the dosage of duloxetine was increased to 60 mg after a week. The patients in the doxazosin group received doxazosin 4 mg once a day. The patients in the sertraline group received doxazosin 4 mg + sertraline 50 mg once a day. National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, the short-form McGill Pain questionnaire (SF-MPQ), and the hospital anxiety and depression scale (HAD) were applied for evaluations during follow-up of 1, 3, and 6 months after treatment.There were slight positive significant correlations between NIH-CPSI scores and HAD scores, moderate positive significant correlations between the quality of life (QOL) and SF-MPQ, and slight positive significant correlations between HAD and QOL. The effective rate in the doxazosin group was 4.88%, 19.51%, and 56.10% after 1, 3, and 6 months, respectively (P < 0.05). The SF-MPQ score in the doxazosin group decreased to 1.80 ± 1.29, 2.66 ± 1.57, and 3.24 ± 1.67 after 1, 3, and 6 months, respectively (P < 0.05). The HAD score in the doxazosin group decreased to 2.24 ± 2.17, 4 ± 2.11, and 4.90 ± 2.62 after 1, 3, and 6 months, respectively (P < 0.05). The effective rate in the sertraline group was 9.76%, 36.59%, and 63.41% after 1, 3, and 6 months, respectively. The SF-MPQ score in the sertraline group decreased to 1.76 ± 1.28, 3.07 ± 2, and 3.93 ± 2.53 after 1, 3, and 6 months, respectively (P < 0.05). The HAD score in the sertraline group decreased to 3.56 ± 4.11, 5.73 ± 5.26, and 7.27 ± 6.50 after 1, 3, and 6 months, respectively (P < 0.05). The effective rate in the duloxetine group was 36.36%, 88.64%, and 88.64% after 1, 3, and 6 months, respectively. The SF-MPQ score in the duloxetine group decreased to 3.61 ± 2.54, 6.05 ± 3.66, and 7.41 ± 4.26 after 1, 3, and 6 months, respectively (P < 0.05). The HAD score in the duloxetine group decreased to 3.14 ± 3.28, 6.93 ± 3.90, and 9.43 ± 4.67 after 1, 3, and 6 months, respectively (P < 0.05). There were significant differences in the reduction of the NIH-CPSI score and the SF-MPQ score between the duloxetine group and the sertraline group and between the duloxetine group and the doxazosin group (P < 0.01). There were significant differences in the reduction of the HAD score at 3 months between the duloxetine group and the doxazosin group, and there were significant differences in the reduction of the HAD score at 6 months among the groups (P < 0.05). The incidence rates of adverse reactions in the duloxetine group, the sertraline group, and the duloxetine group were 29.5%, 17%, and 7.3%, respectively, with adverse events ranging from mild to moderate.There was a clear relationship between the extent of pain and mental factors in CP/CPPS with the main symptom of pain. Doxazosin combined with duloxetine exhibited good safety and efficacy in the treatment of pain disorder in CP/CPPS.

Magnetorheological Finishing for Imprinting Continuous Phase Plate Structure onto Optical Surfaces

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

Menapace, J A; Dixit, S N; Genin, F Y

2004-01-05

Magnetorheological finishing (MRF) techniques have been developed to manufacture continuous phase plates (CPP's) and custom phase corrective structures on polished fused silica surfaces. These phase structures are important for laser applications requiring precise manipulation and control of beam-shape, energy distribution, and wavefront profile. The MRF's unique deterministic-sub-aperture polishing characteristics make it possible to imprint complex topographical information onto optical surfaces at spatial scale-lengths approaching 1 mm. In this study, we present the results of experiments and model calculations that explore imprinting two-dimensional sinusoidal structures. Results show how the MRF removal function impacts and limits imprint fidelity and what must bemore » done to arrive at a high quality surface. We also present several examples of this imprinting technology for fabrication of phase correction plates and CPPs for use at high fluences.« less

Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis.

PubMed

Nakase, Ikuhiko; Noguchi, Kosuke; Fujii, Ikuo; Futaki, Shiroh

2016-10-17

Extracellular vesicles (EVs, exosomes) are approximately 30- to 200-nm-long vesicles that have received increased attention due to their role in cell-to-cell communication. Although EVs are highly anticipated to be a next-generation intracellular delivery tool because of their pharmaceutical advantages, including non-immunogenicity, their cellular uptake efficacy is low because of the repulsion of EVs and negatively charged cell membranes and size limitations in endocytosis. Here, we demonstrate a methodology for achieving enhanced cellular EV uptake using arginine-rich cell-penetrating peptides (CPPs) to induce active macropinocytosis. The induction of macropinocytosis via a simple modification to the exosomal membrane using stearylated octaarginine, which is a representative CPP, significantly enhanced the cellular EV uptake efficacy. Consequently, effective EV-based intracellular delivery of an artificially encapsulated ribosome-inactivating protein, saporin, in EVs was attained.

Prevalence, types, and geographical distribution of Listeria monocytogenes from a survey of retail Queso Fresco and associated cheese processing plants and dairy farms in Sonora, Mexico.

PubMed

Moreno-Enriquez, R I; Garcia-Galaz, A; Acedo-Felix, E; Gonzalez-Rios, I H; Call, J E; Luchansky, J B; Diaz-Cinco, M E

2007-11-01

In the first part of this study, samples were collected from farms, cheese processing plants (CPPs), and retail markets located in various geographical areas of Sonora, Mexico, over a 12-month period during the summer of 2004 and winter of 2005. Four (all Queso Fresco [QF] from retail markets) of 349 total samples tested positive for Listeria monocytogenes (Lm). Of these four positive samples, three were collected in the northern region and one in the southern region of Sonora. Additionally, two were collected during the winter months, and two were collected during the summer months. For the second part of the study, a total of 39 samples from a farm, a CPP, and retail markets were collected and processed according to a combination of the Norma Oficial Mexicana NOM-143-SSA1-1995.10 method (NOM) and the U.S. Food and Drug Administration (FDA) Bacteriological Analytical Manual method, and 27 samples from these same locations were collected and processed according to the U.S. Department of Agriculture Food Safety and Inspection Service method (USDA-FSIS). The NOM-FDA method recovered the pathogen from 6 (15%) of 39 samples (one cheese and five product contact surfaces), while the USDA-FSIS method recovered the pathogen from 5 (18.5%) of 27 samples (all product contact surfaces). In addition, the 40 isolates recovered from the 15 total samples that tested positive for Lm grouped into five distinct pulsotypes that were ca. 60% related, as determined by pulsed-field gel electrophoresis analysis. The results of this study confirmed a 3.4% prevalence of Lm in QF collected from retail markets located in Sonora and no appreciable difference in the effectiveness of either the NOM-FDA or USDA-FSIS method to recover the pathogen from cheese or environmental samples.

Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application

PubMed Central

Wang, Yinsong; Liu, Quan; Chung, Hee Sun; Kwon, Young Min; Shin, Meong Cheol; Lee, Kyuri; Yang, Victor C

2014-01-01

Red blood cells (RBCs) based drug carrier appears to be the most appealing for protein drugs due to their unmatched biocompatability, biodegradability, and long lifespan in the circulation. Numerous methods for encapsulating protein drugs into RBCs were developed, however, most of them induce partial disruption of the cell membrane, resulting in irreversible alterations in both physical and chemical properties of RBCs. Herein, we introduce a novel method for encapsulating proteins into intact RBCs, which was meditated by a cell penetrating peptide (CPP) developed in our lab—low molecular weight protamine (LMWP). L-asparaginase, one of the primary drugs used in treatment of acute lymphoblastic leukemia (ALL), was chosen as a model protein to illustrate the encapsulation into erythrocytes mediated by CPPs. In addition current treatment of ALL using different L-asparaginase delivery and encapsulation methods as well as their associated problems were also reviewed. PMID:24374002

Peptides Displayed as High Density Brush Polymers Resist Proteolysis and Retain Bioactivity

PubMed Central

2015-01-01

We describe a strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers. The utility of this approach is demonstrated by polymerizing well-established cell-penetrating peptides (CPPs) and showing that the resulting polymers are not only resistant to proteolysis but also maintain their ability to enter cells. The scope of this design concept is explored by studying the proteolytic resistance of brush polymers composed of peptides that are substrates for either thrombin or a metalloprotease. Finally, we demonstrate that the proteolytic susceptibility of peptide brush polymers can be tuned by adjusting the density of the polymer brush and offer in silico models to rationalize this finding. We contend that this strategy offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility. PMID:25314576

Cationic cell-penetrating peptide binds to planar lipid bilayers containing negatively charged lipids but does not induce conductive pores.

PubMed

Gurnev, Philip A; Yang, Sung-Tae; Melikov, Kamran C; Chernomordik, Leonid V; Bezrukov, Sergey M

2013-05-07

Using a cation-selective gramicidin A channel as a sensor of the membrane surface charge, we studied interactions of oligoarginine peptide R9C, a prototype cationic cell-penetrating peptide (CPP), with planar lipid membranes. We have found that R9C sorption to the membrane depends strongly on its lipid composition from virtually nonexistent for membranes made of uncharged lipids to very pronounced for membranes containing negatively charged lipids, with charge overcompensation at R9C concentrations exceeding 1 μM. The sorption was reversible as it was removed by addition of polyanionic dextran sulfate to the membrane bathing solution. No membrane poration activity of R9C (as would be manifested by increased bilayer conductance) was detected in the charged or neutral membranes, including those with asymmetric negative/neutral and negative/positive lipid leaflets. We conclude that interaction of R9C with planar lipid bilayers does not involve pore formation in all studied lipid combinations up to 20 μM peptide concentration. However, R9C induces leakage of negatively charged but not neutral liposomes in a process that involves lipid mixing between liposomes. Our findings suggest that direct traversing of CPPs through the uncharged outer leaflet of the plasma membrane bilayer is unlikely and that permeabilization necessarily involves both anionic lipids and CPP-dependent fusion between opposing membranes. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Cell-penetrating peptides meditated encapsulation of protein therapeutics into intact red blood cells and its application.

PubMed

He, Huining; Ye, Junxiao; Wang, Yinsong; Liu, Quan; Chung, Hee Sun; Kwon, Young Min; Shin, Meong Cheol; Lee, Kyuri; Yang, Victor C

2014-02-28

Red blood cells (RBCs) based drug carrier appears to be the most appealing for protein drugs due to their unmatched biocompatability, biodegradability, and long lifespan in the circulation. Numerous methods for encapsulating protein drugs into RBCs were developed, however, most of them induce partial disruption of the cell membrane, resulting in irreversible alterations in both physical and chemical properties of RBCs. Herein, we introduce a novel method for encapsulating proteins into intact RBCs, which was meditated by a cell penetrating peptide (CPP) developed in our lab-low molecular weight protamine (LMWP). l-asparaginase, one of the primary drugs used in treatment of acute lymphoblastic leukemia (ALL), was chosen as a model protein to illustrate the encapsulation into erythrocytes mediated by CPPs. In addition current treatment of ALL using different l-asparaginase delivery and encapsulation methods as well as their associated problems were also reviewed. Copyright © 2013 Elsevier B.V. All rights reserved.

A viral peptide for intracellular delivery

NASA Astrophysics Data System (ADS)

Falanga, Annarita; Tarallo, Rossella; Cantisani, Marco; Della Pepa, Maria Elena; Galdiero, Massimiliano; Galdiero, Stefania

2012-10-01

Biological membranes represent a critical hindrance for administering active molecules which are often unable to reach their designated intracellular target sites. In order to overcome this barrier-like behavior not easily circumvented by many pharmacologically-active molecules, synthetic transporters have been exploited to promote cellular uptake. Linking or complexing therapeutic molecules to peptides that can translocate through the cellular membranes could enhance their internal delivery, and consequently, a higher amount of active compound would reach the site of action. Use of cell penetrating peptides (CPPs) is one of the most promising strategy to efficiently translocate macromolecules through the plasma membrane, and have attracted a lot of attention. New translocating peptides are continuously described and in the present review, we will focus on viral derived peptides, and in particular a peptide (gH625) derived from the herpes simplex virus type 1 (HSV-1) glycoprotein H (gH) that has proved to be a useful delivery vehicle due to its intrinsic properties of inducing membrane perturbation.

CPP-Assisted Intracellular Drug Delivery, What Is Next?

PubMed Central

Ye, Junxiao; Liu, Ergang; Yu, Zhili; Pei, Xing; Chen, Sunhui; Zhang, Pengwei; Shin, Meong-Cheol; Gong, Junbo; He, Huining; Yang, Victor C.

2016-01-01

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology. PMID:27854260

Increased bone morphogenetic protein 7 signalling in the kidneys of dogs affected with a congenital portosystemic shunt.

PubMed

van Dongen, Astrid M; Heuving, Susanne M; Tryfonidou, Marianna A; van Steenbeek, Frank G; Rothuizen, Jan; Penning, Louis C

2015-05-01

Dogs with a congenital portosystemic shunt (CPSS) often have enlarged and hyper-filtrating kidneys. Although expression of different growth factors has been well-described in the livers of dogs affected with a CPSS, their expression in the kidneys has yet to be determined. Bone morphogenetic protein 7 (BMP-7), hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β have been implicated in renal development (BMP-7, HGF) or the onset of renal fibrosis (TGF-β). Moreover, BMP-7 and HGF have protective properties in renal fibrosis. In this study, the expression and activity of BMP-7 were investigated in renal biopsies obtained from 13 dogs affected with a CPSS and compared to similar samples from age-matched healthy control dogs. Both quantitative reverse-transcriptase PCR and Western blotting showed up-regulated BMP-7 signalling in kidneys of CPPS-affected dogs. These research findings may help to explain the renal pathology/dysfunction in dogs affected with a CPSS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents.

PubMed

Cho, Choi-Fong; Wolfe, Justin M; Fadzen, Colin M; Calligaris, David; Hornburg, Kalvis; Chiocca, E Antonio; Agar, Nathalie Y R; Pentelute, Bradley L; Lawler, Sean E

2017-06-06

Culture-based blood-brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robust in vitro BBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics.

CPP-Assisted Intracellular Drug Delivery, What Is Next?

PubMed

Ye, Junxiao; Liu, Ergang; Yu, Zhili; Pei, Xing; Chen, Sunhui; Zhang, Pengwei; Shin, Meong-Cheol; Gong, Junbo; He, Huining; Yang, Victor C

2016-11-14

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology.

Caspase-Activated Cell-Penetrating Peptides Reveal Temporal Coupling Between Endosomal Release and Apoptosis in an RGC-5 Cell Model

PubMed Central

Johnson, James R.; Kocher, Brandon; Barnett, Edward M.; Marasa, Jayne; Piwnica-Worms, David

2012-01-01

Caspase-activatable cell-penetrating peptide (CPP) probes, designed for efficient cell uptake and specificity via cleavable intramolecular quenched-fluorophore strategies, show promise for identifying and imaging retinal ganglion cell apoptosis in vivo. However, initial cell uptake and trafficking events cannot be visualized because the probes are designed to be optically quenched in the intact state. To visualize subcellular activation events in real-time during apoptosis, a new series of matched quenched and non-quenched CPP probes were synthesized. In both native and staurosporine-differentiated RGC-5 cells, probe uptake was time- and concentration-dependent through clathrine-, caveolin- and pinocytosis-mediated endocytic mechanisms. During apoptosis, KcapTR488, a novel dual fluorophore CPP probe, revealed by multi-spectral imaging a temporal coupling of endosomal release and effector caspase activation in RGC-5 cells. The novel CPPs described herein provide new tools to study spatial and temporal regulation of endosomal permeability during apoptosis. PMID:22900707

Translocation and Endocytosis for Cell-penetrating Peptide Internalization

PubMed Central

Jiao, Chen-Yu; Delaroche, Diane; Burlina, Fabienne; Alves, Isabel D.; Chassaing, Gérard; Sagan, Sandrine

2009-01-01

Cell-penetrating peptides (CPPs) share the property of cellular internalization. The question of how these peptides reach the cytoplasm of cells is still widely debated. Herein, we have used a mass spectrometry-based method that enables quantification of internalized and membrane-bound peptides. Internalization of the most used CPP was studied at 37 °C (endocytosis and translocation) and 4 °C (translocation) in wild type and proteoglycan-deficient Chinese hamster ovary cells. Both translocation and endocytosis are internalization pathways used by CPP. The choice of one pathway versus the other depends on the peptide sequence (not the number of positive changes), the extracellular peptide concentration, and the membrane components. There is no relationship between the high affinity of these peptides for the cell membrane and their internalization efficacy. Translocation occurs at low extracellular peptide concentration, whereas endocytosis, a saturable and cooperative phenomenon, is activated at higher concentrations. Translocation operates in a narrow time window, which implies a specific lipid/peptide co-import in cells. PMID:19833724

Switching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides.

PubMed

Favaro, Marianna Teixeira de Pinho; Serna, Naroa; Sánchez-García, Laura; Cubarsi, Rafael; Roldán, Mónica; Sánchez-Chardi, Alejandro; Unzueta, Ugutz; Mangues, Ramón; Ferrer-Miralles, Neus; Azzoni, Adriano Rodrigues; Vázquez, Esther; Villaverde, Antonio

2018-05-16

Arginine-rich protein motifs have been described as potent cell-penetrating peptides (CPPs) but also as rather specific ligands of the cell surface chemokine receptor CXCR4, involved in the infection by the human immunodeficiency virus (HIV). Polyarginines are commonly used to functionalize nanoscale vehicles for gene therapy and drug delivery, aimed to enhance cell penetrability of the therapeutic cargo. However, under which conditions these peptides do act as either unspecific or specific ligands is unknown. We have here explored the cell penetrability of differently charged polyarginines in two alternative presentations, namely as unassembled fusion proteins or assembled in multimeric protein nanoparticles. By this, we have observed that arginine-rich peptides switch between receptor-mediated and receptor-independent mechanisms of cell penetration. The relative weight of these activities is determined by the electrostatic charge of the construct and the oligomerization status of the nanoscale material, both regulatable by conventional protein engineering approaches. Copyright © 2018 Elsevier Inc. All rights reserved.

Design, synthesis, and functional testing of recombinant cell penetrating peptides

NASA Astrophysics Data System (ADS)

Widyaningtyas, S. T.; Soebandrio, A.; Ibrahim, F.; Bela, B.

2017-08-01

Cell penetrating peptides (CPP) are one of the most attractive DNA delivery systems currently in development. In this research, in silico CPP development was performed based on a literature study to look for peptides that induce endosome escape, have the ability to bind DNA, and pass through cell membranes and/or nuclear membranes with a final goal of creating a new CPP to be used as a DNA delivery system. We report herein the successful isolation of three candidate CPP molecules, which have all been successfully expressed and purified by NiNTA. One of the determinants of CPP success as a DNA carrier is the ability of the CPP to bind and protect DNA from the effects of nucleases. The DNA binding test results show that all three CPPs can bind to DNA and protect it from the effects of serum nucleases. These three CPP candidates designed in silico and synthesized in the prokaryote system are eligible candidates for further testing of their ability to deliver DNA in vitro and in vivo.

Transportan 10 improves the anticancer activity of cisplatin.

PubMed

Izabela, Rusiecka; Jarosław, Ruczyński; Magdalena, Alenowicz; Piotr, Rekowski; Ivan, Kocić

2016-05-01

The aim of this paper was to examine whether cell-penetrating peptides (CPPs) such as transportan 10 (TP10) or protein transduction domain (PTD4) may improve the anticancer activity of cisplatin (cPt). The complexes of TP10 or PTD4 with cPt were used in the experiments. They were carried out on two non-cancer (HEK293 (human embryonic kidney) and HEL299 (human embryo lung)) and two cancer (HeLa (human cervical cancer) and OS143B (human osteosarcoma 143B)) cell lines. Both complexes were tested (MTT assay) with respect to their anticancer or cytotoxic actions. TAMRA (fluorescent dye)-stained preparations were visualized in a fluorescence microscope. The long-term effect of TP10 + cPt and its components on non-cancer and cancer cell lines was observed in inverted phase contrast microscopy. In the MTT test (cell viability assay), the complex of TP10 + cPt produced a more potent effect on the cancer cell lines (HeLa, OS143B) in comparison to that observed after separate treatment with TP10 or cPt. At the same time, the action of the complex and its components was rather small on non-cancer cell lines. On the other hand, a complex of another CPP with cPt, i.e., PTD4 + cPt, was without a significant effect on the cancer cell line (OS143B). The images of the fluorescent microscopy showed TAMRA-TP10 or TAMRA-TP10 + cPt in the interior of the HeLa cells. In the case of TAMRA-PTD4 or TAMRA-PTD4 + cPt, only the first compound was found inside the cancer cell line. In contrast, none of the tested compounds gained access to the interior of the non-cancer cells (HEK293, HEL299). Long-term incubation with the TP10 + cPt (estimated by inverted phase contrast microscopy) lead to an enhanced action of the complex on cell viability (decrease in the number of cells and change in their morphology) as compared with that produced by each single agent. With regard to the tested CPPs, only TP10 improved the anticancer activity of cisplatin if both compounds were used in the form of a complex. Additionally, the complex was relatively safe for non-cancer cells. What is more, TP10 also produced an anticancer effect on HeLa and OS143B cell lines.

Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency.

PubMed

Yin, Haifang; Boisguerin, Prisca; Moulton, Hong M; Betts, Corinne; Seow, Yiqi; Boutilier, Jordan; Wang, Qingsong; Walsh, Anthony; Lebleu, Bernard; Wood, Matthew Ja

2013-09-24

We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO) and control peptide 3 (B-3-PMO and 3-B-PMO) were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO) was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG), indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.Molecular Therapy-Nucleic Acids (2013) 2, e124; doi:10.1038/mtna.2013.51; published online 24 September 2013.

Optimisation of shock absorber process parameters using failure mode and effect analysis and genetic algorithm

NASA Astrophysics Data System (ADS)

Mariajayaprakash, Arokiasamy; Senthilvelan, Thiyagarajan; Vivekananthan, Krishnapillai Ponnambal

2013-07-01

The various process parameters affecting the quality characteristics of the shock absorber during the process were identified using the Ishikawa diagram and by failure mode and effect analysis. The identified process parameters are welding process parameters (squeeze, heat control, wheel speed, and air pressure), damper sealing process parameters (load, hydraulic pressure, air pressure, and fixture height), washing process parameters (total alkalinity, temperature, pH value of rinsing water, and timing), and painting process parameters (flowability, coating thickness, pointage, and temperature). In this paper, the process parameters, namely, painting and washing process parameters, are optimized by Taguchi method. Though the defects are reasonably minimized by Taguchi method, in order to achieve zero defects during the processes, genetic algorithm technique is applied on the optimized parameters obtained by Taguchi method.

Endoscopic monoportal removal of a choroid plexus papilloma in the posterior third ventricle in a child.

PubMed

Sufianov, Albert A; Gaibov, Saidi S K; Sufianov, Rinat A

2015-07-01

Currently, only a few reports describe the minimally invasive removal of choroid plexus papillomas (CPPs) and, to the best of the authors' knowledge, no reports detail the resection of such a papilloma through an endoscopic approach in infants. The authors here describe the endoscopic removal of a third ventricle CPP in a child. A 5-month-old male infant presented with progressive macrocephaly, vomiting, and convulsions. A lesion in the posterior third ventricle was detected on brain MRI. Because of the patient's very young age, neuroendoscopy was used as the least invasive technique. The tumor was completely resected through a monoportal neuroendoscopic approach. Histologically, the tumor was classified as a WHO Grade I CPP. After surgery, the patient's condition improved, with no complications during his recovery. Ten-month follow-up neuroimaging revealed no evidence of tumor recurrence or progressive hydrocephaly. In view of the successful neuroendoscopic excision of this posterior third ventricle CPP, the authors believe that this method seems promising in the treatment of young children with intraventricular lesions.

Caseinophosphopeptides released after tryptic hydrolysis versus simulated gastrointestinal digestion of a casein-derived by-product.

PubMed

Cruz-Huerta, E; García-Nebot, M J; Miralles, B; Recio, I; Amigo, L

2015-02-01

The production of caseinophosphopeptides from a casein-derived by-product generated during the manufacture of a functional ingredient based on antihypertensive peptides was attempted. The casein by-product was submitted to tryptic hydrolysis for 30, 60 and 120min and further precipitated with calcium chloride and ethanol at pH 4.0, 6.0 and 8.0. Identification and semi quantification of the derived products by tandem mass spectrometry revealed some qualitative and quantitative changes in the released caseinophosphopeptides over time at the different precipitation pHs. The by-product was also subjected to simulated gastrointestinal digestion. Comparison of the resulting peptides showed large sequence homology in the phosphopeptides released by tryptic hydrolysis and simulated gastrointestinal digestion. Some regions, specifically αS1-CN 43-59, αS1-CN 60-74, β-CN 1-25 and β-CN 30-50 showed resistance to both tryptic hydrolysis and simulated digestion. The results of the present study suggest that this casein-derived by-product can be used as a source of CPPs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

PubMed Central

Grabowski, Benjamin; Schmidt, M. Alexander; Rüter, Christian

2017-01-01

ABSTRACT Human-pathogenic Yersinia produce plasmid-encoded Yersinia outer proteins (Yops), which are necessary to down-regulate anti-bacterial responses that constrict bacterial survival in the host. These Yops are effectively translocated directly from the bacterial into the target cell cytosol by the type III secretion system (T3SS). Cell-penetrating peptides (CPPs) in contrast are characterized by their ability to autonomously cross cell membranes and to transport cargo – independent of additional translocation systems. The recent discovery of bacterial cell-penetrating effector proteins (CPEs) – with the prototype being the T3SS effector protein YopM – established a new class of autonomously translocating immunomodulatory proteins. CPEs represent a vast source of potential self-delivering, anti-inflammatory therapeutics. In this review, we give an update on the characteristic features of the plasmid-encoded Yops and, based on recent findings, propose the further development of these proteins for potential therapeutic applications as natural or artificial cell-penetrating forms of Yops might be of value as bacteria-derived biologics. PMID:28296562

Simultaneously tracing the geographical origin and presence of bovine milk in Italian water buffalo Mozzarella cheese using MALDI-TOF data of casein signature peptides.

PubMed

Caira, Simonetta; Pinto, Gabriella; Nicolai, Maria Adalgisa; Chianese, Lina; Addeo, Francesco

2016-08-01

Water buffalo (WB) casein (CN) and curd samples from indigenous Italian and international breeds were examined with the objective of identifying signature peptides that could function as an indicator to determine the origin of their milk products. CN in complex mixtures were digested with trypsin, and peptide fragments were subsequently identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). The unique presence of a β-CN A variant and an internally deleted αs1-CN (f35-42) variant in international WB milk samples was ascertained by identifying signature tryptic peptides from either dephosphorylated or native CN. Four signature unphosphorylated peptides derived from β-CN A, i.e. (f49-68) Asn(68) (2223.6 Da), (f1-28) Ser(10) (3169.4 Da), (f1-29) Ser(10) (3297.4 Da) and (f33-48) Thr(41) (1982 Da) and two from αs1-CN (f35-42) deleted fragments, i.e. (f23-34) Met(31) (1415.7 Da) and (f43-58) Val(44) (1752.7 Da), were identified. Two signature casein phosphopeptides (CPPs), i.e. β-CN (f1-28) 4P (3489.1 Da) and β-CN (f33-48) 1P (2062.0 Da), were identified in the tryptic hydrolysate of native casein or curd and cheese samples using in-batch hydroxyapatite (HA) chromatography. All these fragments functioned as analytical surrogates of two αs1- and β-casein variants that specifically occur in the milk of international WB breeds. Furthermore, the bovine peptide β-CN (f1-28) 4P had a distinct and lower molecular mass compared with the WB counterpart and functioned as a species-specific marker for all breeds of WB. Advantages of this analytical approach are that (i) peptides are easier to separate than proteins, (ii) signature peptide probes originating from specific casein variants allow for the targeting of all international WB milk, curd and cheese samples and (iii) bovine and WB casein in mixtures can be simultaneously determined in protected designation of origin (PDO) "Mozzarella di Bufala Campana" cheese. This analytical method enabled the specific detection of international WB and bovine casein with a sensitivity threshold of 2 and 0.78 %, respectively. Graphical Abstract Monitoring of prototypic tryptic CPPs by MALDI-TOF analysis in Mediterranean (A), Romanian (B), Indian (C), Polish (D) and Canadian (E) curd samples to guarantee the authenticity of the PDO "Mozzarella di Bufala Campana" cheese.

Towards simplification of hydrologic modeling: Identification of dominant processes

USGS Publications Warehouse

Markstrom, Steven; Hay, Lauren E.; Clark, Martyn P.

2016-01-01

The Precipitation–Runoff Modeling System (PRMS), a distributed-parameter hydrologic model, has been applied to the conterminous US (CONUS). Parameter sensitivity analysis was used to identify: (1) the sensitive input parameters and (2) particular model output variables that could be associated with the dominant hydrologic process(es). Sensitivity values of 35 PRMS calibration parameters were computed using the Fourier amplitude sensitivity test procedure on 110 000 independent hydrologically based spatial modeling units covering the CONUS and then summarized to process (snowmelt, surface runoff, infiltration, soil moisture, evapotranspiration, interflow, baseflow, and runoff) and model performance statistic (mean, coefficient of variation, and autoregressive lag 1). Identified parameters and processes provide insight into model performance at the location of each unit and allow the modeler to identify the most dominant process on the basis of which processes are associated with the most sensitive parameters. The results of this study indicate that: (1) the choice of performance statistic and output variables has a strong influence on parameter sensitivity, (2) the apparent model complexity to the modeler can be reduced by focusing on those processes that are associated with sensitive parameters and disregarding those that are not, (3) different processes require different numbers of parameters for simulation, and (4) some sensitive parameters influence only one hydrologic process, while others may influence many

Multi-Response Parameter Interval Sensitivity and Optimization for the Composite Tape Winding Process.

PubMed

Deng, Bo; Shi, Yaoyao; Yu, Tao; Kang, Chao; Zhao, Pan

2018-01-31

The composite tape winding process, which utilizes a tape winding machine and prepreg tapes, provides a promising way to improve the quality of composite products. Nevertheless, the process parameters of composite tape winding have crucial effects on the tensile strength and void content, which are closely related to the performances of the winding products. In this article, two different object values of winding products, including mechanical performance (tensile strength) and a physical property (void content), were respectively calculated. Thereafter, the paper presents an integrated methodology by combining multi-parameter relative sensitivity analysis and single-parameter sensitivity analysis to obtain the optimal intervals of the composite tape winding process. First, the global multi-parameter sensitivity analysis method was applied to investigate the sensitivity of each parameter in the tape winding processing. Then, the local single-parameter sensitivity analysis method was employed to calculate the sensitivity of a single parameter within the corresponding range. Finally, the stability and instability ranges of each parameter were distinguished. Meanwhile, the authors optimized the process parameter ranges and provided comprehensive optimized intervals of the winding parameters. The verification test validated that the optimized intervals of the process parameters were reliable and stable for winding products manufacturing.

Multi-Response Parameter Interval Sensitivity and Optimization for the Composite Tape Winding Process

PubMed Central

Yu, Tao; Kang, Chao; Zhao, Pan

2018-01-01

The composite tape winding process, which utilizes a tape winding machine and prepreg tapes, provides a promising way to improve the quality of composite products. Nevertheless, the process parameters of composite tape winding have crucial effects on the tensile strength and void content, which are closely related to the performances of the winding products. In this article, two different object values of winding products, including mechanical performance (tensile strength) and a physical property (void content), were respectively calculated. Thereafter, the paper presents an integrated methodology by combining multi-parameter relative sensitivity analysis and single-parameter sensitivity analysis to obtain the optimal intervals of the composite tape winding process. First, the global multi-parameter sensitivity analysis method was applied to investigate the sensitivity of each parameter in the tape winding processing. Then, the local single-parameter sensitivity analysis method was employed to calculate the sensitivity of a single parameter within the corresponding range. Finally, the stability and instability ranges of each parameter were distinguished. Meanwhile, the authors optimized the process parameter ranges and provided comprehensive optimized intervals of the winding parameters. The verification test validated that the optimized intervals of the process parameters were reliable and stable for winding products manufacturing. PMID:29385048

Perceived gender in clear and conversational speech

NASA Astrophysics Data System (ADS)

Booz, Jaime A.

Although many studies have examined acoustic and sociolinguistic differences between male and female speech, the relationship between talker speaking style and perceived gender has not yet been explored. The present study attempts to determine whether clear speech, a style adopted by talkers who perceive some barrier to effective communication, shifts perceptions of femininity for male and female talkers. Much of our understanding of gender perception in voice and speech is based on sustained vowels or single words, eliminating temporal, prosodic, and articulatory cues available in more naturalistic, connected speech. Thus, clear and conversational sentence stimuli, selected from the 41 talkers of the Ferguson Clear Speech Database (Ferguson, 2004) were presented to 17 normal-hearing listeners, aged 18 to 30. They rated the talkers' gender using a visual analog scale with "masculine" and "feminine" endpoints. This response method was chosen to account for within-category shifts of gender perception by allowing nonbinary responses. Mixed-effects regression analysis of listener responses revealed a small but significant effect of speaking style, and this effect was larger for male talkers than female talkers. Because of the high degree of talker variability observed for talker gender, acoustic analyses of these sentences were undertaken to determine the relationship between acoustic changes in clear and conversational speech and perceived femininity. Results of these analyses showed that mean fundamental frequency (fo) and f o standard deviation were significantly correlated to perceived gender for both male and female talkers, and vowel space was significantly correlated only for male talkers. Speaking rate and breathiness measures (CPPS) were not significantly related for either group. Outcomes of this study indicate that adopting a clear speaking style is correlated with increases in perceived femininity. Although the increase was small, some changes associated with making adjustments to improve speech clarity have a larger impact on perceived femininity than others. Using a clear speech strategy alone may not be sufficient for a male speaker to be perceived as female, but could be used as one of many tools to help speakers achieve more "feminine" speech, in conjunction with more specific strategies targeting the acoustic parameters outlined in this study.

A novel cell penetrating peptide carrier for the delivery of nematocidal proteins drug

NASA Astrophysics Data System (ADS)

Kim, Jea Hyun

Nematodes have recently become a primary source of harmful diseases to the environment that inflict harsh damages to pine trees and marine species. However, nematodes cannot be killed by normal pesticides or chemicals due to their thick outer protective layer mainly composed of collagen and cuticles. Thus, a novel approach to trigger intracellular delivery of chemicals through the layers of nematodes is required. In this study, the selection of the novel CPP was carefully progressed through protein database and serial digested fragmentation, internalization of each amino sequence was analyzed through flow cytometry and confocal microscope. As one of the most effective CPP material, JH 1.6 was compared with other major CPPs and its cellular toxicity was investigated. Furthermore, JH 1.6 was attached to various RNA, DNA, and proteins and internalization efficiency was evaluated for mammalian cells. To examine its effects on nematodes in vivo, JH 1.6 was conjugated with nematocidal protein - botulinum neurotoxin (BnT) and treated in C.elegans as a model animal. The results showed that JH 1.6 had high relative internalization rate and low cellular toxicity compared to other major CPP such as TAT and GV1001 peptides.

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model

PubMed Central

Pérez-Alvarado, Carlos; Gómez, Consuelo; Reyes, Miguel; García, Mario; Pérez, Elizabeth; Pérez de la Mora, Carlos; Sanchez, Virginia

2017-01-01

Objective. To evaluate the anti-inflammatory properties of Dialyzable Leukocyte Extract (DLE) in a murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods. Histopathological characterization, prostatein Enzyme-Linked Immunosorbent Assay, and immunohistochemical analysis for CD45, TNF-α, IFN-γ, IL-6, IL-17, and IL-4 molecules were done in prostatic Wistar rats treated with DLE, placebo, or Dexamethasone. Results. Histopathological analysis of animals induced to prostatitis showed inflammatory infiltrate, mainly constituted by leucocytes and mast cells as well as Benign Prostatic Hyperplasia. Serum prostatein concentrations were 14 times higher than those displayed by healthy animals. After DLE and Dexamethasone treatments, the inflammatory infiltrate decreased; the tissue morphology was similar to that of a normal prostate, and the prostatein decreased to the basal levels of healthy animals. DLE treatment produced a decreased expression of the cell surface marker CD45 and the proinflammatory cytokines TNF-α, IFN-γ, IL-6, and IL-17. On the other hand, the expression of anti-inflammatory cytokine IL-4 increased in both the Dexamethasone and DLE groups. Conclusion. DLE is able to modulate the inflammatory response in Experimental Autoimmune Prostatitis (EAP). PMID:28386549

Enhanced and selective permeability of gold nanoparticles functionalized with cell penetrating peptide derived from maurocalcine animal toxin.

PubMed

Khamehchian, Sedigheh; Nikkhah, Maryam; Madani, Rasool; Hosseinkhani, Saman

2016-11-01

Functionalization of gold nanoparticles (GNPs) is suitable for many applications such as biomedical imaging, clinical diagnosis, and targeted delivery by conjugating cell-penetrating peptides (CPPs). Here, we investigated intracellular uptake of GNP conjugated to MCaUF1-9(Ala) , a CPP derived from maurocalcine (MCa) animal toxin, and compared it with TAT functionalized GNP. Peptide conjugated GNP was characterized using UV-Visible spectroscopy, dynamic light scattering, zeta potential, and transmission electron microscopy. Uptake of MCaUF1-9(Ala) and TAT functionalized GNPs was evaluated in three cell lines, HeLa, MDA-MB-231, and A431, using dark field imaging and atomic absorption spectroscopy. According to peptide sequences and type of cells different cell penetrating activity was observed. Peptide functionalized GNP had little effect on cell viability and respect to net charge difference between peptide, showed interesting selectivity against three cell types. Peptide conjugated to GNPs displayed higher uptake than bare GNPs in the all cell lines except HeLa cell with lowest internalization. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2693-2700, 2016. © 2016 Wiley Periodicals, Inc.

Anti-Inflammatory Effect of Dialyzable Leukocyte Extract in Autoimmune Prostatitis: Evaluation in Animal Model.

PubMed

Pérez-Alvarado, Carlos; Gómez, Consuelo; Reyes, Miguel; García, Mario; Pérez, Elizabeth; Pérez de la Mora, Carlos; Sanchez, Virginia; Pérez Ishiwara, D Guillermo

2017-01-01

Objective. To evaluate the anti-inflammatory properties of Dialyzable Leukocyte Extract (DLE) in a murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods. Histopathological characterization, prostatein Enzyme-Linked Immunosorbent Assay, and immunohistochemical analysis for CD45, TNF- α , IFN- γ , IL-6, IL-17, and IL-4 molecules were done in prostatic Wistar rats treated with DLE, placebo, or Dexamethasone. Results. Histopathological analysis of animals induced to prostatitis showed inflammatory infiltrate, mainly constituted by leucocytes and mast cells as well as Benign Prostatic Hyperplasia. Serum prostatein concentrations were 14 times higher than those displayed by healthy animals. After DLE and Dexamethasone treatments, the inflammatory infiltrate decreased; the tissue morphology was similar to that of a normal prostate, and the prostatein decreased to the basal levels of healthy animals. DLE treatment produced a decreased expression of the cell surface marker CD45 and the proinflammatory cytokines TNF- α , IFN- γ , IL-6, and IL-17. On the other hand, the expression of anti-inflammatory cytokine IL-4 increased in both the Dexamethasone and DLE groups. Conclusion. DLE is able to modulate the inflammatory response in Experimental Autoimmune Prostatitis (EAP).

Comprehensive overview of prostatitis.

PubMed

Khan, Farhan Ullah; Ihsan, Awais Ullah; Khan, Hidayat Ullah; Jana, Ruby; Wazir, Junaid; Khongorzul, Puregmaa; Waqar, Muhammad; Zhou, Xiaohui

2017-10-01

Prostatitis is a common urinary tract syndrome that many doctors find problematic to treat effectively. It is the third most commonly found urinary tract disease in men after prostate cancer and Benign Prostate Hyperplasia (BPH). Prostatitis may account for 25% of all office visits made to the urological clinics complaining about the genital and urinary systems all over the world. In the present study, we classified prostatitis and comprehensively elaborated the etiology, pathogenesis, diagnosis, and treatment of acute bacterial prostatitis (category I), chronic bacterial prostatitis (category II), chronic pelvic pain syndrome (CPPS) (category III), and asymptomatic prostatitis (category IV). In addition, we also tried to get some insights about other types of prostatitis-like fungal, viral and gonococcal prostatitis. The aim of this review is to present the detail current perspective of prostatitis in a single review. To the best of our knowledge currently, there is not a single comprehensive review, which can completely elaborate this important topic in an effective way. Furthermore, this review will provide a solid platform to conduct future studies on different aspects such as risk factors, mechanism of pathogenesis, proper diagnosis, and rational treatment plans for fungal, viral, and gonococcal prostatitis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Recent Developments in the VISRAD 3-D Target Design and Radiation Simulation Code

NASA Astrophysics Data System (ADS)

Macfarlane, Joseph; Golovkin, Igor; Sebald, James

2017-10-01

The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, Z, and LMJ. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. VISRAD includes a variety of user-friendly graphics for setting up targets and displaying results, can readily display views from any point in space, and can be used to generate image sequences for animations. We will discuss recent improvements to conveniently assess beam capture on target and beam clearance of diagnostic components, as well as plans for future developments.

Dual-mode enhancement of metallothionein protein with cell transduction and retention peptide fusion.

PubMed

Lim, Kwang Suk; Lim, Myoung-Hwa; Won, Young-Wook; Kim, Jang Kyoung; Kang, Young Cheol; Park, Eun Jeong; Chae, Ji-Won; Kim, So-Mi; Ryu, Seong-Eon; Pak, Youngmi Kim; Kim, Yong-Hee

2013-10-28

Protein transduction domains (PTDs), also known as cell-penetrating peptides (CPPs), have been developed as effective systems for delivering bio-active cargos such as proteins, genes and particles. Further improvements on cell-specific targeting, intracellular organelle targeting and intracellular retention are still necessary to enhance the therapeutic effect of PTD fusion proteins. In order to enhance the cell transduction and retention of anti-oxidative metallothionein protein (MT), MT was recombinantly fused with transcriptional activator (Tat) with or without a short peptide (sMTS) derived from mitochondria malate dehydrogenase (mMDH). Cellular uptake and retention time of fusion protein were significantly increased in the H9c2 cell by sMTS. The Tat-sMTS-MT (TMM) fusion protein protected H9c2 cells more effectively against hypoxia, hyperglycemia and combination compared with Tat-MT (TM) by reducing intracellular ROS level. It maintained the normal blood glucose level over an extended period of time in a streptozotocin-induced diabetic mouse model. PTD-sMTS-MT fusion protein has a potential to be used as a therapeutic protein for the treatment or prevention of diabetes and diabetic complications. © 2013.

Enhancing Endosomal Escape of Transduced Proteins by Photochemical Internalisation

PubMed Central

Mellert, Kevin; Lamla, Markus; Scheffzek, Klaus; Wittig, Rainer; Kaufmann, Dieter

2012-01-01

Induced internalisation of functional proteins into cultured cells has become an important aspect in a rising number of in vitro and in vivo assays. The endo-lysosomal entrapment of the transduced proteins remains the major problem in all transduction protocols. In this study we compared the efficiency, cytotoxicity and protein targeting of different commercially available transduction reagents by transducing a well-studied fluorescently labelled protein (Atto488-bovine serum albumin) into cultured human sarcoma cells. The amount of internalised protein and toxicity differed between the different reagents, but the percentage of transduced cells was consistently high. Furthermore, in all protocols the signals of the transduced Atto488-BSA were predominantly punctual consistent with an endosomal localisation. To overcome the endosomal entrapment, the transduction protocols were combined with a photochemical internalisation (PCI) treatment. Using this combination revealed that an endosomal disruption is highly effective in cell penetrating peptide (CPP) mediated transduction, whereas lipid-mediated transductions lead to a lower signal spreading throughout the cytosol. No change in the signal distribution could be achieved in treatments using non-lipid polymers as a transduction reagent. Therefore, the combination of protein transduction protocols based on CPPs with the endosomolytic treatment PCI can facilitate protein transduction experiments in vitro. PMID:23285056

Enhancing endosomal escape of transduced proteins by photochemical internalisation.

PubMed

Mellert, Kevin; Lamla, Markus; Scheffzek, Klaus; Wittig, Rainer; Kaufmann, Dieter

2012-01-01

Induced internalisation of functional proteins into cultured cells has become an important aspect in a rising number of in vitro and in vivo assays. The endo-lysosomal entrapment of the transduced proteins remains the major problem in all transduction protocols. In this study we compared the efficiency, cytotoxicity and protein targeting of different commercially available transduction reagents by transducing a well-studied fluorescently labelled protein (Atto488-bovine serum albumin) into cultured human sarcoma cells. The amount of internalised protein and toxicity differed between the different reagents, but the percentage of transduced cells was consistently high. Furthermore, in all protocols the signals of the transduced Atto488-BSA were predominantly punctual consistent with an endosomal localisation. To overcome the endosomal entrapment, the transduction protocols were combined with a photochemical internalisation (PCI) treatment. Using this combination revealed that an endosomal disruption is highly effective in cell penetrating peptide (CPP) mediated transduction, whereas lipid-mediated transductions lead to a lower signal spreading throughout the cytosol. No change in the signal distribution could be achieved in treatments using non-lipid polymers as a transduction reagent. Therefore, the combination of protein transduction protocols based on CPPs with the endosomolytic treatment PCI can facilitate protein transduction experiments in vitro.

Parameter optimization of electrochemical machining process using black hole algorithm

NASA Astrophysics Data System (ADS)

Singh, Dinesh; Shukla, Rajkamal

2017-12-01

Advanced machining processes are significant as higher accuracy in machined component is required in the manufacturing industries. Parameter optimization of machining processes gives optimum control to achieve the desired goals. In this paper, electrochemical machining (ECM) process is considered to evaluate the performance of the considered process using black hole algorithm (BHA). BHA considers the fundamental idea of a black hole theory and it has less operating parameters to tune. The two performance parameters, material removal rate (MRR) and overcut (OC) are considered separately to get optimum machining parameter settings using BHA. The variations of process parameters with respect to the performance parameters are reported for better and effective understanding of the considered process using single objective at a time. The results obtained using BHA are found better while compared with results of other metaheuristic algorithms, such as, genetic algorithm (GA), artificial bee colony (ABC) and bio-geography based optimization (BBO) attempted by previous researchers.

Optimization of Parameter Ranges for Composite Tape Winding Process Based on Sensitivity Analysis

NASA Astrophysics Data System (ADS)

Yu, Tao; Shi, Yaoyao; He, Xiaodong; Kang, Chao; Deng, Bo; Song, Shibo

2017-08-01

This study is focus on the parameters sensitivity of winding process for composite prepreg tape. The methods of multi-parameter relative sensitivity analysis and single-parameter sensitivity analysis are proposed. The polynomial empirical model of interlaminar shear strength is established by response surface experimental method. Using this model, the relative sensitivity of key process parameters including temperature, tension, pressure and velocity is calculated, while the single-parameter sensitivity curves are obtained. According to the analysis of sensitivity curves, the stability and instability range of each parameter are recognized. Finally, the optimization method of winding process parameters is developed. The analysis results show that the optimized ranges of the process parameters for interlaminar shear strength are: temperature within [100 °C, 150 °C], tension within [275 N, 387 N], pressure within [800 N, 1500 N], and velocity within [0.2 m/s, 0.4 m/s], respectively.

Identifyability measures to select the parameters to be estimated in a solid-state fermentation distributed parameter model.

PubMed

da Silveira, Christian L; Mazutti, Marcio A; Salau, Nina P G

2016-07-08

Process modeling can lead to of advantages such as helping in process control, reducing process costs and product quality improvement. This work proposes a solid-state fermentation distributed parameter model composed by seven differential equations with seventeen parameters to represent the process. Also, parameters estimation with a parameters identifyability analysis (PIA) is performed to build an accurate model with optimum parameters. Statistical tests were made to verify the model accuracy with the estimated parameters considering different assumptions. The results have shown that the model assuming substrate inhibition better represents the process. It was also shown that eight from the seventeen original model parameters were nonidentifiable and better results were obtained with the removal of these parameters from the estimation procedure. Therefore, PIA can be useful to estimation procedure, since it may reduce the number of parameters that can be evaluated. Further, PIA improved the model results, showing to be an important procedure to be taken. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:905-917, 2016. © 2016 American Institute of Chemical Engineers.

Real-time parameter optimization based on neural network for smart injection molding

NASA Astrophysics Data System (ADS)

Lee, H.; Liau, Y.; Ryu, K.

2018-03-01

The manufacturing industry has been facing several challenges, including sustainability, performance and quality of production. Manufacturers attempt to enhance the competitiveness of companies by implementing CPS (Cyber-Physical Systems) through the convergence of IoT(Internet of Things) and ICT(Information & Communication Technology) in the manufacturing process level. Injection molding process has a short cycle time and high productivity. This features have been making it suitable for mass production. In addition, this process is used to produce precise parts in various industry fields such as automobiles, optics and medical devices. Injection molding process has a mixture of discrete and continuous variables. In order to optimized the quality, variables that is generated in the injection molding process must be considered. Furthermore, Optimal parameter setting is time-consuming work to predict the optimum quality of the product. Since the process parameter cannot be easily corrected during the process execution. In this research, we propose a neural network based real-time process parameter optimization methodology that sets optimal process parameters by using mold data, molding machine data, and response data. This paper is expected to have academic contribution as a novel study of parameter optimization during production compare with pre - production parameter optimization in typical studies.

Optimization of injection molding process parameters for a plastic cell phone housing component

NASA Astrophysics Data System (ADS)

Rajalingam, Sokkalingam; Vasant, Pandian; Khe, Cheng Seong; Merican, Zulkifli; Oo, Zeya

2016-11-01

To produce thin-walled plastic items, injection molding process is one of the most widely used application tools. However, to set optimal process parameters is difficult as it may cause to produce faulty items on injected mold like shrinkage. This study aims at to determine such an optimum injection molding process parameters which can reduce the fault of shrinkage on a plastic cell phone cover items. Currently used setting of machines process produced shrinkage and mis-specified length and with dimensions below the limit. Thus, for identification of optimum process parameters, maintaining closer targeted length and width setting magnitudes with minimal variations, more experiments are needed. The mold temperature, injection pressure and screw rotation speed are used as process parameters in this research. For optimal molding process parameters the Response Surface Methods (RSM) is applied. The major contributing factors influencing the responses were identified from analysis of variance (ANOVA) technique. Through verification runs it was found that the shrinkage defect can be minimized with the optimal setting found by RSM.

Optimization of Dimensional accuracy in plasma arc cutting process employing parametric modelling approach

NASA Astrophysics Data System (ADS)

Naik, Deepak kumar; Maity, K. P.

2018-03-01

Plasma arc cutting (PAC) is a high temperature thermal cutting process employed for the cutting of extensively high strength material which are difficult to cut through any other manufacturing process. This process involves high energized plasma arc to cut any conducting material with better dimensional accuracy in lesser time. This research work presents the effect of process parameter on to the dimensional accuracy of PAC process. The input process parameters were selected as arc voltage, standoff distance and cutting speed. A rectangular plate of 304L stainless steel of 10 mm thickness was taken for the experiment as a workpiece. Stainless steel is very extensively used material in manufacturing industries. Linear dimension were measured following Taguchi’s L16 orthogonal array design approach. Three levels were selected to conduct the experiment for each of the process parameter. In all experiments, clockwise cut direction was followed. The result obtained thorough measurement is further analyzed. Analysis of variance (ANOVA) and Analysis of means (ANOM) were performed to evaluate the effect of each process parameter. ANOVA analysis reveals the effect of input process parameter upon leaner dimension in X axis. The results of the work shows that the optimal setting of process parameter values for the leaner dimension on the X axis. The result of the investigations clearly show that the specific range of input process parameter achieved the improved machinability.

Method and apparatus for assessing weld quality

DOEpatents

Smartt, Herschel B.; Kenney, Kevin L.; Johnson, John A.; Carlson, Nancy M.; Clark, Denis E.; Taylor, Paul L.; Reutzel, Edward W.

2001-01-01

Apparatus for determining a quality of a weld produced by a welding device according to the present invention includes a sensor operatively associated with the welding device. The sensor is responsive to at least one welding process parameter during a welding process and produces a welding process parameter signal that relates to the at least one welding process parameter. A computer connected to the sensor is responsive to the welding process parameter signal produced by the sensor. A user interface operatively associated with the computer allows a user to select a desired welding process. The computer processes the welding process parameter signal produced by the sensor in accordance with one of a constant voltage algorithm, a short duration weld algorithm or a pulsed current analysis module depending on the desired welding process selected by the user. The computer produces output data indicative of the quality of the weld.

Selective laser melting of Ni-rich NiTi: selection of process parameters and the superelastic response

NASA Astrophysics Data System (ADS)

Shayesteh Moghaddam, Narges; Saedi, Soheil; Amerinatanzi, Amirhesam; Saghaian, Ehsan; Jahadakbar, Ahmadreza; Karaca, Haluk; Elahinia, Mohammad

2018-03-01

Material and mechanical properties of NiTi shape memory alloys strongly depend on the fabrication process parameters and the resulting microstructure. In selective laser melting, the combination of parameters such as laser power, scanning speed, and hatch spacing determine the microstructural defects, grain size and texture. Therefore, processing parameters can be adjusted to tailor the microstructure and mechanical response of the alloy. In this work, NiTi samples were fabricated using Ni50.8Ti (at.%) powder via SLM PXM by Phenix/3D Systems and the effects of processing parameters were systematically studied. The relationship between the processing parameters and superelastic properties were investigated thoroughly. It will be shown that energy density is not the only parameter that governs the material response. It will be shown that hatch spacing is the dominant factor to tailor the superelastic response. It will be revealed that with the selection of right process parameters, perfect superelasticity with recoverable strains of up to 5.6% can be observed in the as-fabricated condition.

A review of pharmaceutical extrusion: critical process parameters and scaling-up.

PubMed

Thiry, J; Krier, F; Evrard, B

2015-02-01

Hot melt extrusion has been a widely used process in the pharmaceutical area for three decades. In this field, it is important to optimize the formulation in order to meet specific requirements. However, the process parameters of the extruder should be as much investigated as the formulation since they have a major impact on the final product characteristics. Moreover, a design space should be defined in order to obtain the expected product within the defined limits. This gives some freedom to operate as long as the processing parameters stay within the limits of the design space. Those limits can be investigated by varying randomly the process parameters but it is recommended to use design of experiments. An examination of the literature is reported in this review to summarize the impact of the variation of the process parameters on the final product properties. Indeed, the homogeneity of the mixing, the state of the drug (crystalline or amorphous), the dissolution rate, the residence time, can be influenced by variations in the process parameters. In particular, the impact of the following process parameters: temperature, screw design, screw speed and feeding, on the final product, has been reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

Process Parameter Optimization for Wobbling Laser Spot Welding of Ti6Al4V Alloy

NASA Astrophysics Data System (ADS)

Vakili-Farahani, F.; Lungershausen, J.; Wasmer, K.

Laser beam welding (LBW) coupled with "wobble effect" (fast oscillation of the laser beam) is very promising for high precision micro-joining industry. For this process, similarly to the conventional LBW, the laser welding process parameters play a very significant role in determining the quality of a weld joint. Consequently, four process parameters (laser power, wobble frequency, number of rotations within a single laser pulse and focused position) and 5 responses (penetration, width, heat affected zone (HAZ), area of the fusion zone, area of HAZ and hardness) were investigated for spot welding of Ti6Al4V alloy (grade 5) using a design of experiments (DoE) approach. This paper presents experimental results showing the effects of variating the considered most important process parameters on the spot weld quality of Ti6Al4V alloy. Semi-empirical mathematical models were developed to correlate laser welding parameters to each of the measured weld responses. Adequacies of the models were then examined by various methods such as ANOVA. These models not only allows a better understanding of the wobble laser welding process and predict the process performance but also determines optimal process parameters. Therefore, optimal combination of process parameters was determined considering certain quality criteria set.

Impact of the hard-coded parameters on the hydrologic fluxes of the land surface model Noah-MP

NASA Astrophysics Data System (ADS)

Cuntz, Matthias; Mai, Juliane; Samaniego, Luis; Clark, Martyn; Wulfmeyer, Volker; Attinger, Sabine; Thober, Stephan

2016-04-01

Land surface models incorporate a large number of processes, described by physical, chemical and empirical equations. The process descriptions contain a number of parameters that can be soil or plant type dependent and are typically read from tabulated input files. Land surface models may have, however, process descriptions that contain fixed, hard-coded numbers in the computer code, which are not identified as model parameters. Here we searched for hard-coded parameters in the computer code of the land surface model Noah with multiple process options (Noah-MP) to assess the importance of the fixed values on restricting the model's agility during parameter estimation. We found 139 hard-coded values in all Noah-MP process options, which are mostly spatially constant values. This is in addition to the 71 standard parameters of Noah-MP, which mostly get distributed spatially by given vegetation and soil input maps. We performed a Sobol' global sensitivity analysis of Noah-MP to variations of the standard and hard-coded parameters for a specific set of process options. 42 standard parameters and 75 hard-coded parameters were active with the chosen process options. The sensitivities of the hydrologic output fluxes latent heat and total runoff as well as their component fluxes were evaluated. These sensitivities were evaluated at twelve catchments of the Eastern United States with very different hydro-meteorological regimes. Noah-MP's hydrologic output fluxes are sensitive to two thirds of its standard parameters. The most sensitive parameter is, however, a hard-coded value in the formulation of soil surface resistance for evaporation, which proved to be oversensitive in other land surface models as well. Surface runoff is sensitive to almost all hard-coded parameters of the snow processes and the meteorological inputs. These parameter sensitivities diminish in total runoff. Assessing these parameters in model calibration would require detailed snow observations or the calculation of hydrologic signatures of the runoff data. Latent heat and total runoff exhibit very similar sensitivities towards standard and hard-coded parameters in Noah-MP because of their tight coupling via the water balance. It should therefore be comparable to calibrate Noah-MP either against latent heat observations or against river runoff data. Latent heat and total runoff are sensitive to both, plant and soil parameters. Calibrating only a parameter sub-set of only soil parameters, for example, thus limits the ability to derive realistic model parameters. It is thus recommended to include the most sensitive hard-coded model parameters that were exposed in this study when calibrating Noah-MP.

Effect of processing parameters on FDM process

NASA Astrophysics Data System (ADS)

Chari, V. Srinivasa; Venkatesh, P. R.; Krupashankar, Dinesh, Veena

2018-04-01

This paper focused on the process parameters on fused deposition modeling (FDM). Infill, resolution, temperature are the process variables considered for experimental studies. Compression strength, Hardness test microstructure are the outcome parameters, this experimental study done based on the taguchi's L9 orthogonal array is used. Taguchi array used to build the 9 different models and also to get the effective output results on the under taken parameters. The material used for this experimental study is Polylactic Acid (PLA).

Effect of Electron Beam Freeform Fabrication (EBF3) Processing Parameters on Composition of Ti-6-4

NASA Technical Reports Server (NTRS)

Lach, Cynthia L.; Taminger, Karen; Schuszler, A. Bud, II; Sankaran, Sankara; Ehlers, Helen; Nasserrafi, Rahbar; Woods, Bryan

2007-01-01

The Electron Beam Freeform Fabrication (EBF3) process developed at NASA Langley Research Center was evaluated using a design of experiments approach to determine the effect of processing parameters on the composition and geometry of Ti-6-4 deposits. The effects of three processing parameters: beam power, translation speed, and wire feed rate, were investigated by varying one while keeping the remaining parameters constant. A three-factorial, three-level, fully balanced mutually orthogonal array (L27) design of experiments approach was used to examine the effects of low, medium, and high settings for the processing parameters on the chemistry, geometry, and quality of the resulting deposits. Single bead high deposits were fabricated and evaluated for 27 experimental conditions. Loss of aluminum in Ti-6-4 was observed in EBF3 processing due to selective vaporization of the aluminum from the sustained molten pool in the vacuum environment; therefore, the chemistries of the deposits were measured and compared with the composition of the initial wire and base plate to determine if the loss of aluminum could be minimized through careful selection of processing parameters. The influence of processing parameters and coupling between these parameters on bulk composition, measured by Direct Current Plasma (DCP), local microchemistries determined by Wavelength Dispersive Spectrometry (WDS), and deposit geometry will also be discussed.

Clinical applications of low-intensity pulsed ultrasound and its potential role in urology

PubMed Central

Lin, Guiting; Lei, Hongen; Lue, Tom F.; Guo, Yinglu

2016-01-01

Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that delivered at a much lower intensity (<3 W/cm2) than traditional ultrasound energy and output in the mode of pulse wave, and it is typically used for therapeutic purpose in rehabilitation medicine. LIPUS has minimal thermal effects due to its low intensity and pulsed output mode, and its non-thermal effects which is normally claimed to induce therapeutic changes in tissues attract most researchers’ attentions. LIPUS have been demonstrated to have a rage of biological effects on tissues, including promoting bone-fracture healing, accelerating soft-tissue regeneration, inhibiting inflammatory responses and so on. Recent studies showed that biological effects of LIPUS in healing morbid body tissues may be mainly associated with the upregulation of cell proliferation through activation of integrin receptors and Rho/ROCK/Src/ERK signaling pathway, and with promoting multilineage differentiation of mesenchyme stem/progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. Hopefully, LIPUS may become an effective clinical procedure for the treatment of urological diseases, such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), erectile dysfunction (ED), and stress urinary incontinence (SUI) in the field of urology. It still needs an intense effort for basic-science and clinical investigators to explore the biomedical applications of ultrasound. PMID:27141455

Intelligent methods for the process parameter determination of plastic injection molding

NASA Astrophysics Data System (ADS)

Gao, Huang; Zhang, Yun; Zhou, Xundao; Li, Dequn

2018-03-01

Injection molding is one of the most widely used material processing methods in producing plastic products with complex geometries and high precision. The determination of process parameters is important in obtaining qualified products and maintaining product quality. This article reviews the recent studies and developments of the intelligent methods applied in the process parameter determination of injection molding. These intelligent methods are classified into three categories: Case-based reasoning methods, expert system- based methods, and data fitting and optimization methods. A framework of process parameter determination is proposed after comprehensive discussions. Finally, the conclusions and future research topics are discussed.

Study on loading path optimization of internal high pressure forming process

NASA Astrophysics Data System (ADS)

Jiang, Shufeng; Zhu, Hengda; Gao, Fusheng

2017-09-01

In the process of internal high pressure forming, there is no formula to describe the process parameters and forming results. The article use numerical simulation to obtain several input parameters and corresponding output result, use the BP neural network to found their mapping relationship, and with weighted summing method make each evaluating parameters to set up a formula which can evaluate quality. Then put the training BP neural network into the particle swarm optimization, and take the evaluating formula of the quality as adapting formula of particle swarm optimization, finally do the optimization and research at the range of each parameters. The results show that the parameters obtained by the BP neural network algorithm and the particle swarm optimization algorithm can meet the practical requirements. The method can solve the optimization of the process parameters in the internal high pressure forming process.

Grey Relational Analysis Coupled with Principal Component Analysis for Optimization of Stereolithography Process to Enhance Part Quality

NASA Astrophysics Data System (ADS)

Raju, B. S.; Sekhar, U. Chandra; Drakshayani, D. N.

2017-08-01

The paper investigates optimization of stereolithography process for SL5530 epoxy resin material to enhance part quality. The major characteristics indexed for performance selected to evaluate the processes are tensile strength, Flexural strength, Impact strength and Density analysis and corresponding process parameters are Layer thickness, Orientation and Hatch spacing. In this study, the process is intrinsically with multiple parameters tuning so that grey relational analysis which uses grey relational grade as performance index is specially adopted to determine the optimal combination of process parameters. Moreover, the principal component analysis is applied to evaluate the weighting values corresponding to various performance characteristics so that their relative importance can be properly and objectively desired. The results of confirmation experiments reveal that grey relational analysis coupled with principal component analysis can effectively acquire the optimal combination of process parameters. Hence, this confirm that the proposed approach in this study can be an useful tool to improve the process parameters in stereolithography process, which is very useful information for machine designers as well as RP machine users.

A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process.

PubMed

Kothari, Bhaveshkumar H; Fahmy, Raafat; Claycamp, H Gregg; Moore, Christine M V; Chatterjee, Sharmista; Hoag, Stephen W

2017-05-01

The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.

Parameter interdependence and uncertainty induced by lumping in a hydrologic model

NASA Astrophysics Data System (ADS)

Gallagher, Mark R.; Doherty, John

2007-05-01

Throughout the world, watershed modeling is undertaken using lumped parameter hydrologic models that represent real-world processes in a manner that is at once abstract, but nevertheless relies on algorithms that reflect real-world processes and parameters that reflect real-world hydraulic properties. In most cases, values are assigned to the parameters of such models through calibration against flows at watershed outlets. One criterion by which the utility of the model and the success of the calibration process are judged is that realistic values are assigned to parameters through this process. This study employs regularization theory to examine the relationship between lumped parameters and corresponding real-world hydraulic properties. It demonstrates that any kind of parameter lumping or averaging can induce a substantial amount of "structural noise," which devices such as Box-Cox transformation of flows and autoregressive moving average (ARMA) modeling of residuals are unlikely to render homoscedastic and uncorrelated. Furthermore, values estimated for lumped parameters are unlikely to represent average values of the hydraulic properties after which they are named and are often contaminated to a greater or lesser degree by the values of hydraulic properties which they do not purport to represent at all. As a result, the question of how rigidly they should be bounded during the parameter estimation process is still an open one.

Effect of Friction Stir Process Parameters on the Mechanical and Thermal Behavior of 5754-H111 Aluminum Plates.

PubMed

Serio, Livia Maria; Palumbo, Davide; De Filippis, Luigi Alberto Ciro; Galietti, Umberto; Ludovico, Antonio Domenico

2016-02-23

A study of the Friction Stir Welding (FSW) process was carried out in order to evaluate the influence of process parameters on the mechanical properties of aluminum plates (AA5754-H111). The process was monitored during each test by means of infrared cameras in order to correlate temperature information with eventual changes of the mechanical properties of joints. In particular, two process parameters were considered for tests: the welding tool rotation speed and the welding tool traverse speed. The quality of joints was evaluated by means of destructive and non-destructive tests. In this regard, the presence of defects and the ultimate tensile strength (UTS) were investigated for each combination of the process parameters. A statistical analysis was carried out to assess the correlation between the thermal behavior of joints and the process parameters, also proving the capability of Infrared Thermography for on-line monitoring of the quality of joints.

[Optimize dropping process of Ginkgo biloba dropping pills by using design space approach].

PubMed

Shen, Ji-Chen; Wang, Qing-Qing; Chen, An; Pan, Fang-Lai; Gong, Xing-Chu; Qu, Hai-Bin

2017-07-01

In this paper, a design space approach was applied to optimize the dropping process of Ginkgo biloba dropping pills. Firstly, potential critical process parameters and potential process critical quality attributes were determined through literature research and pre-experiments. Secondly, experiments were carried out according to Box-Behnken design. Then the critical process parameters and critical quality attributes were determined based on the experimental results. Thirdly, second-order polynomial models were used to describe the quantitative relationships between critical process parameters and critical quality attributes. Finally, a probability-based design space was calculated and verified. The verification results showed that efficient production of Ginkgo biloba dropping pills can be guaranteed by operating within the design space parameters. The recommended operation ranges for the critical dropping process parameters of Ginkgo biloba dropping pills were as follows: dropping distance of 5.5-6.7 cm, and dropping speed of 59-60 drops per minute, providing a reference for industrial production of Ginkgo biloba dropping pills. Copyright© by the Chinese Pharmaceutical Association.

Effect of Friction Stir Process Parameters on the Mechanical and Thermal Behavior of 5754-H111 Aluminum Plates

PubMed Central

Serio, Livia Maria; Palumbo, Davide; De Filippis, Luigi Alberto Ciro; Galietti, Umberto; Ludovico, Antonio Domenico

2016-01-01

A study of the Friction Stir Welding (FSW) process was carried out in order to evaluate the influence of process parameters on the mechanical properties of aluminum plates (AA5754-H111). The process was monitored during each test by means of infrared cameras in order to correlate temperature information with eventual changes of the mechanical properties of joints. In particular, two process parameters were considered for tests: the welding tool rotation speed and the welding tool traverse speed. The quality of joints was evaluated by means of destructive and non-destructive tests. In this regard, the presence of defects and the ultimate tensile strength (UTS) were investigated for each combination of the process parameters. A statistical analysis was carried out to assess the correlation between the thermal behavior of joints and the process parameters, also proving the capability of Infrared Thermography for on-line monitoring of the quality of joints. PMID:28773246

Multiscale analysis of the correlation of processing parameters on viscidity of composites fabricated by automated fiber placement

NASA Astrophysics Data System (ADS)

Han, Zhenyu; Sun, Shouzheng; Fu, Yunzhong; Fu, Hongya

2017-10-01

Viscidity is an important physical indicator for assessing fluidity of resin that is beneficial to contact resin with the fibers effectively and reduce manufacturing defects during automated fiber placement (AFP) process. However, the effect of processing parameters on viscidity evolution is rarely studied during AFP process. In this paper, viscidities under different scales are analyzed based on multi-scale analysis method. Firstly, viscous dissipation energy (VDE) within meso-unit under different processing parameters is assessed by using finite element method (FEM). According to multi-scale energy transfer model, meso-unit energy is used as the boundary condition for microscopic analysis. Furthermore, molecular structure of micro-system is built by molecular dynamics (MD) method. And viscosity curves are then obtained by integrating stress autocorrelation function (SACF) with time. Finally, the correlation characteristics of processing parameters to viscosity are revealed by using gray relational analysis method (GRAM). A group of processing parameters is found out to achieve the stability of viscosity and better fluidity of resin.

Mining manufacturing data for discovery of high productivity process characteristics.

PubMed

Charaniya, Salim; Le, Huong; Rangwala, Huzefa; Mills, Keri; Johnson, Kevin; Karypis, George; Hu, Wei-Shou

2010-06-01

Modern manufacturing facilities for bioproducts are highly automated with advanced process monitoring and data archiving systems. The time dynamics of hundreds of process parameters and outcome variables over a large number of production runs are archived in the data warehouse. This vast amount of data is a vital resource to comprehend the complex characteristics of bioprocesses and enhance production robustness. Cell culture process data from 108 'trains' comprising production as well as inoculum bioreactors from Genentech's manufacturing facility were investigated. Each run constitutes over one-hundred on-line and off-line temporal parameters. A kernel-based approach combined with a maximum margin-based support vector regression algorithm was used to integrate all the process parameters and develop predictive models for a key cell culture performance parameter. The model was also used to identify and rank process parameters according to their relevance in predicting process outcome. Evaluation of cell culture stage-specific models indicates that production performance can be reliably predicted days prior to harvest. Strong associations between several temporal parameters at various manufacturing stages and final process outcome were uncovered. This model-based data mining represents an important step forward in establishing a process data-driven knowledge discovery in bioprocesses. Implementation of this methodology on the manufacturing floor can facilitate a real-time decision making process and thereby improve the robustness of large scale bioprocesses. 2010 Elsevier B.V. All rights reserved.

Zener Diode Compact Model Parameter Extraction Using Xyce-Dakota Optimization.

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

Buchheit, Thomas E.; Wilcox, Ian Zachary; Sandoval, Andrew J

This report presents a detailed process for compact model parameter extraction for DC circuit Zener diodes. Following the traditional approach of Zener diode parameter extraction, circuit model representation is defined and then used to capture the different operational regions of a real diode's electrical behavior. The circuit model contains 9 parameters represented by resistors and characteristic diodes as circuit model elements. The process of initial parameter extraction, the identification of parameter values for the circuit model elements, is presented in a way that isolates the dependencies between certain electrical parameters and highlights both the empirical nature of the extraction andmore » portions of the real diode physical behavior which of the parameters are intended to represent. Optimization of the parameters, a necessary part of a robost parameter extraction process, is demonstrated using a 'Xyce-Dakota' workflow, discussed in more detail in the report. Among other realizations during this systematic approach of electrical model parameter extraction, non-physical solutions are possible and can be difficult to avoid because of the interdependencies between the different parameters. The process steps described are fairly general and can be leveraged for other types of semiconductor device model extractions. Also included in the report are recommendations for experiment setups for generating optimum dataset for model extraction and the Parameter Identification and Ranking Table (PIRT) for Zener diodes.« less

Investigation into the influence of laser energy input on selective laser melted thin-walled parts by response surface method

NASA Astrophysics Data System (ADS)

Liu, Yang; Zhang, Jian; Pang, Zhicong; Wu, Weihui

2018-04-01

Selective laser melting (SLM) provides a feasible way for manufacturing of complex thin-walled parts directly, however, the energy input during SLM process, namely derived from the laser power, scanning speed, layer thickness and scanning space, etc. has great influence on the thin wall's qualities. The aim of this work is to relate the thin wall's parameters (responses), namely track width, surface roughness and hardness to the process parameters considered in this research (laser power, scanning speed and layer thickness) and to find out the optimal manufacturing conditions. Design of experiment (DoE) was used by implementing composite central design to achieve better manufacturing qualities. Mathematical models derived from the statistical analysis were used to establish the relationships between the process parameters and the responses. Also, the effects of process parameters on each response were determined. Then, a numerical optimization was performed to find out the optimal process set at which the quality features are at their desired values. Based on this study, the relationship between process parameters and SLMed thin-walled structure was revealed and thus, the corresponding optimal process parameters can be used to manufactured thin-walled parts with high quality.

Optimization of Gas Metal Arc Welding Process Parameters

NASA Astrophysics Data System (ADS)

Kumar, Amit; Khurana, M. K.; Yadav, Pradeep K.

2016-09-01

This study presents the application of Taguchi method combined with grey relational analysis to optimize the process parameters of gas metal arc welding (GMAW) of AISI 1020 carbon steels for multiple quality characteristics (bead width, bead height, weld penetration and heat affected zone). An orthogonal array of L9 has been implemented to fabrication of joints. The experiments have been conducted according to the combination of voltage (V), current (A) and welding speed (Ws). The results revealed that the welding speed is most significant process parameter. By analyzing the grey relational grades, optimal parameters are obtained and significant factors are known using ANOVA analysis. The welding parameters such as speed, welding current and voltage have been optimized for material AISI 1020 using GMAW process. To fortify the robustness of experimental design, a confirmation test was performed at selected optimal process parameter setting. Observations from this method may be useful for automotive sub-assemblies, shipbuilding and vessel fabricators and operators to obtain optimal welding conditions.

Influence of tool geometry and processing parameters on welding defects and mechanical properties for friction stir welding of 6061 Aluminium alloy

NASA Astrophysics Data System (ADS)

Daneji, A.; Ali, M.; Pervaiz, S.

2018-04-01

Friction stir welding (FSW) is a form of solid state welding process for joining metals, alloys, and selective composites. Over the years, FSW development has provided an improved way of producing welding joints, and consequently got accepted in numerous industries such as aerospace, automotive, rail and marine etc. In FSW, the base metal properties control the material’s plastic flow under the influence of a rotating tool whereas, the process and tool parameters play a vital role in the quality of weld. In the current investigation, an array of square butt joints of 6061 Aluminum alloy was to be welded under varying FSW process and tool geometry related parameters, after which the resulting weld was evaluated for the corresponding mechanical properties and welding defects. The study incorporates FSW process and tool parameters such as welding speed, pin height and pin thread pitch as input parameters. However, the weld quality related defects and mechanical properties were treated as output parameters. The experimentation paves way to investigate the correlation between the inputs and the outputs. The correlation between inputs and outputs were used as tool to predict the optimized FSW process and tool parameters for a desired weld output of the base metals under investigation. The study also provides reflection on the effect of said parameters on a welding defect such as wormhole.

Self-tuning regulator for an interacting CSTR process

NASA Astrophysics Data System (ADS)

Rajendra Mungale, Niraj; Upadhyay, Akshay; Jaganatha Pandian, B.

2017-11-01

In the paper we have laid emphasis on STR that is Self Tuning Regulator and its application for an interacting process. CSTR has a great importance in Chemical Process when we deal with controlling different parameters of a process using CSTR. Basically CSTR is used to maintain a constant liquid temperature in the process. The proposed method called self-tuning regulator, is a different scheme where process parameters are updated and the controller parameters are obtained from the solution of a design problem. The paper deals with STR and methods associated with it.

Evaluation of Control Parameters for the Activated Sludge Process

ERIC Educational Resources Information Center

Stall, T. Ray; Sherrard, Josephy H.

1978-01-01

An evaluation of the use of the parameters currently being used to design and operate the activated sludge process is presented. The advantages and disadvantages for the use of each parameter are discussed. (MR)

Sensitivity analysis of the add-on price estimate for the edge-defined film-fed growth process

NASA Technical Reports Server (NTRS)

Mokashi, A. R.; Kachare, A. H.

1981-01-01

The analysis is in terms of cost parameters and production parameters. The cost parameters include equipment, space, direct labor, materials, and utilities. The production parameters include growth rate, process yield, and duty cycle. A computer program was developed specifically to do the sensitivity analysis.

Improving tablet coating robustness by selecting critical process parameters from retrospective data.

PubMed

Galí, A; García-Montoya, E; Ascaso, M; Pérez-Lozano, P; Ticó, J R; Miñarro, M; Suñé-Negre, J M

2016-09-01

Although tablet coating processes are widely used in the pharmaceutical industry, they often lack adequate robustness. Up-scaling can be challenging as minor changes in parameters can lead to varying quality results. To select critical process parameters (CPP) using retrospective data of a commercial product and to establish a design of experiments (DoE) that would improve the robustness of the coating process. A retrospective analysis of data from 36 commercial batches. Batches were selected based on the quality results generated during batch release, some of which revealed quality deviations concerning the appearance of the coated tablets. The product is already marketed and belongs to the portfolio of a multinational pharmaceutical company. The Statgraphics 5.1 software was used for data processing to determine critical process parameters in order to propose new working ranges. This study confirms that it is possible to determine the critical process parameters and create design spaces based on retrospective data of commercial batches. This type of analysis is thus converted into a tool to optimize the robustness of existing processes. Our results show that a design space can be established with minimum investment in experiments, since current commercial batch data are processed statistically.

Multiresponse Optimization of Process Parameters in Turning of GFRP Using TOPSIS Method

PubMed Central

Parida, Arun Kumar; Routara, Bharat Chandra

2014-01-01

Taguchi's design of experiment is utilized to optimize the process parameters in turning operation with dry environment. Three parameters, cutting speed (v), feed (f), and depth of cut (d), with three different levels are taken for the responses like material removal rate (MRR) and surface roughness (R a). The machining is conducted with Taguchi L9 orthogonal array, and based on the S/N analysis, the optimal process parameters for surface roughness and MRR are calculated separately. Considering the larger-the-better approach, optimal process parameters for material removal rate are cutting speed at level 3, feed at level 2, and depth of cut at level 3, that is, v 3-f 2-d 3. Similarly for surface roughness, considering smaller-the-better approach, the optimal process parameters are cutting speed at level 1, feed at level 1, and depth of cut at level 3, that is, v 1-f 1-d 3. Results of the main effects plot indicate that depth of cut is the most influencing parameter for MRR but cutting speed is the most influencing parameter for surface roughness and feed is found to be the least influencing parameter for both the responses. The confirmation test is conducted for both MRR and surface roughness separately. Finally, an attempt has been made to optimize the multiresponses using technique for order preference by similarity to ideal solution (TOPSIS) with Taguchi approach. PMID:27437503

Terrestrial photovoltaic cell process testing

NASA Technical Reports Server (NTRS)

Burger, D. R.

1985-01-01

The paper examines critical test parameters, criteria for selecting appropriate tests, and the use of statistical controls and test patterns to enhance PV-cell process test results. The coverage of critical test parameters is evaluated by examining available test methods and then screening these methods by considering the ability to measure those critical parameters which are most affected by the generic process, the cost of the test equipment and test performance, and the feasibility for process testing.

Terrestrial photovoltaic cell process testing

NASA Astrophysics Data System (ADS)

Burger, D. R.

The paper examines critical test parameters, criteria for selecting appropriate tests, and the use of statistical controls and test patterns to enhance PV-cell process test results. The coverage of critical test parameters is evaluated by examining available test methods and then screening these methods by considering the ability to measure those critical parameters which are most affected by the generic process, the cost of the test equipment and test performance, and the feasibility for process testing.

Application of dragonfly algorithm for optimal performance analysis of process parameters in turn-mill operations- A case study

NASA Astrophysics Data System (ADS)

Vikram, K. Arun; Ratnam, Ch; Lakshmi, VVK; Kumar, A. Sunny; Ramakanth, RT

2018-02-01

Meta-heuristic multi-response optimization methods are widely in use to solve multi-objective problems to obtain Pareto optimal solutions during optimization. This work focuses on optimal multi-response evaluation of process parameters in generating responses like surface roughness (Ra), surface hardness (H) and tool vibration displacement amplitude (Vib) while performing operations like tangential and orthogonal turn-mill processes on A-axis Computer Numerical Control vertical milling center. Process parameters like tool speed, feed rate and depth of cut are considered as process parameters machined over brass material under dry condition with high speed steel end milling cutters using Taguchi design of experiments (DOE). Meta-heuristic like Dragonfly algorithm is used to optimize the multi-objectives like ‘Ra’, ‘H’ and ‘Vib’ to identify the optimal multi-response process parameters combination. Later, the results thus obtained from multi-objective dragonfly algorithm (MODA) are compared with another multi-response optimization technique Viz. Grey relational analysis (GRA).

Identification of Optimum Magnetic Behavior of NanoCrystalline CmFeAl Type Heusler Alloy Powders Using Response Surface Methodology

NASA Astrophysics Data System (ADS)

Srivastava, Y.; Srivastava, S.; Boriwal, L.

2016-09-01

Mechanical alloying is a novelistic solid state process that has received considerable attention due to many advantages over other conventional processes. In the present work, Co2FeAl healer alloy powder, prepared successfully from premix basic powders of Cobalt (Co), Iron (Fe) and Aluminum (Al) in stoichiometric of 60Co-26Fe-14Al (weight %) by novelistic mechano-chemical route. Magnetic properties of mechanically alloyed powders were characterized by vibrating sample magnetometer (VSM). 2 factor 5 level design matrix was applied to experiment process. Experimental results were used for response surface methodology. Interaction between the input process parameters and the response has been established with the help of regression analysis. Further analysis of variance technique was applied to check the adequacy of developed model and significance of process parameters. Test case study was performed with those parameters, which was not selected for main experimentation but range was same. Response surface methodology, the process parameters must be optimized to obtain improved magnetic properties. Further optimum process parameters were identified using numerical and graphical optimization techniques.

Workflow for Criticality Assessment Applied in Biopharmaceutical Process Validation Stage 1.

PubMed

Zahel, Thomas; Marschall, Lukas; Abad, Sandra; Vasilieva, Elena; Maurer, Daniel; Mueller, Eric M; Murphy, Patrick; Natschläger, Thomas; Brocard, Cécile; Reinisch, Daniela; Sagmeister, Patrick; Herwig, Christoph

2017-10-12

Identification of critical process parameters that impact product quality is a central task during regulatory requested process validation. Commonly, this is done via design of experiments and identification of parameters significantly impacting product quality (rejection of the null hypothesis that the effect equals 0). However, parameters which show a large uncertainty and might result in an undesirable product quality limit critical to the product, may be missed. This might occur during the evaluation of experiments since residual/un-modelled variance in the experiments is larger than expected a priori. Estimation of such a risk is the task of the presented novel retrospective power analysis permutation test. This is evaluated using a data set for two unit operations established during characterization of a biopharmaceutical process in industry. The results show that, for one unit operation, the observed variance in the experiments is much larger than expected a priori, resulting in low power levels for all non-significant parameters. Moreover, we present a workflow of how to mitigate the risk associated with overlooked parameter effects. This enables a statistically sound identification of critical process parameters. The developed workflow will substantially support industry in delivering constant product quality, reduce process variance and increase patient safety.

A simulation to study the feasibility of improving the temporal resolution of LAGEOS geodynamic solutions by using a sequential process noise filter

NASA Technical Reports Server (NTRS)

Hartman, Brian Davis

1995-01-01

A key drawback to estimating geodetic and geodynamic parameters over time based on satellite laser ranging (SLR) observations is the inability to accurately model all the forces acting on the satellite. Errors associated with the observations and the measurement model can detract from the estimates as well. These 'model errors' corrupt the solutions obtained from the satellite orbit determination process. Dynamical models for satellite motion utilize known geophysical parameters to mathematically detail the forces acting on the satellite. However, these parameters, while estimated as constants, vary over time. These temporal variations must be accounted for in some fashion to maintain meaningful solutions. The primary goal of this study is to analyze the feasibility of using a sequential process noise filter for estimating geodynamic parameters over time from the Laser Geodynamics Satellite (LAGEOS) SLR data. This evaluation is achieved by first simulating a sequence of realistic LAGEOS laser ranging observations. These observations are generated using models with known temporal variations in several geodynamic parameters (along track drag and the J(sub 2), J(sub 3), J(sub 4), and J(sub 5) geopotential coefficients). A standard (non-stochastic) filter and a stochastic process noise filter are then utilized to estimate the model parameters from the simulated observations. The standard non-stochastic filter estimates these parameters as constants over consecutive fixed time intervals. Thus, the resulting solutions contain constant estimates of parameters that vary in time which limits the temporal resolution and accuracy of the solution. The stochastic process noise filter estimates these parameters as correlated process noise variables. As a result, the stochastic process noise filter has the potential to estimate the temporal variations more accurately since the constraint of estimating the parameters as constants is eliminated. A comparison of the temporal resolution of solutions obtained from standard sequential filtering methods and process noise sequential filtering methods shows that the accuracy is significantly improved using process noise. The results show that the positional accuracy of the orbit is improved as well. The temporal resolution of the resulting solutions are detailed, and conclusions drawn about the results. Benefits and drawbacks of using process noise filtering in this type of scenario are also identified.

A Taguchi approach on optimal process control parameters for HDPE pipe extrusion process

NASA Astrophysics Data System (ADS)

Sharma, G. V. S. S.; Rao, R. Umamaheswara; Rao, P. Srinivasa

2017-06-01

High-density polyethylene (HDPE) pipes find versatile applicability for transportation of water, sewage and slurry from one place to another. Hence, these pipes undergo tremendous pressure by the fluid carried. The present work entails the optimization of the withstanding pressure of the HDPE pipes using Taguchi technique. The traditional heuristic methodology stresses on a trial and error approach and relies heavily upon the accumulated experience of the process engineers for determining the optimal process control parameters. This results in setting up of less-than-optimal values. Hence, there arouse a necessity to determine optimal process control parameters for the pipe extrusion process, which can ensure robust pipe quality and process reliability. In the proposed optimization strategy, the design of experiments (DoE) are conducted wherein different control parameter combinations are analyzed by considering multiple setting levels of each control parameter. The concept of signal-to-noise ratio ( S/ N ratio) is applied and ultimately optimum values of process control parameters are obtained as: pushing zone temperature of 166 °C, Dimmer speed at 08 rpm, and Die head temperature to be 192 °C. Confirmation experimental run is also conducted to verify the analysis and research result and values proved to be in synchronization with the main experimental findings and the withstanding pressure showed a significant improvement from 0.60 to 1.004 Mpa.

Influence of additive laser manufacturing parameters on surface using density of partially melted particles

NASA Astrophysics Data System (ADS)

Rosa, Benoit; Brient, Antoine; Samper, Serge; Hascoët, Jean-Yves

2016-12-01

Mastering the additive laser manufacturing surface is a real challenge and would allow functional surfaces to be obtained without finishing. Direct Metal Deposition (DMD) surfaces are composed by directional and chaotic textures that are directly linked to the process principles. The aim of this work is to obtain surface topographies by mastering the operating process parameters. Based on experimental investigation, the influence of operating parameters on the surface finish has been modeled. Topography parameters and multi-scale analysis have been used in order to characterize the DMD obtained surfaces. This study also proposes a methodology to characterize DMD chaotic texture through topography filtering and 3D image treatment. In parallel, a new parameter is proposed: density of particles (D p). Finally, this study proposes a regression modeling between process parameters and density of particles parameter.

Effects of build parameters on linear wear loss in plastic part produced by fused deposition modeling

NASA Astrophysics Data System (ADS)

Mohamed, Omar Ahmed; Masood, Syed Hasan; Bhowmik, Jahar Lal

2017-07-01

Fused Deposition Modeling (FDM) is one of the prominent additive manufacturing technologies for producing polymer products. FDM is a complex additive manufacturing process that can be influenced by many process conditions. The industrial demands required from the FDM process are increasing with higher level product functionality and properties. The functionality and performance of FDM manufactured parts are greatly influenced by the combination of many various FDM process parameters. Designers and researchers always pay attention to study the effects of FDM process parameters on different product functionalities and properties such as mechanical strength, surface quality, dimensional accuracy, build time and material consumption. However, very limited studies have been carried out to investigate and optimize the effect of FDM build parameters on wear performance. This study focuses on the effect of different build parameters on micro-structural and wear performance of FDM specimens using definitive screening design based quadratic model. This would reduce the cost and effort of additive manufacturing engineer to have a systematic approachto make decision among the manufacturing parameters to achieve the desired product quality.

Parameter extraction using global particle swarm optimization approach and the influence of polymer processing temperature on the solar cell parameters

NASA Astrophysics Data System (ADS)

Kumar, S.; Singh, A.; Dhar, A.

2017-08-01

The accurate estimation of the photovoltaic parameters is fundamental to gain an insight of the physical processes occurring inside a photovoltaic device and thereby to optimize its design, fabrication processes, and quality. A simulative approach of accurately determining the device parameters is crucial for cell array and module simulation when applied in practical on-field applications. In this work, we have developed a global particle swarm optimization (GPSO) approach to estimate the different solar cell parameters viz., ideality factor (η), short circuit current (Isc), open circuit voltage (Voc), shunt resistant (Rsh), and series resistance (Rs) with wide a search range of over ±100 % for each model parameter. After validating the accurateness and global search power of the proposed approach with synthetic and noisy data, we applied the technique to the extract the PV parameters of ZnO/PCDTBT based hybrid solar cells (HSCs) prepared under different annealing conditions. Further, we examine the variation of extracted model parameters to unveil the physical processes occurring when different annealing temperatures are employed during the device fabrication and establish the role of improved charge transport in polymer films from independent FET measurements. The evolution of surface morphology, optical absorption, and chemical compositional behaviour of PCDTBT co-polymer films as a function of processing temperature has also been captured in the study and correlated with the findings from the PV parameters extracted using GPSO approach.

Processing Parameters Optimization for Material Deposition Efficiency in Laser Metal Deposited Titanium Alloy

NASA Astrophysics Data System (ADS)

Mahamood, Rasheedat M.; Akinlabi, Esther T.

2016-03-01

Ti6Al4V is an important Titanium alloy that is mostly used in many applications such as: aerospace, petrochemical and medicine. The excellent corrosion resistance property, the high strength to weight ratio and the retention of properties at high temperature makes them to be favoured in most applications. The high cost of Titanium and its alloys makes their use to be prohibitive in some applications. Ti6Al4V can be cladded on a less expensive material such as steel, thereby reducing cost and providing excellent properties. Laser Metal Deposition (LMD) process, an additive manufacturing process is capable of producing complex part directly from the 3-D CAD model of the part and it also has the capability of handling multiple materials. Processing parameters play an important role in LMD process and in order to achieve desired results at a minimum cost, then the processing parameters need to be properly controlled. This paper investigates the role of processing parameters: laser power, scanning speed, powder flow rate and gas flow rate, on the material utilization efficiency in laser metal deposited Ti6Al4V. A two-level full factorial design of experiment was used in this investigation, to be able to understand the processing parameters that are most significant as well as the interactions among these processing parameters. Four process parameters were used, each with upper and lower settings which results in a combination of sixteen experiments. The laser power settings used was 1.8 and 3 kW, the scanning speed was 0.05 and 0.1 m/s, the powder flow rate was 2 and 4 g/min and the gas flow rate was 2 and 4 l/min. The experiments were designed and analyzed using Design Expert 8 software. The software was used to generate the optimized process parameters which were found to be laser power of 3.2 kW, scanning speed of 0.06 m/s, powder flow rate of 2 g/min and gas flow rate of 3 l/min.

Warpage improvement on wheel caster by optimizing the process parameters using genetic algorithm (GA)

NASA Astrophysics Data System (ADS)

Safuan, N. S.; Fathullah, M.; Shayfull, Z.; Nasir, S. M.; Hazwan, M. H. M.

2017-09-01

In injection moulding process, the defects will always encountered and affected the final product shape and functionality. This study is concerning on minimizing warpage and optimizing the process parameter of injection moulding part. Apart from eliminating product wastes, this project also giving out best recommended parameters setting. This research studied on five parameters. The optimization showed that warpage have been improved 42.64% from 0.6524 mm to 0.30879 mm in Autodesk Moldflow Insight (AMI) simulation result and Genetic Algorithm (GA) respectively.

Calibrating the sqHIMMELI v1.0 wetland methane emission model with hierarchical modeling and adaptive MCMC

NASA Astrophysics Data System (ADS)

Susiluoto, Jouni; Raivonen, Maarit; Backman, Leif; Laine, Marko; Makela, Jarmo; Peltola, Olli; Vesala, Timo; Aalto, Tuula

2018-03-01

Estimating methane (CH4) emissions from natural wetlands is complex, and the estimates contain large uncertainties. The models used for the task are typically heavily parameterized and the parameter values are not well known. In this study, we perform a Bayesian model calibration for a new wetland CH4 emission model to improve the quality of the predictions and to understand the limitations of such models.The detailed process model that we analyze contains descriptions for CH4 production from anaerobic respiration, CH4 oxidation, and gas transportation by diffusion, ebullition, and the aerenchyma cells of vascular plants. The processes are controlled by several tunable parameters. We use a hierarchical statistical model to describe the parameters and obtain the posterior distributions of the parameters and uncertainties in the processes with adaptive Markov chain Monte Carlo (MCMC), importance resampling, and time series analysis techniques. For the estimation, the analysis utilizes measurement data from the Siikaneva flux measurement site in southern Finland. The uncertainties related to the parameters and the modeled processes are described quantitatively. At the process level, the flux measurement data are able to constrain the CH4 production processes, methane oxidation, and the different gas transport processes. The posterior covariance structures explain how the parameters and the processes are related. Additionally, the flux and flux component uncertainties are analyzed both at the annual and daily levels. The parameter posterior densities obtained provide information regarding importance of the different processes, which is also useful for development of wetland methane emission models other than the square root HelsinkI Model of MEthane buiLd-up and emIssion for peatlands (sqHIMMELI). The hierarchical modeling allows us to assess the effects of some of the parameters on an annual basis. The results of the calibration and the cross validation suggest that the early spring net primary production could be used to predict parameters affecting the annual methane production. Even though the calibration is specific to the Siikaneva site, the hierarchical modeling approach is well suited for larger-scale studies and the results of the estimation pave way for a regional or global-scale Bayesian calibration of wetland emission models.

Correlations of Melt Pool Geometry and Process Parameters During Laser Metal Deposition by Coaxial Process Monitoring

NASA Astrophysics Data System (ADS)

Ocylok, Sörn; Alexeev, Eugen; Mann, Stefan; Weisheit, Andreas; Wissenbach, Konrad; Kelbassa, Ingomar

One major demand of today's laser metal deposition (LMD) processes is to achieve a fail-save build-up regarding changing conditions like heat accumulations. Especially for the repair of thin parts like turbine blades is the knowledge about the correlations between melt pool behavior and process parameters like laser power, feed rate and powder mass stream indispensable. The paper will show the process layout with the camera based coaxial monitoring system and the quantitative influence of the process parameters on the melt pool geometry. Therefore the diameter, length and area of the melt pool are measured by a video analytic system at various parameters and compared with the track wide in cross-sections and the laser spot diameter. The influence of changing process conditions on the melt pool is also investigated. On the base of these results an enhanced process of the build-up of a multilayer one track fillet geometry will be presented.

Remote Sensing Image Quality Assessment Experiment with Post-Processing

NASA Astrophysics Data System (ADS)

Jiang, W.; Chen, S.; Wang, X.; Huang, Q.; Shi, H.; Man, Y.

2018-04-01

This paper briefly describes the post-processing influence assessment experiment, the experiment includes three steps: the physical simulation, image processing, and image quality assessment. The physical simulation models sampled imaging system in laboratory, the imaging system parameters are tested, the digital image serving as image processing input are produced by this imaging system with the same imaging system parameters. The gathered optical sampled images with the tested imaging parameters are processed by 3 digital image processes, including calibration pre-processing, lossy compression with different compression ratio and image post-processing with different core. Image quality assessment method used is just noticeable difference (JND) subject assessment based on ISO20462, through subject assessment of the gathered and processing images, the influence of different imaging parameters and post-processing to image quality can be found. The six JND subject assessment experimental data can be validated each other. Main conclusions include: image post-processing can improve image quality; image post-processing can improve image quality even with lossy compression, image quality with higher compression ratio improves less than lower ratio; with our image post-processing method, image quality is better, when camera MTF being within a small range.

An Optimized Trajectory Planning for Welding Robot

NASA Astrophysics Data System (ADS)

Chen, Zhilong; Wang, Jun; Li, Shuting; Ren, Jun; Wang, Quan; Cheng, Qunchao; Li, Wentao

2018-03-01

In order to improve the welding efficiency and quality, this paper studies the combined planning between welding parameters and space trajectory for welding robot and proposes a trajectory planning method with high real-time performance, strong controllability and small welding error. By adding the virtual joint at the end-effector, the appropriate virtual joint model is established and the welding process parameters are represented by the virtual joint variables. The trajectory planning is carried out in the robot joint space, which makes the control of the welding process parameters more intuitive and convenient. By using the virtual joint model combined with the B-spline curve affine invariant, the welding process parameters are indirectly controlled by controlling the motion curve of the real joint. To solve the optimal time solution as the goal, the welding process parameters and joint space trajectory joint planning are optimized.

MODFLOW-2000, the U.S. Geological Survey modular ground-water model; user guide to the observation, sensitivity, and parameter-estimation processes and three post-processing programs

USGS Publications Warehouse

Hill, Mary C.; Banta, E.R.; Harbaugh, A.W.; Anderman, E.R.

2000-01-01

This report documents the Observation, Sensitivity, and Parameter-Estimation Processes of the ground-water modeling computer program MODFLOW-2000. The Observation Process generates model-calculated values for comparison with measured, or observed, quantities. A variety of statistics is calculated to quantify this comparison, including a weighted least-squares objective function. In addition, a number of files are produced that can be used to compare the values graphically. The Sensitivity Process calculates the sensitivity of hydraulic heads throughout the model with respect to specified parameters using the accurate sensitivity-equation method. These are called grid sensitivities. If the Observation Process is active, it uses the grid sensitivities to calculate sensitivities for the simulated values associated with the observations. These are called observation sensitivities. Observation sensitivities are used to calculate a number of statistics that can be used (1) to diagnose inadequate data, (2) to identify parameters that probably cannot be estimated by regression using the available observations, and (3) to evaluate the utility of proposed new data. The Parameter-Estimation Process uses a modified Gauss-Newton method to adjust values of user-selected input parameters in an iterative procedure to minimize the value of the weighted least-squares objective function. Statistics produced by the Parameter-Estimation Process can be used to evaluate estimated parameter values; statistics produced by the Observation Process and post-processing program RESAN-2000 can be used to evaluate how accurately the model represents the actual processes; statistics produced by post-processing program YCINT-2000 can be used to quantify the uncertainty of model simulated values. Parameters are defined in the Ground-Water Flow Process input files and can be used to calculate most model inputs, such as: for explicitly defined model layers, horizontal hydraulic conductivity, horizontal anisotropy, vertical hydraulic conductivity or vertical anisotropy, specific storage, and specific yield; and, for implicitly represented layers, vertical hydraulic conductivity. In addition, parameters can be defined to calculate the hydraulic conductance of the River, General-Head Boundary, and Drain Packages; areal recharge rates of the Recharge Package; maximum evapotranspiration of the Evapotranspiration Package; pumpage or the rate of flow at defined-flux boundaries of the Well Package; and the hydraulic head at constant-head boundaries. The spatial variation of model inputs produced using defined parameters is very flexible, including interpolated distributions that require the summation of contributions from different parameters. Observations can include measured hydraulic heads or temporal changes in hydraulic heads, measured gains and losses along head-dependent boundaries (such as streams), flows through constant-head boundaries, and advective transport through the system, which generally would be inferred from measured concentrations. MODFLOW-2000 is intended for use on any computer operating system. The program consists of algorithms programmed in Fortran 90, which efficiently performs numerical calculations and is fully compatible with the newer Fortran 95. The code is easily modified to be compatible with FORTRAN 77. Coordination for multiple processors is accommodated using Message Passing Interface (MPI) commands. The program is designed in a modular fashion that is intended to support inclusion of new capabilities.

Parameter prediction based on Improved Process neural network and ARMA error compensation in Evaporation Process

NASA Astrophysics Data System (ADS)

Qian, Xiaoshan

2018-01-01

The traditional model of evaporation process parameters have continuity and cumulative characteristics of the prediction error larger issues, based on the basis of the process proposed an adaptive particle swarm neural network forecasting method parameters established on the autoregressive moving average (ARMA) error correction procedure compensated prediction model to predict the results of the neural network to improve prediction accuracy. Taking a alumina plant evaporation process to analyze production data validation, and compared with the traditional model, the new model prediction accuracy greatly improved, can be used to predict the dynamic process of evaporation of sodium aluminate solution components.

Optimisation of process parameters on thin shell part using response surface methodology (RSM)

NASA Astrophysics Data System (ADS)

Faiz, J. M.; Shayfull, Z.; Nasir, S. M.; Fathullah, M.; Rashidi, M. M.

2017-09-01

This study is carried out to focus on optimisation of process parameters by simulation using Autodesk Moldflow Insight (AMI) software. The process parameters are taken as the input in order to analyse the warpage value which is the output in this study. There are some significant parameters that have been used which are melt temperature, mould temperature, packing pressure, and cooling time. A plastic part made of Polypropylene (PP) has been selected as the study part. Optimisation of process parameters is applied in Design Expert software with the aim to minimise the obtained warpage value. Response Surface Methodology (RSM) has been applied in this study together with Analysis of Variance (ANOVA) in order to investigate the interactions between parameters that are significant to the warpage value. Thus, the optimised warpage value can be obtained using the model designed using RSM due to its minimum error value. This study comes out with the warpage value improved by using RSM.

An Advanced User Interface Approach for Complex Parameter Study Process Specification in the Information Power Grid

NASA Technical Reports Server (NTRS)

Yarrow, Maurice; McCann, Karen M.; Biswas, Rupak; VanderWijngaart, Rob; Yan, Jerry C. (Technical Monitor)

2000-01-01

The creation of parameter study suites has recently become a more challenging problem as the parameter studies have now become multi-tiered and the computational environment has become a supercomputer grid. The parameter spaces are vast, the individual problem sizes are getting larger, and researchers are now seeking to combine several successive stages of parameterization and computation. Simultaneously, grid-based computing offers great resource opportunity but at the expense of great difficulty of use. We present an approach to this problem which stresses intuitive visual design tools for parameter study creation and complex process specification, and also offers programming-free access to grid-based supercomputer resources and process automation.

An Adaptive Kalman Filter Using a Simple Residual Tuning Method

NASA Technical Reports Server (NTRS)

Harman, Richard R.

1999-01-01

One difficulty in using Kalman filters in real world situations is the selection of the correct process noise, measurement noise, and initial state estimate and covariance. These parameters are commonly referred to as tuning parameters. Multiple methods have been developed to estimate these parameters. Most of those methods such as maximum likelihood, subspace, and observer Kalman Identification require extensive offline processing and are not suitable for real time processing. One technique, which is suitable for real time processing, is the residual tuning method. Any mismodeling of the filter tuning parameters will result in a non-white sequence for the filter measurement residuals. The residual tuning technique uses this information to estimate corrections to those tuning parameters. The actual implementation results in a set of sequential equations that run in parallel with the Kalman filter. A. H. Jazwinski developed a specialized version of this technique for estimation of process noise. Equations for the estimation of the measurement noise have also been developed. These algorithms are used to estimate the process noise and measurement noise for the Wide Field Infrared Explorer star tracker and gyro.

Evolution of process control parameters during extended co-composting of green waste and solid fraction of cattle slurry to obtain growing media.

PubMed

Cáceres, Rafaela; Coromina, Narcís; Malińska, Krystyna; Marfà, Oriol

2015-03-01

This study aimed to monitor process parameters when two by-products (green waste - GW, and the solid fraction of cattle slurry - SFCS) were composted to obtain growing media. Using compost in growing medium mixtures involves prolonged composting processes that can last at least half a year. It is therefore crucial to study the parameters that affect compost stability as measured in the field in order to shorten the composting process at composting facilities. Two mixtures were prepared: GW25 (25% GW and 75% SFCS, v/v) and GW75 (75% GW and 25% SFCS, v/v). The different raw mixtures resulted in the production of two different growing media, and the evolution of process management parameters was different. A new parameter has been proposed to deal with attaining the thermophilic temperature range and maintaining it during composting, not only it would be useful to optimize composting processes, but also to assess the hygienization degree. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cell-penetrating peptide-doxorubicin conjugate loaded NGR-modified nanobubbles for ultrasound triggered drug delivery.

PubMed

Lin, Wen; Xie, Xiangyang; Deng, Jianping; Liu, Hui; Chen, Ying; Fu, Xudong; Liu, Hong; Yang, Yang

2016-01-01

A new drug-targeting system for CD13(+) tumors has been developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, the CPP-doxorubicin conjugate (CPP-DOX) was entrapped in the asparagine-glycine-arginine (NGR) peptide modified NB (CPP-DOX/NGR-NB) and the penetration of CPP-DOX was temporally masked; local ultrasound stimulation could trigger the CPP-DOX release from NB and activate its penetration. The CPP-DOX/NGR-NBs had particle sizes of about 200 nm and drug entrapment efficiency larger than 90%. In vitro release results showed that over 85% of the encapsulated DOX or CPP-DOX would release from NBs in the presence of ultrasound, while less than 1.5% of that (30 min) without ultrasound. Cell experiments showed the higher cellular CPP-DOX uptake of CPP-DOX/NGR-NB among the various NB formulations in Human fibrosarcoma cells (HT-1080, CD13(+)). The CPP-DOX/NGR-NB with ultrasound treatment exhibited an increased cytotoxic activity than the one without ultrasound. In nude mice xenograft of HT-1080 cells, CPP-DOX/NGR-NB with ultrasound showed a higher tumor inhibition effect (3.1% of T/C%, day 24), longer median survival time (50 days) and excellent body safety compared with the normal DOX injection group. These results indicate that the constructed vesicle would be a promising drug delivery system for specific cancer treatment.

Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy

PubMed Central

Shabanpoor, Fazel; McClorey, Graham; Saleh, Amer F.; Järver, Peter; Wood, Matthew J.A.; Gait, Michael J.

2015-01-01

The potential for therapeutic application of splice-switching oligonucleotides (SSOs) to modulate pre-mRNA splicing is increasingly evident in a number of diseases. However, the primary drawback of this approach is poor cell and in vivo oligonucleotide uptake efficacy. Biological activities can be significantly enhanced through the use of synthetically conjugated cationic cell penetrating peptides (CPPs). Studies to date have focused on the delivery of a single SSO conjugated to a CPP, but here we describe the conjugation of two phosphorodiamidate morpholino oligonucleotide (PMO) SSOs to a single CPP for simultaneous delivery and pre-mRNA targeting of two separate genes, exon 23 of the Dmd gene and exon 5 of the Acvr2b gene, in a mouse model of Duchenne muscular dystrophy. Conjugations of PMOs to a single CPP were carried out through an amide bond in one case and through a triazole linkage (‘click chemistry’) in the other. The most active bi-specific CPP–PMOs demonstrated comparable exon skipping levels for both pre-mRNA targets when compared to individual CPP–PMO conjugates both in cell culture and in vivo in the mdx mouse model. Thus, two SSOs with different target sequences conjugated to a single CPP are biologically effective and potentially suitable for future therapeutic exploitation. PMID:25468897

Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

PubMed Central

Grijalvo, Santiago; Alagia, Adele

2018-01-01

Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs) and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs) or restoring the anomalous levels of non-coding RNAs (ncRNAs) that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs), carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs), peptide nucleic acids (PNAs) as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed. PMID:29415514

Does systemic administration of casein phosphopeptides affect orthodontic movement and root resorption in rats?

PubMed

Crowther, Lachlan; Shen, Gang; Almuzian, Mohammed; Jones, Allan; Walsh, William; Oliver, Rema; Petocz, Peter; Tarraf, Nour E; Darendeliler, M Ali

2017-10-01

To assess the potential effects of casein phosphopeptides (CPPs) on orthodontically induced iatrogenic root resorption (OIIRR) and orthodontic teeth movement. Forty Wistar rats (aged 11 weeks) were randomly divided into experimental group (EG; n = 20) that received a diet supplemented with CPP and control group (CG; n = 20) devoid of diet supplement. A 150 g force was applied using nickel titanium (NiTi) coil that was bonded on maxillary incisors and extended unilaterally to a maxillary first molar. At Day 28, animals in both groups were euthanized. Volumetric assessment of root resorption craters and linear measurement of maxillary first molars movement were blindly examined using a micro-computed tomography scan. Nine rats were excluded from the experiment due to loss during general anesthesia or appliances' failure. Intra-operator reproducibility was high in both volumetric and linear measurements, 92.8 per cent and 98.5-97.6 per cent, respectively. The results reveal that dietary CPP has statistically insignificant effect on the overall OIIRR and orthodontic movement. CPP seems to have statistically insignificant effect on the volume of OIIRR and orthodontic movement in rats. A long-term study with larger sample size using a different concentration of CPP is required to clarify the dentoalveolar effect of CPP. © The Author 2017. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com

A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape.

PubMed

Salomone, Fabrizio; Cardarelli, Francesco; Di Luca, Mariagrazia; Boccardi, Claudia; Nifosì, Riccardo; Bardi, Giuseppe; Di Bari, Lorenzo; Serresi, Michela; Beltram, Fabio

2012-11-10

Efficient endocytosis into a wide range of target cells and low toxicity make the arginine-rich Tat peptide (Tat(11): YGRKKRRQRRR, residues 47-57 of HIV-1 Tat protein) an excellent transporter for delivery purposes. Unfortunately, molecules taken up by endocytosis undergo endosomal entrapment and possible metabolic degradation. Escape from the endosome is therefore actively researched. In this context, antimicrobial peptides (AMPs) provide viable templates for the design of new membrane-disruptive motifs. In particular the Cecropin-A and Melittin hybrids (CMs) are among the smallest and most effective peptides with membrane-perturbing abilities. Here we present a novel chimeric peptide in which the Tat(11) motif is fused to the CM(18) hybrid (KWKLFKKIGAVLKVLTTG, residues 1-7 of Cecropin-A and 2-12 of Melittin). When administered to cells, CM(18)-Tat(11) combines the two desired functionalities: efficient uptake and destabilization of endocytotic-vesicle membranes. We show that this chimeric peptide effectively increases cargo-molecule cytoplasm availability and allows the subsequent intracellular localization of diverse membrane-impermeable molecules (i.e. Tat(11)-EGFP fusion protein, calcein, dextrans, and plasmidic DNA) with no detectable cytotoxicity. The present results open the way to the rational engineering of "modular" cell-penetrating peptides (CPPs) that combine (i) efficient translocation from the extracellular milieu into vesicles and (ii) efficient release of molecules from vesicles into the cytoplasm. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of process parameters on microstructure and electrical conductivity during FSW of Al-6101 and Pure Copper

NASA Astrophysics Data System (ADS)

Sharma, Nidhi; Khan, Zahid A.; Siddiquee, Arshad Noor; Shihab, Suha K.; Atif Wahid, Mohd

2018-04-01

Copper (Cu) is predominantly used material as a conducting element in electrical and electronic components due to its high conductivity. Aluminum (Al) being lighter in weight and more conductive on weight basis than that of Cu is able to replace or partially replace Cu to make lighter and cost effective electrical components. Conventional methods of joining Al to Cu, such as, fusion welding process have many shortcomings. Friction Stir Welding (FSW) is a solid state welding process which overcomes the shortcoming of the fusion welding. FSW parameters affect the mechanical and electrical properties of the joint. This study aims to evaluate the effect of different process parameters such as shoulder diameter, pin offset, welding and rotational speed on the microstructure and electrical conductivity of the dissimilar Al-Cu joint. FSW is performed using cylindrical pin profile, and four process parameters. Each parameter at different levels is varied according to Taguchi’s L18 standard orthogonal array. It is found that the electrical conductivity of the FSWed joints are equal to that of aluminum at all the welded sections. FSW is found to be an effective technique to join Al to Cu without compromising with the electrical properties. However, the electrical conductivity gets influenced by the process parameters in the stir zone. The optimal combination of the FSW parameters for maximum electrical conductivity is determined. The analysis of variance (ANOVA) technique applied on stir zone suggests that the rotational speed and tool pin offset are the significant parameters to influence the electrical conductivity.

Assessment of Process Capability: the case of Soft Drinks Processing Unit

NASA Astrophysics Data System (ADS)

Sri Yogi, Kottala

2018-03-01

The process capability studies have significant impact in investigating process variation which is important in achieving product quality characteristics. Its indices are to measure the inherent variability of a process and thus to improve the process performance radically. The main objective of this paper is to understand capability of the process being produced within specification of the soft drinks processing unit, a premier brands being marketed in India. A few selected critical parameters in soft drinks processing: concentration of gas volume, concentration of brix, torque of crock has been considered for this study. Assessed some relevant statistical parameters: short term capability, long term capability as a process capability indices perspective. For assessment we have used real time data of soft drinks bottling company which is located in state of Chhattisgarh, India. As our research output suggested reasons for variations in the process which is validated using ANOVA and also predicted Taguchi cost function, assessed also predicted waste monetarily this shall be used by organization for improving process parameters. This research work has substantially benefitted the organization in understanding the various variations of selected critical parameters for achieving zero rejection.

Experimental Research on Selective Laser Melting AlSi10Mg Alloys: Process, Densification and Performance

NASA Astrophysics Data System (ADS)

Chen, Zhen; Wei, Zhengying; Wei, Pei; Chen, Shenggui; Lu, Bingheng; Du, Jun; Li, Junfeng; Zhang, Shuzhe

2017-12-01

In this work, a set of experiments was designed to investigate the effect of process parameters on the relative density of the AlSi10Mg parts manufactured by SLM. The influence of laser scan speed v, laser power P and hatch space H, which were considered as the dominant parameters, on the powder melting and densification behavior was also studied experimentally. In addition, the laser energy density was introduced to evaluate the combined effect of the above dominant parameters, so as to control the SLM process integrally. As a result, a high relative density (> 97%) was obtained by SLM at an optimized laser energy density of 3.5-5.5 J/mm2. Moreover, a parameter-densification map was established to visually select the optimum process parameters for the SLM-processed AlSi10Mg parts with elevated density and required mechanical properties. The results provide an important experimental guidance for obtaining AlSi10Mg components with full density and gradient functional porosity by SLM.

A Study on the Influence of Process Parameters on the Viscoelastic Properties of ABS Components Manufactured by FDM Process

NASA Astrophysics Data System (ADS)

Dakshinamurthy, Devika; Gupta, Srinivasa

2018-04-01

Fused Deposition Modelling (FDM) is a fast growing Rapid Prototyping (RP) technology due to its ability to build parts having complex geometrical shape in reasonable time period. The quality of built parts depends on many process variables. In this study, the influence of three FDM process parameters namely, slice height, raster angle and raster width on viscoelastic properties of Acrylonitrile Butadiene Styrene (ABS) RP-specimen is studied. Statistically designed experiments have been conducted for finding the optimum process parameter setting for enhancing the storage modulus. Dynamic Mechanical Analysis has been used to understand the viscoelastic properties at various parameter settings. At the optimal parameter setting the storage modulus and loss modulus of the ABS-RP specimen was 1008 and 259.9 MPa respectively. The relative percentage contribution of slice height and raster width on the viscoelastic properties of the FDM-RP components was found to be 55 and 31 % respectively.

An Adaptive Kalman Filter using a Simple Residual Tuning Method

NASA Technical Reports Server (NTRS)

Harman, Richard R.

1999-01-01

One difficulty in using Kalman filters in real world situations is the selection of the correct process noise, measurement noise, and initial state estimate and covariance. These parameters are commonly referred to as tuning parameters. Multiple methods have been developed to estimate these parameters. Most of those methods such as maximum likelihood, subspace, and observer Kalman Identification require extensive offline processing and are not suitable for real time processing. One technique, which is suitable for real time processing, is the residual tuning method. Any mismodeling of the filter tuning parameters will result in a non-white sequence for the filter measurement residuals. The residual tuning technique uses this information to estimate corrections to those tuning parameters. The actual implementation results in a set of sequential equations that run in parallel with the Kalman filter. Equations for the estimation of the measurement noise have also been developed. These algorithms are used to estimate the process noise and measurement noise for the Wide Field Infrared Explorer star tracker and gyro.

Optimization of hybrid laser - TIG welding of 316LN steel using response surface methodology (RSM)

NASA Astrophysics Data System (ADS)

Ragavendran, M.; Chandrasekhar, N.; Ravikumar, R.; Saxena, Rajesh; Vasudevan, M.; Bhaduri, A. K.

2017-07-01

In the present study, the hybrid laser - TIG welding parameters for welding of 316LN austenitic stainless steel have been investigated by combining a pulsed laser beam with a TIG welding heat source at the weld pool. Laser power, pulse frequency, pulse duration, TIG current were presumed as the welding process parameters whereas weld bead width, weld cross-sectional area and depth of penetration (DOP) were considered as the process responses. Central composite design was used to complete the design matrix and welding experiments were conducted based on the design matrix. Weld bead measurements were then carried out to generate the dataset. Multiple regression models correlating the process parameters with the responses have been developed. The accuracy of the models were found to be good. Then, the desirability approach optimization technique was employed for determining the optimum process parameters to obtain the desired weld bead profile. Validation experiments were then carried out from the determined optimum process parameters. There was good agreement between the predicted and measured values.

Integrated controls design optimization

DOEpatents

Lou, Xinsheng; Neuschaefer, Carl H.

2015-09-01

A control system (207) for optimizing a chemical looping process of a power plant includes an optimizer (420), an income algorithm (230) and a cost algorithm (225) and a chemical looping process models. The process models are used to predict the process outputs from process input variables. Some of the process in puts and output variables are related to the income of the plant; and some others are related to the cost of the plant operations. The income algorithm (230) provides an income input to the optimizer (420) based on a plurality of input parameters (215) of the power plant. The cost algorithm (225) provides a cost input to the optimizer (420) based on a plurality of output parameters (220) of the power plant. The optimizer (420) determines an optimized operating parameter solution based on at least one of the income input and the cost input, and supplies the optimized operating parameter solution to the power plant.

Optimization and Simulation of SLM Process for High Density H13 Tool Steel Parts

NASA Astrophysics Data System (ADS)

Laakso, Petri; Riipinen, Tuomas; Laukkanen, Anssi; Andersson, Tom; Jokinen, Antero; Revuelta, Alejandro; Ruusuvuori, Kimmo

This paper demonstrates the successful printing and optimization of processing parameters of high-strength H13 tool steel by Selective Laser Melting (SLM). D-Optimal Design of Experiments (DOE) approach is used for parameter optimization of laser power, scanning speed and hatch width. With 50 test samples (1×1×1cm) we establish parameter windows for these three parameters in relation to part density. The calculated numerical model is found to be in good agreement with the density data obtained from the samples using image analysis. A thermomechanical finite element simulation model is constructed of the SLM process and validated by comparing the calculated densities retrieved from the model with the experimentally determined densities. With the simulation tool one can explore the effect of different parameters on density before making any printed samples. Establishing a parameter window provides the user with freedom for parameter selection such as choosing parameters that result in fastest print speed.

Optimum Design of Forging Process Parameters and Preform Shape under Uncertainties

NASA Astrophysics Data System (ADS)

Repalle, Jalaja; Grandhi, Ramana V.

2004-06-01

Forging is a highly complex non-linear process that is vulnerable to various uncertainties, such as variations in billet geometry, die temperature, material properties, workpiece and forging equipment positional errors and process parameters. A combination of these uncertainties could induce heavy manufacturing losses through premature die failure, final part geometric distortion and production risk. Identifying the sources of uncertainties, quantifying and controlling them will reduce risk in the manufacturing environment, which will minimize the overall cost of production. In this paper, various uncertainties that affect forging tool life and preform design are identified, and their cumulative effect on the forging process is evaluated. Since the forging process simulation is computationally intensive, the response surface approach is used to reduce time by establishing a relationship between the system performance and the critical process design parameters. Variability in system performance due to randomness in the parameters is computed by applying Monte Carlo Simulations (MCS) on generated Response Surface Models (RSM). Finally, a Robust Methodology is developed to optimize forging process parameters and preform shape. The developed method is demonstrated by applying it to an axisymmetric H-cross section disk forging to improve the product quality and robustness.

PMMA/PS coaxial electrospinning: a statistical analysis on processing parameters

NASA Astrophysics Data System (ADS)

Rahmani, Shahrzad; Arefazar, Ahmad; Latifi, Masoud

2017-08-01

Coaxial electrospinning, as a versatile method for producing core-shell fibers, is known to be very sensitive to two classes of influential factors including material and processing parameters. Although coaxial electrospinning has been the focus of many studies, the effects of processing parameters on the outcomes of this method have not yet been well investigated. A good knowledge of the impacts of processing parameters and their interactions on coaxial electrospinning can make it possible to better control and optimize this process. Hence, in this study, the statistical technique of response surface method (RSM) using the design of experiments on four processing factors of voltage, distance, core and shell flow rates was applied. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), oil immersion and Fluorescent microscopy were used to characterize fiber morphology. The core and shell diameters of fibers were measured and the effects of all factors and their interactions were discussed. Two polynomial models with acceptable R-squares were proposed to describe the core and shell diameters as functions of the processing parameters. Voltage and distance were recognized as the most significant and influential factors on shell diameter, while core diameter was mainly under the influence of core and shell flow rates besides the voltage.

Mammalian cell culture process for monoclonal antibody production: nonlinear modelling and parameter estimation.

PubMed

Selişteanu, Dan; Șendrescu, Dorin; Georgeanu, Vlad; Roman, Monica

2015-01-01

Monoclonal antibodies (mAbs) are at present one of the fastest growing products of pharmaceutical industry, with widespread applications in biochemistry, biology, and medicine. The operation of mAbs production processes is predominantly based on empirical knowledge, the improvements being achieved by using trial-and-error experiments and precedent practices. The nonlinearity of these processes and the absence of suitable instrumentation require an enhanced modelling effort and modern kinetic parameter estimation strategies. The present work is dedicated to nonlinear dynamic modelling and parameter estimation for a mammalian cell culture process used for mAb production. By using a dynamical model of such kind of processes, an optimization-based technique for estimation of kinetic parameters in the model of mammalian cell culture process is developed. The estimation is achieved as a result of minimizing an error function by a particle swarm optimization (PSO) algorithm. The proposed estimation approach is analyzed in this work by using a particular model of mammalian cell culture, as a case study, but is generic for this class of bioprocesses. The presented case study shows that the proposed parameter estimation technique provides a more accurate simulation of the experimentally observed process behaviour than reported in previous studies.

Mammalian Cell Culture Process for Monoclonal Antibody Production: Nonlinear Modelling and Parameter Estimation

PubMed Central

Selişteanu, Dan; Șendrescu, Dorin; Georgeanu, Vlad

2015-01-01

Monoclonal antibodies (mAbs) are at present one of the fastest growing products of pharmaceutical industry, with widespread applications in biochemistry, biology, and medicine. The operation of mAbs production processes is predominantly based on empirical knowledge, the improvements being achieved by using trial-and-error experiments and precedent practices. The nonlinearity of these processes and the absence of suitable instrumentation require an enhanced modelling effort and modern kinetic parameter estimation strategies. The present work is dedicated to nonlinear dynamic modelling and parameter estimation for a mammalian cell culture process used for mAb production. By using a dynamical model of such kind of processes, an optimization-based technique for estimation of kinetic parameters in the model of mammalian cell culture process is developed. The estimation is achieved as a result of minimizing an error function by a particle swarm optimization (PSO) algorithm. The proposed estimation approach is analyzed in this work by using a particular model of mammalian cell culture, as a case study, but is generic for this class of bioprocesses. The presented case study shows that the proposed parameter estimation technique provides a more accurate simulation of the experimentally observed process behaviour than reported in previous studies. PMID:25685797

Optimization of Primary Drying in Lyophilization during Early Phase Drug Development using a Definitive Screening Design with Formulation and Process Factors.

PubMed

Goldman, Johnathan M; More, Haresh T; Yee, Olga; Borgeson, Elizabeth; Remy, Brenda; Rowe, Jasmine; Sadineni, Vikram

2018-06-08

Development of optimal drug product lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the drug product formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. In order to overcome these development difficulties, an eight factor definitive screening design (DSD), including both formulation and process parameters, was executed on a fully human monoclonal antibody (mAb) drug product. The DSD enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different drug product formulations. This concept is demonstrated on a mAb drug product where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments (DoE) approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions. Copyright © 2018. Published by Elsevier Inc.

Experiments for practical education in process parameter optimization for selective laser sintering to increase workpiece quality

NASA Astrophysics Data System (ADS)

Reutterer, Bernd; Traxler, Lukas; Bayer, Natascha; Drauschke, Andreas

2016-04-01

Selective Laser Sintering (SLS) is considered as one of the most important additive manufacturing processes due to component stability and its broad range of usable materials. However the influence of the different process parameters on mechanical workpiece properties is still poorly studied, leading to the fact that further optimization is necessary to increase workpiece quality. In order to investigate the impact of various process parameters, laboratory experiments are implemented to improve the understanding of the SLS limitations and advantages on an educational level. Experiments are based on two different workstations, used to teach students the fundamentals of SLS. First of all a 50 W CO2 laser workstation is used to investigate the interaction of the laser beam with the used material in accordance with varied process parameters to analyze a single-layered test piece. Second of all the FORMIGA P110 laser sintering system from EOS is used to print different 3D test pieces in dependence on various process parameters. Finally quality attributes are tested including warpage, dimension accuracy or tensile strength. For dimension measurements and evaluation of the surface structure a telecentric lens in combination with a camera is used. A tensile test machine allows testing of the tensile strength and the interpreting of stress-strain curves. The developed laboratory experiments are suitable to teach students the influence of processing parameters. In this context they will be able to optimize the input parameters depending on the component which has to be manufactured and to increase the overall quality of the final workpiece.

Laser welding of polymers: phenomenological model for a quick and reliable process quality estimation considering beam shape influences

NASA Astrophysics Data System (ADS)

Timpe, Nathalie F.; Stuch, Julia; Scholl, Marcus; Russek, Ulrich A.

2016-03-01

This contribution presents a phenomenological, analytical model for laser welding of polymers which is suited for a quick process quality estimation for the practitioner. Besides material properties of the polymer and processing parameters like welding pressure, feed rate and laser power the model is based on a simple few parameter description of the size and shape of the laser power density distribution (PDD) in the processing zone. The model allows an estimation of the weld seam tensile strength. It is based on energy balance considerations within a thin sheet with the thickness of the optical penetration depth on the surface of the absorbing welding partner. The joining process itself is modelled by a phenomenological approach. The model reproduces the experimentally known process windows for the main process parameters correctly. Using the parameters describing the shape of the laser PDD the critical dependence of the process windows on the PDD shape will be predicted and compared with experiments. The adaption of the model to other laser manufacturing processes where the PDD influence can be modelled comparably will be discussed.

Application of Quality by Design to the characterization of the cell culture process of an Fc-Fusion protein.

PubMed

Rouiller, Yolande; Solacroup, Thomas; Deparis, Véronique; Barbafieri, Marco; Gleixner, Ralf; Broly, Hervé; Eon-Duval, Alex

2012-06-01

The production bioreactor step of an Fc-Fusion protein manufacturing cell culture process was characterized following Quality by Design principles. Using scientific knowledge derived from the literature and process knowledge gathered during development studies and manufacturing to support clinical trials, potential critical and key process parameters with a possible impact on product quality and process performance, respectively, were determined during a risk assessment exercise. The identified process parameters were evaluated using a design of experiment approach. The regression models generated from the data allowed characterizing the impact of the identified process parameters on quality attributes. The main parameters having an impact on product titer were pH and dissolved oxygen, while those having the highest impact on process- and product-related impurities and variants were pH and culture duration. The models derived from characterization studies were used to define the cell culture process design space. The design space limits were set in such a way as to ensure that the drug substance material would consistently have the desired quality. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of functionally-oriented technological processes of electroerosive processing

NASA Astrophysics Data System (ADS)

Syanov, S. Yu

2018-03-01

The stages of the development of functionally oriented technological processes of electroerosive processing from the separation of the surfaces of parts and their service functions to the determination of the parameters of the process of electric erosion, which will provide not only the quality parameters of the surface layer, but also the required operational properties, are described.

[Feedforward control strategy and its application in quality improvement of ethanol precipitation process of danhong injection].

PubMed

Yan, Bin-Jun; Guo, Zheng-Tai; Qu, Hai-Bin; Zhao, Bu-Chang; Zhao, Tao

2013-06-01

In this work, a feedforward control strategy basing on the concept of quality by design was established for the manufacturing process of traditional Chinese medicine to reduce the impact of the quality variation of raw materials on drug. In the research, the ethanol precipitation process of Danhong injection was taken as an application case of the method established. Box-Behnken design of experiments was conducted. Mathematical models relating the attributes of the concentrate, the process parameters and the quality of the supernatants produced were established. Then an optimization model for calculating the best process parameters basing on the attributes of the concentrate was built. The quality of the supernatants produced by ethanol precipitation with optimized and non-optimized process parameters were compared. The results showed that using the feedforward control strategy for process parameters optimization can control the quality of the supernatants effectively. The feedforward control strategy proposed can enhance the batch-to-batch consistency of the supernatants produced by ethanol precipitation.

Effects of Processing Parameters on the Forming Quality of C-Shaped Thermosetting Composite Laminates in Hot Diaphragm Forming Process

NASA Astrophysics Data System (ADS)

Bian, X. X.; Gu, Y. Z.; Sun, J.; Li, M.; Liu, W. P.; Zhang, Z. G.

2013-10-01

In this study, the effects of processing temperature and vacuum applying rate on the forming quality of C-shaped carbon fiber reinforced epoxy resin matrix composite laminates during hot diaphragm forming process were investigated. C-shaped prepreg preforms were produced using a home-made hot diaphragm forming equipment. The thickness variations of the preforms and the manufacturing defects after diaphragm forming process, including fiber wrinkling and voids, were evaluated to understand the forming mechanism. Furthermore, both interlaminar slipping friction and compaction behavior of the prepreg stacks were experimentally analyzed for showing the importance of the processing parameters. In addition, autoclave processing was used to cure the C-shaped preforms to investigate the changes of the defects before and after cure process. The results show that the C-shaped prepreg preforms with good forming quality can be achieved through increasing processing temperature and reducing vacuum applying rate, which obviously promote prepreg interlaminar slipping process. The process temperature and forming rate in hot diaphragm forming process strongly influence prepreg interply frictional force, and the maximum interlaminar frictional force can be taken as a key parameter for processing parameter optimization. Autoclave process is effective in eliminating voids in the preforms and can alleviate fiber wrinkles to a certain extent.

Gaussian process inference for estimating pharmacokinetic parameters of dynamic contrast-enhanced MR images.

PubMed

Wang, Shijun; Liu, Peter; Turkbey, Baris; Choyke, Peter; Pinto, Peter; Summers, Ronald M

2012-01-01

In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps.

Knowledge transmission model with differing initial transmission and retransmission process

NASA Astrophysics Data System (ADS)

Wang, Haiying; Wang, Jun; Small, Michael

2018-10-01

Knowledge transmission is a cyclic dynamic diffusion process. The rate of acceptance of knowledge differs upon whether or not the recipient has previously held the knowledge. In this paper, the knowledge transmission process is divided into an initial and a retransmission procedure, each with its own transmission and self-learning parameters. Based on epidemic spreading model, we propose a naive-evangelical-agnostic (VEA) knowledge transmission model and derive mean-field equations to describe the dynamics of knowledge transmission in homogeneous networks. Theoretical analysis identifies a criterion for the persistence of knowledge, i.e., the reproduction number R0 depends on the minor effective parameters between the initial and retransmission process. Moreover, the final size of evangelical individuals is only related to retransmission process parameters. Numerical simulations validate the theoretical analysis. Furthermore, the simulations indicate that increasing the initial transmission parameters, including first transmission and self-learning rates of naive individuals, can accelerate the velocity of knowledge transmission efficiently but have no effect on the final size of evangelical individuals. In contrast, the retransmission parameters, including retransmission and self-learning rates of agnostic individuals, have a significant effect on the rate of knowledge transmission, i.e., the larger parameters the greater final density of evangelical individuals.

Review of Relationship Between Particle Deformation, Coating Microstructure, and Properties in High-Pressure Cold Spray

NASA Astrophysics Data System (ADS)

Rokni, M. R.; Nutt, S. R.; Widener, C. A.; Champagne, V. K.; Hrabe, R. H.

2017-08-01

In the cold spray (CS) process, deposits are produced by depositing powder particles at high velocity onto a substrate. Powders deposited by CS do not undergo melting before or upon impacting the substrate. This feature makes CS suitable for deposition of a wide variety of materials, most commonly metallic alloys, but also ceramics and composites. During processing, the particles undergo severe plastic deformation and create a more mechanical and less metallurgical bond with the underlying material. The deformation behavior of an individual particle depends on multiple material and process parameters that are classified into three major groups—powder characteristics, geometric parameters, and processing parameters, each with their own subcategories. Changing any of these parameters leads to evolution of a different microstructure and consequently changes the mechanical properties in the deposit. While cold spray technology has matured during the last decade, the process is inherently complex, and thus, the effects of deposition parameters on particle deformation, deposit microstructure, and mechanical properties remain unclear. The purpose of this paper is to review the parameters that have been investigated up to now with an emphasis on the existent relationships between particle deformation behavior, microstructure, and mechanical properties of various cold spray deposits.

Intelligent Modeling Combining Adaptive Neuro Fuzzy Inference System and Genetic Algorithm for Optimizing Welding Process Parameters

NASA Astrophysics Data System (ADS)

Gowtham, K. N.; Vasudevan, M.; Maduraimuthu, V.; Jayakumar, T.

2011-04-01

Modified 9Cr-1Mo ferritic steel is used as a structural material for steam generator components of power plants. Generally, tungsten inert gas (TIG) welding is preferred for welding of these steels in which the depth of penetration achievable during autogenous welding is limited. Therefore, activated flux TIG (A-TIG) welding, a novel welding technique, has been developed in-house to increase the depth of penetration. In modified 9Cr-1Mo steel joints produced by the A-TIG welding process, weld bead width, depth of penetration, and heat-affected zone (HAZ) width play an important role in determining the mechanical properties as well as the performance of the weld joints during service. To obtain the desired weld bead geometry and HAZ width, it becomes important to set the welding process parameters. In this work, adaptative neuro fuzzy inference system is used to develop independent models correlating the welding process parameters like current, voltage, and torch speed with weld bead shape parameters like depth of penetration, bead width, and HAZ width. Then a genetic algorithm is employed to determine the optimum A-TIG welding process parameters to obtain the desired weld bead shape parameters and HAZ width.

Optimal Design of Material and Process Parameters in Powder Injection Molding

NASA Astrophysics Data System (ADS)

Ayad, G.; Barriere, T.; Gelin, J. C.; Song, J.; Liu, B.

2007-04-01

The paper is concerned with optimization and parametric identification for the different stages in Powder Injection Molding process that consists first in injection of powder mixture with polymer binder and then to the sintering of the resulting powders part by solid state diffusion. In the first part, one describes an original methodology to optimize the process and geometry parameters in injection stage based on the combination of design of experiments and an adaptive Response Surface Modeling. Then the second part of the paper describes the identification strategy that one proposes for the sintering stage, using the identification of sintering parameters from dilatometeric curves followed by the optimization of the sintering process. The proposed approaches are applied to the optimization of material and process parameters for manufacturing a ceramic femoral implant. One demonstrates that the proposed approach give satisfactory results.

Effects of the Deslagging Process on some Physicochemical Parameters of Honey

PubMed Central

Ranjbar, Ali Mohammad; Sadeghpour, Omid; Khanavi, Mahnaz; Shams Ardekani, Mohammad Reza; Moloudian, Hamid; Hajimahmoodi, Mannan

2015-01-01

Some physicochemical parameters of honey have been introduced by the International Honey Commission to evaluate its quality and origin but processes such as heating and filtering can affect these parameters. In traditional Iranian medicine, deslagging process involves boiling honey in an equal volume of water and removing the slag formed during process. The aim of this study was to determine the effects of deslagging process on parameters of color intensity, diastase evaluation, electrical conductivity, pH, free acidity, refractive index, hydroxy methyl furfural (HMF), proline and water contents according to the International Honey Committee (IHC) standards. The results showed that deslagged honey was significantly different from control honey in terms of color intensity, pH, diastase number, HMF and proline content. It can be concluded that the new standards are needed to regulate deslagged honey. PMID:25901175

The impact of standard and hard-coded parameters on the hydrologic fluxes in the Noah-MP land surface model

NASA Astrophysics Data System (ADS)

Cuntz, Matthias; Mai, Juliane; Samaniego, Luis; Clark, Martyn; Wulfmeyer, Volker; Branch, Oliver; Attinger, Sabine; Thober, Stephan

2016-09-01

Land surface models incorporate a large number of process descriptions, containing a multitude of parameters. These parameters are typically read from tabulated input files. Some of these parameters might be fixed numbers in the computer code though, which hinder model agility during calibration. Here we identified 139 hard-coded parameters in the model code of the Noah land surface model with multiple process options (Noah-MP). We performed a Sobol' global sensitivity analysis of Noah-MP for a specific set of process options, which includes 42 out of the 71 standard parameters and 75 out of the 139 hard-coded parameters. The sensitivities of the hydrologic output fluxes latent heat and total runoff as well as their component fluxes were evaluated at 12 catchments within the United States with very different hydrometeorological regimes. Noah-MP's hydrologic output fluxes are sensitive to two thirds of its applicable standard parameters (i.e., Sobol' indexes above 1%). The most sensitive parameter is, however, a hard-coded value in the formulation of soil surface resistance for direct evaporation, which proved to be oversensitive in other land surface models as well. Surface runoff is sensitive to almost all hard-coded parameters of the snow processes and the meteorological inputs. These parameter sensitivities diminish in total runoff. Assessing these parameters in model calibration would require detailed snow observations or the calculation of hydrologic signatures of the runoff data. Latent heat and total runoff exhibit very similar sensitivities because of their tight coupling via the water balance. A calibration of Noah-MP against either of these fluxes should therefore give comparable results. Moreover, these fluxes are sensitive to both plant and soil parameters. Calibrating, for example, only soil parameters hence limit the ability to derive realistic model parameters. It is thus recommended to include the most sensitive hard-coded model parameters that were exposed in this study when calibrating Noah-MP.

Determination of Process Parameters for High-Density, Ti-6Al-4V Parts Using Additive Manufacturing

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

Kamath, C.

In our earlier work, we described an approach for determining the process parameters that re- sult in high-density parts manufactured using the additive-manufacturing process of selective laser melting (SLM). Our approach, which combines simple simulations and experiments, was demon- strated using 316L stainless steel. We have also used the approach successfully for several other materials. This short note summarizes the results of our work in determining process parameters for Ti-6Al-4V using a Concept Laser M2 system.

Study of the joining of polycarbonate panels in butt joint configuration through friction stir welding

NASA Astrophysics Data System (ADS)

Astarita, Antonello; Boccarusso, Luca; Carrino, Luigi; Durante, Massimo; Minutolo, Fabrizio Memola Capece; Squillace, Antonino

2018-05-01

Polycarbonate sheets, 3 mm thick, were successfully friction stir welded in butt joint configuration. Aiming to study the feasibility of the process and the influence of the process parameters joints under different processing conditions, obtained by varying the tool rotational speed and the tool travel speed, were realized. Tensile tests were carried out to characterize the joints. Moreover the forces arising during the process were recorded and carefully studied. The experimental outcomes proved the feasibility of the process when the process parameters are properly set, joints retaining more than 70% of the UTS of the base material were produced. The trend of the forces was described and explained, the influence of the process parameters was also introduced.

Analysing the influence of FSP process parameters on IGC susceptibility of AA5083 using Sugeno - Fuzzy model

NASA Astrophysics Data System (ADS)

Jayakarthick, C.; Povendhan, A. P.; Vaira Vignesh, R.; Padmanaban, R.

2018-02-01

Aluminium alloy AA5083 was friction stir processed to improve the intergranular corrosion (IGC) resistance. FSP trials were performed by varying the process parameters as per Taguchi’s L18 orthogonal array. IGC resistance of the friction stir processed specimens were found by immersing them in concentrated nitric acid and measuring the mass loss per unit area. Results indicate that dispersion and partial dissolution of secondary phase increased IGC resistance of the friction stir processed specimens. A Sugeno fuzzy model was developed to study the effect of FSP process parameters on the IGC susceptibility of friction stir processed specimens. Tool Rotation Speed, Tool Traverse Speed and Shoulder Diameter have a significant effect on the IGC susceptibility of the friction stir processed specimens.

Development of viral nanoparticles for efficient intracellular delivery

NASA Astrophysics Data System (ADS)

Wu, Zhuojun; Chen, Kevin; Yildiz, Ibrahim; Dirksen, Anouk; Fischer, Rainer; Dawson, Philip E.; Steinmetz, Nicole F.

2012-05-01

Viral nanoparticles (VNPs) based on plant viruses such as Cowpea mosaic virus (CPMV) can be used for a broad range of biomedical applications because they present a robust scaffold that allows functionalization by chemical conjugation and genetic modification, thereby offering an efficient drug delivery platform that can target specific cells and tissues. VNPs such as CPMV show natural affinity to cells; however, cellular uptake is inefficient. Here we show that chemical modification of the CPMV surface with a highly reactive, specific and UV-traceable hydrazone linker allows bioconjugation of polyarginine (R5) cell penetrating peptides (CPPs), which can overcome these limitations. The resulting CPMV-R5 particles were taken up into a human cervical cancer cell line (HeLa) more efficiently than native particles. Uptake efficiency was dependent on the density of R5 peptides on the surface of the VNP; particles displaying 40 R5 peptides per CPMV (denoted as CPMV-R5H) interact strongly with the plasma membrane and are taken up into the cells via an energy-dependent mechanism whereas particles displaying 10 R5 peptides per CPMV (CPMV-R5L) are only slowly taken up. The fate of CPMV-R5 versus native CPMV particles within cells was evaluated in a co-localization time course study. It was indicated that the intracellular localization of CPMV-R5 and CPMV differs; CPMV remains trapped in Lamp-1 positive endolysosomes over long time frames; in contrast, 30-50% of the CPMV-R5 particles transitioned from the endosome into other cellular vesicles or compartments. Our data provide the groundwork for the development of efficient drug delivery formulations based on CPMV-R5.Viral nanoparticles (VNPs) based on plant viruses such as Cowpea mosaic virus (CPMV) can be used for a broad range of biomedical applications because they present a robust scaffold that allows functionalization by chemical conjugation and genetic modification, thereby offering an efficient drug delivery platform that can target specific cells and tissues. VNPs such as CPMV show natural affinity to cells; however, cellular uptake is inefficient. Here we show that chemical modification of the CPMV surface with a highly reactive, specific and UV-traceable hydrazone linker allows bioconjugation of polyarginine (R5) cell penetrating peptides (CPPs), which can overcome these limitations. The resulting CPMV-R5 particles were taken up into a human cervical cancer cell line (HeLa) more efficiently than native particles. Uptake efficiency was dependent on the density of R5 peptides on the surface of the VNP; particles displaying 40 R5 peptides per CPMV (denoted as CPMV-R5H) interact strongly with the plasma membrane and are taken up into the cells via an energy-dependent mechanism whereas particles displaying 10 R5 peptides per CPMV (CPMV-R5L) are only slowly taken up. The fate of CPMV-R5 versus native CPMV particles within cells was evaluated in a co-localization time course study. It was indicated that the intracellular localization of CPMV-R5 and CPMV differs; CPMV remains trapped in Lamp-1 positive endolysosomes over long time frames; in contrast, 30-50% of the CPMV-R5 particles transitioned from the endosome into other cellular vesicles or compartments. Our data provide the groundwork for the development of efficient drug delivery formulations based on CPMV-R5. Electronic supplementary information (ESI) available: Experimental details and additional supporting data. See DOI: 10.1039/c2nr30366c

Testosterone and Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Propensity Score-Matched Analysis.

PubMed

Lee, Jun Ho; Lee, Sung Won

2016-07-01

A recent study investigated the role of testosterone (T) in chronic prostatitis or chronic pelvic pain syndrome (CP/CPPS). However, only a small amount of data is available to date, and the results are inconsistent. To evaluate the relation between total T (TT) and CP/CPPS. We conducted a propensity-matched study by identifying men with a TT level lower than 3.5 ng/mL among 8,336 men in their 40s and 50s. A control group of men with a TT level of at least 3.5 ng/mL matched for age, metabolic syndrome, and body mass index at a 5:1 ratio was selected for comparison. Using the same cohort and methods, another case group (TT < 3.0 ng/mL) and control group (TT ≥ 3.0 ng/mL) were selected. The National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) was administered. A χ(2) test, a t-test and logistic regression analyses were used to evaluate the relation between TT and prostatitis-like symptoms. Association of TT with NIH-CPSI score. After propensity score matching, 948 cases (TT < 3.5 ng/mL) and 4,740 controls (TT ≥ 3.5 ng/mL) were included. The ratio of mild and moderate to severe prostatitis-like symptoms was higher in the case group than in the control group (24.0% vs 27.4%, P = .001). The ratio of moderate to severe prostatitis-like symptoms also was higher in the case group than in the control group (6.2% vs 9.2%, P = .028). The pain domain of the NIH-CPSI, quality of life, and total NIH-CPSI scores also were higher in the case group. Ratios of severe lower urinary tract symptoms (12.6% vs 15.1%, P = .044) to maximal flow rate no higher than 10 mL/sec (3.8% vs 5.3%, P = .044) and postvoid residual urine volume of at least 100 mL (4.0% vs 5.6%, P = .035), which suggest high pressure in the prostate urethra, were higher in the case group. After adjusting for voided volume during uroflowmetry and total prostate volume, the relations of a TT level lower than 3.5 ng/mL to a maximal flow rate no higher than 10 mL/sec (odds ratio = 1.402, 95% CI = 1.017-1.934, P = .039) and to a postvoid residual urine volume of at least 100 mL (odds ratio = 1.410, 95% CI = 1.031-1.927, P = .031) were maintained. Using the cutoff TT value of 3.0 ng/mL, 437 cases (TT < 3.0 ng/mL) and 2,185 controls (TT ≥ 3.0 ng/mL) were included. The result of the 3.0-ng/mL cutoff value for TT showed a higher incidence of prostatitis-like symptoms in the group with a TT level lower than 3.0 ng/mL, but this was not statistically significant. Low TT level (<3.5 ng/mL) was significantly correlated with prostatitis-like symptoms in this study. Copyright © 2016. Published by Elsevier Inc.

Geometry modeling of single track cladding deposited by high power diode laser with rectangular beam spot

NASA Astrophysics Data System (ADS)

Liu, Huaming; Qin, Xunpeng; Huang, Song; Hu, Zeqi; Ni, Mao

2018-01-01

This paper presents an investigation on the relationship between the process parameters and geometrical characteristics of the sectional profile for the single track cladding (STC) deposited by High Power Diode Laser (HPDL) with rectangle beam spot (RBS). To obtain the geometry parameters, namely cladding width Wc and height Hc of the sectional profile, a full factorial design (FFD) of experiment was used to conduct the experiments with a total of 27. The pre-placed powder technique has been employed during laser cladding. The influence of the process parameters including laser power, powder thickness and scanning speed on the Wc and Hc was analyzed in detail. A nonlinear fitting model was used to fit the relationship between the process parameters and geometry parameters. And a circular arc was adopted to describe the geometry profile of the cross-section of STC. The above models were confirmed by all the experiments. The results indicated that the geometrical characteristics of the sectional profile of STC can be described as the circular arc, and the other geometry parameters of the sectional profile can be calculated only using Wc and Hc. Meanwhile, the Wc and Hc can be predicted through the process parameters.

Selection of the most influential factors on the water-jet assisted underwater laser process by adaptive neuro-fuzzy technique

NASA Astrophysics Data System (ADS)

Nikolić, Vlastimir; Petković, Dalibor; Lazov, Lyubomir; Milovančević, Miloš

2016-07-01

Water-jet assisted underwater laser cutting has shown some advantages as it produces much less turbulence, gas bubble and aerosols, resulting in a more gentle process. However, this process has relatively low efficiency due to different losses in water. It is important to determine which parameters are the most important for the process. In this investigation was analyzed the water-jet assisted underwater laser cutting parameters forecasting based on the different parameters. The method of ANFIS (adaptive neuro fuzzy inference system) was applied to the data in order to select the most influential factors for water-jet assisted underwater laser cutting parameters forecasting. Three inputs are considered: laser power, cutting speed and water-jet speed. The ANFIS process for variable selection was also implemented in order to detect the predominant factors affecting the forecasting of the water-jet assisted underwater laser cutting parameters. According to the results the combination of laser power cutting speed forms the most influential combination foe the prediction of water-jet assisted underwater laser cutting parameters. The best prediction was observed for the bottom kerf-width (R2 = 0.9653). The worst prediction was observed for dross area per unit length (R2 = 0.6804). According to the results, a greater improvement in estimation accuracy can be achieved by removing the unnecessary parameter.

Properties of pellets manufactured by wet extrusion/spheronization process using kappa-carrageenan: effect of process parameters.

PubMed

Thommes, Markus; Kleinebudde, Peter

2007-11-09

The aim of this study was to systematically evaluate the pelletization process parameters of kappa-carrageenan-containing formulations. The study dealt with the effect of 4 process parameters--screw speed, number of die holes, friction plate speed, and spheronizer temperature--on the pellet properties of shape, size, size distribution, tensile strength, and drug release. These parameters were varied systematically in a 2(4) full factorial design. In addition, 4 drugs--phenacetin, chloramphenicol, dimenhydrinate, and lidocaine hydrochloride--were investigated under constant process conditions. The most spherical pellets were achieved in a high yield by using a large number of die holes and a high spheronizer speed. There was no relevant influence of the investigated process parameters on the size distribution, mechanical stability, and drug release. The poorly soluble drugs, phenacetin and chloramphenicol, resulted in pellets with adequate shape, size, and tensile strength and a fast drug release. The salts of dimenhydrinate and lidocaine affected pellet shape, mechanical stability, and the drug release properties using an aqueous solution of pH 3 as a granulation liquid. In the case of dimenhydrinate, this was attributed to the ionic interactions with kappa-carrageenan, resulting in a stable matrix during dissolution that did not disintegrate. The effect of lidocaine is comparable to the effect of sodium ions, which suppress the gelling of carrageenan, resulting in pellets with fast disintegration and drug release characteristics. The pellet properties are affected by the process parameters and the active pharmaceutical ingredient used.

Optimization of process parameters in drilling of fibre hybrid composite using Taguchi and grey relational analysis

NASA Astrophysics Data System (ADS)

Vijaya Ramnath, B.; Sharavanan, S.; Jeykrishnan, J.

2017-03-01

Nowadays quality plays a vital role in all the products. Hence, the development in manufacturing process focuses on the fabrication of composite with high dimensional accuracy and also incurring low manufacturing cost. In this work, an investigation on machining parameters has been performed on jute-flax hybrid composite. Here, the two important responses characteristics like surface roughness and material removal rate are optimized by employing 3 machining input parameters. The input variables considered are drill bit diameter, spindle speed and feed rate. Machining is done on CNC vertical drilling machine at different levels of drilling parameters. Taguchi’s L16 orthogonal array is used for optimizing individual tool parameters. Analysis Of Variance is used to find the significance of individual parameters. The simultaneous optimization of the process parameters is done by grey relational analysis. The results of this investigation shows that, spindle speed and drill bit diameter have most effect on material removal rate and surface roughness followed by feed rate.

The combined effect of wet granulation process parameters and dried granule moisture content on tablet quality attributes.

PubMed

Gabbott, Ian P; Al Husban, Farhan; Reynolds, Gavin K

2016-09-01

A pharmaceutical compound was used to study the effect of batch wet granulation process parameters in combination with the residual moisture content remaining after drying on granule and tablet quality attributes. The effect of three batch wet granulation process parameters was evaluated using a multivariate experimental design, with a novel constrained design space. Batches were characterised for moisture content, granule density, crushing strength, porosity, disintegration time and dissolution. Mechanisms of the effect of the process parameters on the granule and tablet quality attributes are proposed. Water quantity added during granulation showed a significant effect on granule density and tablet dissolution rate. Mixing time showed a significant effect on tablet crushing strength, and mixing speed showed a significant effect on the distribution of tablet crushing strengths obtained. The residual moisture content remaining after granule drying showed a significant effect on tablet crushing strength. The effect of moisture on tablet tensile strength has been reported before, but not in combination with granulation parameters and granule properties, and the impact on tablet dissolution was not assessed. Correlations between the energy input during granulation, the density of granules produced, and the quality attributes of the final tablets were also identified. Understanding the impact of the granulation and drying process parameters on granule and tablet properties provides a basis for process optimisation and scaling. Copyright © 2016 Elsevier B.V. All rights reserved.

A concept of volume rendering guided search process to analyze medical data set.

PubMed

Zhou, Jianlong; Xiao, Chun; Wang, Zhiyan; Takatsuka, Masahiro

2008-03-01

This paper firstly presents an approach of parallel coordinates based parameter control panel (PCP). The PCP is used to control parameters of focal region-based volume rendering (FRVR) during data analysis. It uses a parallel coordinates style interface. Different rendering parameters represented with nodes on each axis, and renditions based on related parameters are connected using polylines to show dependencies between renditions and parameters. Based on the PCP, a concept of volume rendering guided search process is proposed. The search pipeline is divided into four phases. Different parameters of FRVR are recorded and modulated in the PCP during search phases. The concept shows that volume visualization could play the role of guiding a search process in the rendition space to help users to efficiently find local structures of interest. The usability of the proposed approach is evaluated to show its effectiveness.

Quantitative Experimental Study of Defects Induced by Process Parameters in the High-Pressure Die Cast Process

NASA Astrophysics Data System (ADS)

Sharifi, P.; Jamali, J.; Sadayappan, K.; Wood, J. T.

2018-05-01

A quantitative experimental study of the effects of process parameters on the formation of defects during solidification of high-pressure die cast magnesium alloy components is presented. The parameters studied are slow-stage velocity, fast-stage velocity, intensification pressure, and die temperature. The amount of various defects are quantitatively characterized. Multiple runs of the commercial casting simulation package, ProCAST™, are used to model the mold-filling and solidification events. Several locations in the component including knit lines, last-to-fill region, and last-to-solidify region are identified as the critical regions that have a high concentration of defects. The area fractions of total porosity, shrinkage porosity, gas porosity, and externally solidified grains are separately measured. This study shows that the process parameters, fluid flow and local solidification conditions, play major roles in the formation of defects during HPDC process.

Economic design of control charts considering process shift distributions

NASA Astrophysics Data System (ADS)

Vommi, Vijayababu; Kasarapu, Rukmini V.

2014-09-01

Process shift is an important input parameter in the economic design of control charts. Earlier control chart designs considered constant shifts to occur in the mean of the process for a given assignable cause. This assumption has been criticized by many researchers since it may not be realistic to produce a constant shift whenever an assignable cause occurs. To overcome this difficulty, in the present work, a distribution for the shift parameter has been considered instead of a single value for a given assignable cause. Duncan's economic design model for chart has been extended to incorporate the distribution for the process shift parameter. It is proposed to minimize total expected loss-cost to obtain the control chart parameters. Further, three types of process shifts namely, positively skewed, uniform and negatively skewed distributions are considered and the situations where it is appropriate to use the suggested methodology are recommended.

An experimental analysis of process parameters to manufacture micro-channels in AISI H13 tempered steel by laser micro-milling

NASA Astrophysics Data System (ADS)

Teixidor, D.; Ferrer, I.; Ciurana, J.

2012-04-01

This paper reports the characterization of laser machining (milling) process to manufacture micro-channels in order to understand the incidence of process parameters on the final features. Selection of process operational parameters is highly critical for successful laser micromachining. A set of designed experiments is carried out in a pulsed Nd:YAG laser system using AISI H13 hardened tool steel as work material. Several micro-channels have been manufactured as micro-mold cavities varying parameters such as scanning speed (SS), pulse intensity (PI) and pulse frequency (PF). Results are obtained by evaluating the dimensions and the surface finish of the micro-channel. The dimensions and shape of the micro-channels produced with laser-micro-milling process exhibit variations. In general the use of low scanning speeds increases the quality of the feature in both surface finishing and dimensional.

A Bayesian Approach to Determination of F, D, and Z Values Used in Steam Sterilization Validation.

PubMed

Faya, Paul; Stamey, James D; Seaman, John W

2017-01-01

For manufacturers of sterile drug products, steam sterilization is a common method used to provide assurance of the sterility of manufacturing equipment and products. The validation of sterilization processes is a regulatory requirement and relies upon the estimation of key resistance parameters of microorganisms. Traditional methods have relied upon point estimates for the resistance parameters. In this paper, we propose a Bayesian method for estimation of the well-known D T , z , and F o values that are used in the development and validation of sterilization processes. A Bayesian approach allows the uncertainty about these values to be modeled using probability distributions, thereby providing a fully risk-based approach to measures of sterility assurance. An example is given using the survivor curve and fraction negative methods for estimation of resistance parameters, and we present a means by which a probabilistic conclusion can be made regarding the ability of a process to achieve a specified sterility criterion. LAY ABSTRACT: For manufacturers of sterile drug products, steam sterilization is a common method used to provide assurance of the sterility of manufacturing equipment and products. The validation of sterilization processes is a regulatory requirement and relies upon the estimation of key resistance parameters of microorganisms. Traditional methods have relied upon point estimates for the resistance parameters. In this paper, we propose a Bayesian method for estimation of the critical process parameters that are evaluated in the development and validation of sterilization processes. A Bayesian approach allows the uncertainty about these parameters to be modeled using probability distributions, thereby providing a fully risk-based approach to measures of sterility assurance. An example is given using the survivor curve and fraction negative methods for estimation of resistance parameters, and we present a means by which a probabilistic conclusion can be made regarding the ability of a process to achieve a specified sterility criterion. © PDA, Inc. 2017.

Hot-crack test for aluminium alloys welds using TIG process

NASA Astrophysics Data System (ADS)

Niel, A.; Deschaux-Beaume, F.; Bordreuil, C.; Fras, G.

2010-06-01

Hot cracking is a critical defect frequently observed during welding of aluminium alloys. In order to better understand the interaction between cracking phenomenon, process parameters, mechanical factors and microstructures resulting from solidification after welding, an original hot-cracking test during welding is developed. According to in-situ observations and post mortem analyses, hot cracking mechanisms are investigated, taking into account the interaction between microstructural parameters, depending on the thermal cycles, and mechanical parameters, depending on geometry and clamping conditions of the samples and on the thermal field on the sample. Finally, a process map indicating the limit between cracking and non-cracking zones according to welding parameters is presented.

ASRM test report: Autoclave cure process development

NASA Technical Reports Server (NTRS)

Nachbar, D. L.; Mitchell, Suzanne

1992-01-01

ASRM insulated segments will be autoclave cured following insulation pre-form installation and strip wind operations. Following competitive bidding, Aerojet ASRM Division (AAD) Purchase Order 100142 was awarded to American Fuel Cell and Coated Fabrics Company, Inc. (Amfuel), Magnolia, AR, for subcontracted insulation autoclave cure process development. Autoclave cure process development test requirements were included in Task 3 of TM05514, Manufacturing Process Development Specification for Integrated Insulation Characterization and Stripwind Process Development. The test objective was to establish autoclave cure process parameters for ASRM insulated segments. Six tasks were completed to: (1) evaluate cure parameters that control acceptable vulcanization of ASRM Kevlar-filled EPDM insulation material; (2) identify first and second order impact parameters on the autoclave cure process; and (3) evaluate insulation material flow-out characteristics to support pre-form configuration design.

Automated method for the systematic interpretation of resonance peaks in spectrum data

DOEpatents

Damiano, B.; Wood, R.T.

1997-04-22

A method is described for spectral signature interpretation. The method includes the creation of a mathematical model of a system or process. A neural network training set is then developed based upon the mathematical model. The neural network training set is developed by using the mathematical model to generate measurable phenomena of the system or process based upon model input parameter that correspond to the physical condition of the system or process. The neural network training set is then used to adjust internal parameters of a neural network. The physical condition of an actual system or process represented by the mathematical model is then monitored by extracting spectral features from measured spectra of the actual process or system. The spectral features are then input into said neural network to determine the physical condition of the system or process represented by the mathematical model. More specifically, the neural network correlates the spectral features (i.e. measurable phenomena) of the actual process or system with the corresponding model input parameters. The model input parameters relate to specific components of the system or process, and, consequently, correspond to the physical condition of the process or system. 1 fig.

Automated method for the systematic interpretation of resonance peaks in spectrum data

DOEpatents

Damiano, Brian; Wood, Richard T.

1997-01-01

A method for spectral signature interpretation. The method includes the creation of a mathematical model of a system or process. A neural network training set is then developed based upon the mathematical model. The neural network training set is developed by using the mathematical model to generate measurable phenomena of the system or process based upon model input parameter that correspond to the physical condition of the system or process. The neural network training set is then used to adjust internal parameters of a neural network. The physical condition of an actual system or process represented by the mathematical model is then monitored by extracting spectral features from measured spectra of the actual process or system. The spectral features are then input into said neural network to determine the physical condition of the system or process represented by the mathematical. More specifically, the neural network correlates the spectral features (i.e. measurable phenomena) of the actual process or system with the corresponding model input parameters. The model input parameters relate to specific components of the system or process, and, consequently, correspond to the physical condition of the process or system.

Optimisation of process parameters on thin shell part using response surface methodology (RSM) and genetic algorithm (GA)

NASA Astrophysics Data System (ADS)

Faiz, J. M.; Shayfull, Z.; Nasir, S. M.; Fathullah, M.; Hazwan, M. H. M.

2017-09-01

This study conducts the simulation on optimisation of injection moulding process parameters using Autodesk Moldflow Insight (AMI) software. This study has applied some process parameters which are melt temperature, mould temperature, packing pressure, and cooling time in order to analyse the warpage value of the part. Besides, a part has been selected to be studied which made of Polypropylene (PP). The combination of the process parameters is analysed using Analysis of Variance (ANOVA) and the optimised value is obtained using Response Surface Methodology (RSM). The RSM as well as Genetic Algorithm are applied in Design Expert software in order to minimise the warpage value. The outcome of this study shows that the warpage value improved by using RSM and GA.

Effect of Burnishing Parameters on Surface Finish

NASA Astrophysics Data System (ADS)

Shirsat, Uddhav; Ahuja, Basant; Dhuttargaon, Mukund

2017-08-01

Burnishing is cold working process in which hard balls are pressed against the surface, resulting in improved surface finish. The surface gets compressed and then plasticized. This is a highly finishing process which is becoming more popular. Surface quality of the product improves its aesthetic appearance. The product made up of aluminum material is subjected to burnishing process during which kerosene is used as a lubricant. In this study factors affecting burnishing process such as burnishing force, speed, feed, work piece diameter and ball diameter are considered as input parameters while surface finish is considered as an output parameter In this study, experiments are designed using 25 factorial design in order to analyze the relationship between input and output parameters. The ANOVA technique and F-test are used for further analysis.

Comparing Parameter Estimation Techniques for an Electrical Power Transformer Oil Temperature Prediction Model

NASA Technical Reports Server (NTRS)

Morris, A. Terry

1999-01-01

This paper examines various sources of error in MIT's improved top oil temperature rise over ambient temperature model and estimation process. The sources of error are the current parameter estimation technique, quantization noise, and post-processing of the transformer data. Results from this paper will show that an output error parameter estimation technique should be selected to replace the current least squares estimation technique. The output error technique obtained accurate predictions of transformer behavior, revealed the best error covariance, obtained consistent parameter estimates, and provided for valid and sensible parameters. This paper will also show that the output error technique should be used to minimize errors attributed to post-processing (decimation) of the transformer data. Models used in this paper are validated using data from a large transformer in service.

An empirical analysis of the distribution of the duration of overshoots in a stationary gaussian stochastic process

NASA Technical Reports Server (NTRS)

Parrish, R. S.; Carter, M. C.

1974-01-01

This analysis utilizes computer simulation and statistical estimation. Realizations of stationary gaussian stochastic processes with selected autocorrelation functions are computer simulated. Analysis of the simulated data revealed that the mean and the variance of a process were functionally dependent upon the autocorrelation parameter and crossing level. Using predicted values for the mean and standard deviation, by the method of moments, the distribution parameters was estimated. Thus, given the autocorrelation parameter, crossing level, mean, and standard deviation of a process, the probability of exceeding the crossing level for a particular length of time was calculated.

Influence of Different Container Closure Systems and Capping Process Parameters on Product Quality and Container Closure Integrity (CCI) in GMP Drug Product Manufacturing.

PubMed

Mathaes, Roman; Mahler, Hanns-Christian; Roggo, Yves; Huwyler, Joerg; Eder, Juergen; Fritsch, Kamila; Posset, Tobias; Mohl, Silke; Streubel, Alexander

2016-01-01

Capping equipment used in good manufacturing practice manufacturing features different designs and a variety of adjustable process parameters. The overall capping result is a complex interplay of the different capping process parameters and is insufficiently described in literature. It remains poorly studied how the different capping equipment designs and capping equipment process parameters (e.g., pre-compression force, capping plate height, turntable rotating speed) contribute to the final residual seal force of a sealed container closure system and its relation to container closure integrity and other drug product quality parameters. Stopper compression measured by computer tomography correlated to residual seal force measurements.In our studies, we used different container closure system configurations from different good manufacturing practice drug product fill & finish facilities to investigate the influence of differences in primary packaging, that is, vial size and rubber stopper design on the capping process and the capped drug product. In addition, we compared two large-scale good manufacturing practice manufacturing capping equipment and different capping equipment settings and their impact on product quality and integrity, as determined by residual seal force.The capping plate to plunger distance had a major influence on the obtained residual seal force values of a sealed vial, whereas the capping pre-compression force and the turntable rotation speed showed only a minor influence on the residual seal force of a sealed vial. Capping process parameters could not easily be transferred from capping equipment of different manufacturers. However, the residual seal force tester did provide a valuable tool to compare capping performance of different capping equipment. No vial showed any leakage greater than 10(-8)mbar L/s as measured by a helium mass spectrometry system, suggesting that container closure integrity was warranted in the residual seal force range tested for the tested container closure systems. Capping equipment used in good manufacturing practice manufacturing features different designs and a variety of adjustable process parameters. The overall capping result is a complex interplay of the different capping process parameters and is insufficiently described in the literature. It remains poorly studied how the different capping equipment designs and capping equipment process parameters contribute to the final capping result.In this study, we used different container closure system configurations from different good manufacturing process drug product fill & finish facilities to investigate the influence of the vial size and the rubber stopper design on the capping process. In addition, we compared two examples of large-scale good manufacturing process capping equipment and different capping equipment settings and their impact on product quality and integrity, as determined by residual seal force. © PDA, Inc. 2016.

Experimental investigations on the effect of process parameters with the use of minimum quantity solid lubrication in turning

NASA Astrophysics Data System (ADS)

Makhesana, Mayur A.; Patel, K. M.; Mawandiya, B. K.

2018-04-01

Turning process is a very basic process in any field of mechanical application. During turning process, most of the energy is converted into heat because of the friction between work piece and tool. Heat generation can affect the surface quality of the work piece and tool life. To reduce the heat generation, Conventional Lubrication process is used in most of the industry. Minimum quantity lubrication has been an effective alternative to improve the performance of machining process. In this present work, effort has been made to study the effect of various process parameters on the surface roughness and power consumption during turning of EN8 steel material. Result revealed the effect of depth of cut and feed on the obtained surface roughness value. Further the effect of solid lubricant has been also studied and optimization of process parameters is also done for the turning process.

WE-G-204-01: BEST IN PHYSICS (IMAGING): Effect of Image Processing Parameters On Nodule Detectability in Chest Radiography

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

Little, K; Lu, Z; MacMahon, H

Purpose: To investigate the effect of varying system image processing parameters on lung nodule detectability in digital radiography. Methods: An anthropomorphic chest phantom was imaged in the posterior-anterior position using a GE Discovery XR656 digital radiography system. To simulate lung nodules, a polystyrene board with 6.35mm diameter PMMA spheres was placed adjacent to the phantom (into the x-ray path). Due to magnification, the projected simulated nodules had a diameter in the radiographs of approximately 7.5 mm. The images were processed using one of GE’s default chest settings (Factory3) and reprocessed by varying the “Edge” and “Tissue Contrast” processing parameters, whichmore » were the two user-configurable parameters for a single edge and contrast enhancement algorithm. For each parameter setting, the nodule signals were calculated by subtracting the chest-only image from the image with simulated nodules. Twenty nodule signals were averaged, Gaussian filtered, and radially averaged in order to generate an approximately noiseless signal. For each processing parameter setting, this noise-free signal and 180 background samples from across the lung were used to estimate ideal observer performance in a signal-known-exactly detection task. Performance was estimated using a channelized Hotelling observer with 10 Laguerre-Gauss channel functions. Results: The “Edge” and “Tissue Contrast” parameters each had an effect on the detectability as calculated by the model observer. The CHO-estimated signal detectability ranged from 2.36 to 2.93 and was highest for “Edge” = 4 and “Tissue Contrast” = −0.15. In general, detectability tended to decrease as “Edge” was increased and as “Tissue Contrast” was increased. A human observer study should be performed to validate the relation to human detection performance. Conclusion: Image processing parameters can affect lung nodule detection performance in radiography. While validation with a human observer study is needed, model observer detectability for common tasks could provide a means for optimizing image processing parameters.« less

A software tool to assess uncertainty in transient-storage model parameters using Monte Carlo simulations

USGS Publications Warehouse

Ward, Adam S.; Kelleher, Christa A.; Mason, Seth J. K.; Wagener, Thorsten; McIntyre, Neil; McGlynn, Brian L.; Runkel, Robert L.; Payn, Robert A.

2017-01-01

Researchers and practitioners alike often need to understand and characterize how water and solutes move through a stream in terms of the relative importance of in-stream and near-stream storage and transport processes. In-channel and subsurface storage processes are highly variable in space and time and difficult to measure. Storage estimates are commonly obtained using transient-storage models (TSMs) of the experimentally obtained solute-tracer test data. The TSM equations represent key transport and storage processes with a suite of numerical parameters. Parameter values are estimated via inverse modeling, in which parameter values are iteratively changed until model simulations closely match observed solute-tracer data. Several investigators have shown that TSM parameter estimates can be highly uncertain. When this is the case, parameter values cannot be used reliably to interpret stream-reach functioning. However, authors of most TSM studies do not evaluate or report parameter certainty. Here, we present a software tool linked to the One-dimensional Transport with Inflow and Storage (OTIS) model that enables researchers to conduct uncertainty analyses via Monte-Carlo parameter sampling and to visualize uncertainty and sensitivity results. We demonstrate application of our tool to 2 case studies and compare our results to output obtained from more traditional implementation of the OTIS model. We conclude by suggesting best practices for transient-storage modeling and recommend that future applications of TSMs include assessments of parameter certainty to support comparisons and more reliable interpretations of transport processes.

CO 2 laser cutting of MDF . 1. Determination of process parameter settings

NASA Astrophysics Data System (ADS)

Lum, K. C. P.; Ng, S. L.; Black, I.

2000-02-01

This paper details an investigation into the laser processing of medium-density fibreboard (MDF). Part 1 reports on the determination of process parameter settings for the effective cutting of MDF by CO 2 laser, using an established experimental methodology developed to study the interrelationship between and effects of varying laser set-up parameters. Results are presented for both continuous wave (CW) and pulse mode (PM) cutting, and the associated cut quality effects have been commented on.

Apparatus and method for fluid analysis

DOEpatents

Wilson, Bary W.; Peters, Timothy J.; Shepard, Chester L.; Reeves, James H.

2004-11-02

The present invention is an apparatus and method for analyzing a fluid used in a machine or in an industrial process line. The apparatus has at least one meter placed proximate the machine or process line and in contact with the machine or process fluid for measuring at least one parameter related to the fluid. The at least one parameter is a standard laboratory analysis parameter. The at least one meter includes but is not limited to viscometer, element meter, optical meter, particulate meter, and combinations thereof.

Analysis of the shrinkage at the thick plate part using response surface methodology

NASA Astrophysics Data System (ADS)

Hatta, N. M.; Azlan, M. Z.; Shayfull, Z.; Roselina, S.; Nasir, S. M.

2017-09-01

Injection moulding is well known for its manufacturing process especially in producing plastic products. To measure the final product quality, there are lots of precautions to be taken into such as parameters setting at the initial stage of the process. Sometimes, if these parameters were set up wrongly, defects may be occurred and one of the well-known defects in the injection moulding process is a shrinkage. To overcome this problem, a maximisation at the precaution stage by making an optimal adjustment on the parameter setting need to be done and this paper focuses on analysing the shrinkage by optimising the parameter at thick plate part with the help of Response Surface Methodology (RSM) and ANOVA analysis. From the previous study, the outstanding parameter gained from the optimisation method in minimising the shrinkage at the moulded part was packing pressure. Therefore, with the reference from the previous literature, packing pressure was selected as the parameter setting for this study with other three parameters which are melt temperature, cooling time and mould temperature. The analysis of the process was obtained from the simulation by Autodesk Moldflow Insight (AMI) software and the material used for moulded part was Acrylonitrile Butadiene Styrene (ABS). The analysis and result were obtained and it found that the shrinkage can be minimised and the significant parameters were found as packing pressure, mould temperature and melt temperature.

Utilization of Expert Knowledge in a Multi-Objective Hydrologic Model Automatic Calibration Process

NASA Astrophysics Data System (ADS)

Quebbeman, J.; Park, G. H.; Carney, S.; Day, G. N.; Micheletty, P. D.

2016-12-01

Spatially distributed continuous simulation hydrologic models have a large number of parameters for potential adjustment during the calibration process. Traditional manual calibration approaches of such a modeling system is extremely laborious, which has historically motivated the use of automatic calibration procedures. With a large selection of model parameters, achieving high degrees of objective space fitness - measured with typical metrics such as Nash-Sutcliffe, Kling-Gupta, RMSE, etc. - can easily be achieved using a range of evolutionary algorithms. A concern with this approach is the high degree of compensatory calibration, with many similarly performing solutions, and yet grossly varying parameter set solutions. To help alleviate this concern, and mimic manual calibration processes, expert knowledge is proposed for inclusion within the multi-objective functions, which evaluates the parameter decision space. As a result, Pareto solutions are identified with high degrees of fitness, but also create parameter sets that maintain and utilize available expert knowledge resulting in more realistic and consistent solutions. This process was tested using the joint SNOW-17 and Sacramento Soil Moisture Accounting method (SAC-SMA) within the Animas River basin in Colorado. Three different elevation zones, each with a range of parameters, resulted in over 35 model parameters simultaneously calibrated. As a result, high degrees of fitness were achieved, in addition to the development of more realistic and consistent parameter sets such as those typically achieved during manual calibration procedures.

Reason, emotion and decision-making: risk and reward computation with feeling.

PubMed

Quartz, Steven R

2009-05-01

Many models of judgment and decision-making posit distinct cognitive and emotional contributions to decision-making under uncertainty. Cognitive processes typically involve exact computations according to a cost-benefit calculus, whereas emotional processes typically involve approximate, heuristic processes that deliver rapid evaluations without mental effort. However, it remains largely unknown what specific parameters of uncertain decision the brain encodes, the extent to which these parameters correspond to various decision-making frameworks, and their correspondence to emotional and rational processes. Here, I review research suggesting that emotional processes encode in a precise quantitative manner the basic parameters of financial decision theory, indicating a reorientation of emotional and cognitive contributions to risky choice.

Chickpea seeds germination rational parameters optimization

NASA Astrophysics Data System (ADS)

Safonova, Yu A.; Ivliev, M. N.; Lemeshkin, A. V.

2018-05-01

The paper presents the influence of chickpea seeds bioactivation parameters on their enzymatic activity experimental results. Optimal bioactivation process modes were obtained by regression-factor analysis: process temperature - 13.6 °C, process duration - 71.5 h. It was found that in the germination process, the proteolytic, amylolytic and lipolytic enzymes activity increased, and the urease enzyme activity is reduced. The dependences of enzyme activity on chickpea seeds germination conditions were obtained by mathematical processing of experimental data. The calculated data are in good agreement with the experimental ones. This confirms the optimization efficiency based on experiments mathematical planning in order to determine the enzymatic activity of chickpea seeds germination optimal parameters of bioactivated seeds.

Stochastic Modeling and Analysis of Multiple Nonlinear Accelerated Degradation Processes through Information Fusion

PubMed Central

Sun, Fuqiang; Liu, Le; Li, Xiaoyang; Liao, Haitao

2016-01-01

Accelerated degradation testing (ADT) is an efficient technique for evaluating the lifetime of a highly reliable product whose underlying failure process may be traced by the degradation of the product’s performance parameters with time. However, most research on ADT mainly focuses on a single performance parameter. In reality, the performance of a modern product is usually characterized by multiple parameters, and the degradation paths are usually nonlinear. To address such problems, this paper develops a new s-dependent nonlinear ADT model for products with multiple performance parameters using a general Wiener process and copulas. The general Wiener process models the nonlinear ADT data, and the dependency among different degradation measures is analyzed using the copula method. An engineering case study on a tuner’s ADT data is conducted to demonstrate the effectiveness of the proposed method. The results illustrate that the proposed method is quite effective in estimating the lifetime of a product with s-dependent performance parameters. PMID:27509499

Stochastic Modeling and Analysis of Multiple Nonlinear Accelerated Degradation Processes through Information Fusion.

PubMed

Sun, Fuqiang; Liu, Le; Li, Xiaoyang; Liao, Haitao

2016-08-06

Accelerated degradation testing (ADT) is an efficient technique for evaluating the lifetime of a highly reliable product whose underlying failure process may be traced by the degradation of the product's performance parameters with time. However, most research on ADT mainly focuses on a single performance parameter. In reality, the performance of a modern product is usually characterized by multiple parameters, and the degradation paths are usually nonlinear. To address such problems, this paper develops a new s-dependent nonlinear ADT model for products with multiple performance parameters using a general Wiener process and copulas. The general Wiener process models the nonlinear ADT data, and the dependency among different degradation measures is analyzed using the copula method. An engineering case study on a tuner's ADT data is conducted to demonstrate the effectiveness of the proposed method. The results illustrate that the proposed method is quite effective in estimating the lifetime of a product with s-dependent performance parameters.

Attaining insight into interactions between hydrologic model parameters and geophysical attributes for national-scale model parameter estimation

NASA Astrophysics Data System (ADS)

Mizukami, N.; Clark, M. P.; Newman, A. J.; Wood, A.; Gutmann, E. D.

2017-12-01

Estimating spatially distributed model parameters is a grand challenge for large domain hydrologic modeling, especially in the context of hydrologic model applications such as streamflow forecasting. Multi-scale Parameter Regionalization (MPR) is a promising technique that accounts for the effects of fine-scale geophysical attributes (e.g., soil texture, land cover, topography, climate) on model parameters and nonlinear scaling effects on model parameters. MPR computes model parameters with transfer functions (TFs) that relate geophysical attributes to model parameters at the native input data resolution and then scales them using scaling functions to the spatial resolution of the model implementation. One of the biggest challenges in the use of MPR is identification of TFs for each model parameter: both functional forms and geophysical predictors. TFs used to estimate the parameters of hydrologic models typically rely on previous studies or were derived in an ad-hoc, heuristic manner, potentially not utilizing maximum information content contained in the geophysical attributes for optimal parameter identification. Thus, it is necessary to first uncover relationships among geophysical attributes, model parameters, and hydrologic processes (i.e., hydrologic signatures) to obtain insight into which and to what extent geophysical attributes are related to model parameters. We perform multivariate statistical analysis on a large-sample catchment data set including various geophysical attributes as well as constrained VIC model parameters at 671 unimpaired basins over the CONUS. We first calibrate VIC model at each catchment to obtain constrained parameter sets. Additionally, parameter sets sampled during the calibration process are used for sensitivity analysis using various hydrologic signatures as objectives to understand the relationships among geophysical attributes, parameters, and hydrologic processes.

Dependence of quantitative accuracy of CT perfusion imaging on system parameters

NASA Astrophysics Data System (ADS)

Li, Ke; Chen, Guang-Hong

2017-03-01

Deconvolution is a popular method to calculate parametric perfusion parameters from four dimensional CT perfusion (CTP) source images. During the deconvolution process, the four dimensional space is squeezed into three-dimensional space by removing the temporal dimension, and a prior knowledge is often used to suppress noise associated with the process. These additional complexities confound the understanding about deconvolution-based CTP imaging system and how its quantitative accuracy depends on parameters and sub-operations involved in the image formation process. Meanwhile, there has been a strong clinical need in answering this question, as physicians often rely heavily on the quantitative values of perfusion parameters to make diagnostic decisions, particularly during an emergent clinical situation (e.g. diagnosis of acute ischemic stroke). The purpose of this work was to develop a theoretical framework that quantitatively relates the quantification accuracy of parametric perfusion parameters with CTP acquisition and post-processing parameters. This goal was achieved with the help of a cascaded systems analysis for deconvolution-based CTP imaging systems. Based on the cascaded systems analysis, the quantitative relationship between regularization strength, source image noise, arterial input function, and the quantification accuracy of perfusion parameters was established. The theory could potentially be used to guide developments of CTP imaging technology for better quantification accuracy and lower radiation dose.

Method for automatically evaluating a transition from a batch manufacturing technique to a lean manufacturing technique

DOEpatents

Ivezic, Nenad; Potok, Thomas E.

2003-09-30

A method for automatically evaluating a manufacturing technique comprises the steps of: receiving from a user manufacturing process step parameters characterizing a manufacturing process; accepting from the user a selection for an analysis of a particular lean manufacturing technique; automatically compiling process step data for each process step in the manufacturing process; automatically calculating process metrics from a summation of the compiled process step data for each process step; and, presenting the automatically calculated process metrics to the user. A method for evaluating a transition from a batch manufacturing technique to a lean manufacturing technique can comprise the steps of: collecting manufacturing process step characterization parameters; selecting a lean manufacturing technique for analysis; communicating the selected lean manufacturing technique and the manufacturing process step characterization parameters to an automatic manufacturing technique evaluation engine having a mathematical model for generating manufacturing technique evaluation data; and, using the lean manufacturing technique evaluation data to determine whether to transition from an existing manufacturing technique to the selected lean manufacturing technique.

Synchrotron-Based X-ray Microtomography Characterization of the Effect of Processing Variables on Porosity Formation in Laser Power-Bed Additive Manufacturing of Ti-6Al-4V

NASA Astrophysics Data System (ADS)

Cunningham, Ross; Narra, Sneha P.; Montgomery, Colt; Beuth, Jack; Rollett, A. D.

2017-03-01

The porosity observed in additively manufactured (AM) parts is a potential concern for components intended to undergo high-cycle fatigue without post-processing to remove such defects. The morphology of pores can help identify their cause: irregularly shaped lack of fusion or key-holing pores can usually be linked to incorrect processing parameters, while spherical pores suggest trapped gas. Synchrotron-based x-ray microtomography was performed on laser powder-bed AM Ti-6Al-4V samples over a range of processing conditions to investigate the effects of processing parameters on porosity. The process mapping technique was used to control melt pool size. Tomography was also performed on the powder to measure porosity within the powder that may transfer to the parts. As observed previously in experiments with electron beam powder-bed fabrication, significant variations in porosity were found as a function of the processing parameters. A clear connection between processing parameters and resulting porosity formation mechanism was observed in that inadequate melt pool overlap resulted in lack-of-fusion pores whereas excess power density produced keyhole pores.

Optimization of process parameters in welding of dissimilar steels using robot TIG welding

NASA Astrophysics Data System (ADS)

Navaneeswar Reddy, G.; VenkataRamana, M.

2018-03-01

Robot TIG welding is a modern technique used for joining two work pieces with high precision. Design of Experiments is used to conduct experiments by varying weld parameters like current, wire feed and travelling speed. The welding parameters play important role in joining of dissimilar stainless steel SS 304L and SS430. In this work, influences of welding parameter on Robot TIG Welded specimens are investigated using Response Surface Methodology. The Micro Vickers hardness tests of the weldments are measured. The process parameters are optimized to maximize the hardness of the weldments.

Parameter-induced uncertainty quantification of a regional N2O and NO3 inventory using the biogeochemical model LandscapeDNDC

NASA Astrophysics Data System (ADS)

Haas, Edwin; Klatt, Steffen; Kraus, David; Werner, Christian; Ruiz, Ignacio Santa Barbara; Kiese, Ralf; Butterbach-Bahl, Klaus

2014-05-01

Numerical simulation models are increasingly used to estimate greenhouse gas emissions at site to regional and national scales and are outlined as the most advanced methodology (Tier 3) for national emission inventory in the framework of UNFCCC reporting. Process-based models incorporate the major processes of the carbon and nitrogen cycle of terrestrial ecosystems like arable land and grasslands and are thus thought to be widely applicable at various spatial and temporal scales. The high complexity of ecosystem processes mirrored by such models requires a large number of model parameters. Many of those parameters are lumped parameters describing simultaneously the effect of environmental drivers on e.g. microbial community activity and individual processes. Thus, the precise quantification of true parameter states is often difficult or even impossible. As a result model uncertainty is not solely originating from input uncertainty but also subject to parameter-induced uncertainty. In this study we quantify regional parameter-induced model uncertainty on nitrous oxide (N2O) emissions and nitrate (NO3) leaching from arable soils of Saxony (Germany) using the biogeochemical model LandscapeDNDC. For this we calculate a regional inventory using a joint parameter distribution for key parameters describing microbial C and N turnover processes as obtained by a Bayesian calibration study. We representatively sampled 400 different parameter vectors from the discrete joint parameter distribution comprising approximately 400,000 parameter combinations and used these to calculate 400 individual realizations of the regional inventory. The spatial domain (represented by 4042 polygons) is set up with spatially explicit soil and climate information and a region-typical 3-year crop rotation consisting of winter wheat, rape- seed, and winter barley. Average N2O emission from arable soils in the state of Saxony across all 400 realizations was 1.43 ± 1.25 [kg N / ha] with a median value of 1.05 [kg N / ha]. Using the default IPCC emission factor approach (Tier 1) for direct emissions reveal a higher average N2O emission of 1.51 [kg N / ha] due to fertilizer use. In the regional uncertainty quantification the 20% likelihood range for N2O emissions is 0.79 - 1.37 [kg N / ha] (50% likelihood: 0.46 - 2.05 [kg N / ha]; 90% likelihood: 0.11 - 4.03 [kg N / ha]). Respective quantities were calculated for nitrate leaching. The method has proven its applicability to quantify parameter-induced uncertainty of simulated regional greenhouse gas emission and nitrate leaching inventories using process based biogeochemical models.

Process Development of Porcelain Ceramic Material with Binder Jetting Process for Dental Applications

NASA Astrophysics Data System (ADS)

Miyanaji, Hadi; Zhang, Shanshan; Lassell, Austin; Zandinejad, Amirali; Yang, Li

2016-03-01

Custom ceramic structures possess significant potentials in many applications such as dentistry and aerospace where extreme environments are present. Specifically, highly customized geometries with adequate performance are needed for various dental prostheses applications. This paper demonstrates the development of process and post-process parameters for a dental porcelain ceramic material using binder jetting additive manufacturing (AM). Various process parameters such as binder amount, drying power level, drying time and powder spread speed were studied experimentally for their effect on geometrical and mechanical characteristics of green parts. In addition, the effects of sintering and printing parameters on the qualities of the densified ceramic structures were also investigated experimentally. The results provide insights into the process-property relationships for the binder jetting AM process, and some of the challenges of the process that need to be further characterized for the successful adoption of the binder jetting technology in high quality ceramic fabrications are discussed.

Multi-objective optimization model of CNC machining to minimize processing time and environmental impact

NASA Astrophysics Data System (ADS)

Hamada, Aulia; Rosyidi, Cucuk Nur; Jauhari, Wakhid Ahmad

2017-11-01

Minimizing processing time in a production system can increase the efficiency of a manufacturing company. Processing time are influenced by application of modern technology and machining parameter. Application of modern technology can be apply by use of CNC machining, one of the machining process can be done with a CNC machining is turning. However, the machining parameters not only affect the processing time but also affect the environmental impact. Hence, optimization model is needed to optimize the machining parameters to minimize the processing time and environmental impact. This research developed a multi-objective optimization to minimize the processing time and environmental impact in CNC turning process which will result in optimal decision variables of cutting speed and feed rate. Environmental impact is converted from environmental burden through the use of eco-indicator 99. The model were solved by using OptQuest optimization software from Oracle Crystal Ball.

Effect of processing parameters on reaction bonding of silicon nitride

NASA Technical Reports Server (NTRS)

Richman, M. H.; Gregory, O. J.; Magida, M. B.

1980-01-01

Reaction bonded silicon nitride was developed. The relationship between the various processing parameters and the resulting microstructures was to design and synthesize reaction bonded materials with improved room temperature mechanical properties.

MODFLOW-2000, the U.S. Geological Survey Modular Ground-Water Model -Documentation of the Hydrogeologic-Unit Flow (HUF) Package

USGS Publications Warehouse

Anderman, E.R.; Hill, M.C.

2000-01-01

This report documents the Hydrogeologic-Unit Flow (HUF) Package for the groundwater modeling computer program MODFLOW-2000. The HUF Package is an alternative internal flow package that allows the vertical geometry of the system hydrogeology to be defined explicitly within the model using hydrogeologic units that can be different than the definition of the model layers. The HUF Package works with all the processes of MODFLOW-2000. For the Ground-Water Flow Process, the HUF Package calculates effective hydraulic properties for the model layers based on the hydraulic properties of the hydrogeologic units, which are defined by the user using parameters. The hydraulic properties are used to calculate the conductance coefficients and other terms needed to solve the ground-water flow equation. The sensitivity of the model to the parameters defined within the HUF Package input file can be calculated using the Sensitivity Process, using observations defined with the Observation Process. Optimal values of the parameters can be estimated by using the Parameter-Estimation Process. The HUF Package is nearly identical to the Layer-Property Flow (LPF) Package, the major difference being the definition of the vertical geometry of the system hydrogeology. Use of the HUF Package is illustrated in two test cases, which also serve to verify the performance of the package by showing that the Parameter-Estimation Process produces the true parameter values when exact observations are used.

Systems and methods for optimal power flow on a radial network

DOEpatents

Low, Steven H.; Peng, Qiuyu

2018-04-24

Node controllers and power distribution networks in accordance with embodiments of the invention enable distributed power control. One embodiment includes a node controller including a distributed power control application; a plurality of node operating parameters describing the operating parameter of a node and a set of at least one node selected from the group consisting of an ancestor node and at least one child node; wherein send node operating parameters to nodes in the set of at least one node; receive operating parameters from the nodes in the set of at least one node; calculate a plurality of updated node operating parameters using an iterative process to determine the updated node operating parameters using the node operating parameters that describe the operating parameters of the node and the set of at least one node, where the iterative process involves evaluation of a closed form solution; and adjust node operating parameters.

Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling.

PubMed

Bitterlich, A; Laabs, C; Krautstrunk, I; Dengler, M; Juhnke, M; Grandeury, A; Bunjes, H; Kwade, A

2015-05-01

The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process. Copyright © 2015 Elsevier B.V. All rights reserved.

Variational estimation of process parameters in a simplified atmospheric general circulation model

NASA Astrophysics Data System (ADS)

Lv, Guokun; Koehl, Armin; Stammer, Detlef

2016-04-01

Parameterizations are used to simulate effects of unresolved sub-grid-scale processes in current state-of-the-art climate model. The values of the process parameters, which determine the model's climatology, are usually manually adjusted to reduce the difference of model mean state to the observed climatology. This process requires detailed knowledge of the model and its parameterizations. In this work, a variational method was used to estimate process parameters in the Planet Simulator (PlaSim). The adjoint code was generated using automatic differentiation of the source code. Some hydrological processes were switched off to remove the influence of zero-order discontinuities. In addition, the nonlinearity of the model limits the feasible assimilation window to about 1day, which is too short to tune the model's climatology. To extend the feasible assimilation window, nudging terms for all state variables were added to the model's equations, which essentially suppress all unstable directions. In identical twin experiments, we found that the feasible assimilation window could be extended to over 1-year and accurate parameters could be retrieved. Although the nudging terms transform to a damping of the adjoint variables and therefore tend to erases the information of the data over time, assimilating climatological information is shown to provide sufficient information on the parameters. Moreover, the mechanism of this regularization is discussed.

Prediction of Tensile Strength of Friction Stir Weld Joints with Adaptive Neuro-Fuzzy Inference System (ANFIS) and Neural Network

NASA Technical Reports Server (NTRS)

Dewan, Mohammad W.; Huggett, Daniel J.; Liao, T. Warren; Wahab, Muhammad A.; Okeil, Ayman M.

2015-01-01

Friction-stir-welding (FSW) is a solid-state joining process where joint properties are dependent on welding process parameters. In the current study three critical process parameters including spindle speed (??), plunge force (????), and welding speed (??) are considered key factors in the determination of ultimate tensile strength (UTS) of welded aluminum alloy joints. A total of 73 weld schedules were welded and tensile properties were subsequently obtained experimentally. It is observed that all three process parameters have direct influence on UTS of the welded joints. Utilizing experimental data, an optimized adaptive neuro-fuzzy inference system (ANFIS) model has been developed to predict UTS of FSW joints. A total of 1200 models were developed by varying the number of membership functions (MFs), type of MFs, and combination of four input variables (??,??,????,??????) utilizing a MATLAB platform. Note EFI denotes an empirical force index derived from the three process parameters. For comparison, optimized artificial neural network (ANN) models were also developed to predict UTS from FSW process parameters. By comparing ANFIS and ANN predicted results, it was found that optimized ANFIS models provide better results than ANN. This newly developed best ANFIS model could be utilized for prediction of UTS of FSW joints.

Regionalization of post-processed ensemble runoff forecasts

NASA Astrophysics Data System (ADS)

Olav Skøien, Jon; Bogner, Konrad; Salamon, Peter; Smith, Paul; Pappenberger, Florian

2016-05-01

For many years, meteorological models have been run with perturbated initial conditions or parameters to produce ensemble forecasts that are used as a proxy of the uncertainty of the forecasts. However, the ensembles are usually both biased (the mean is systematically too high or too low, compared with the observed weather), and has dispersion errors (the ensemble variance indicates a too low or too high confidence in the forecast, compared with the observed weather). The ensembles are therefore commonly post-processed to correct for these shortcomings. Here we look at one of these techniques, referred to as Ensemble Model Output Statistics (EMOS) (Gneiting et al., 2005). Originally, the post-processing parameters were identified as a fixed set of parameters for a region. The application of our work is the European Flood Awareness System (http://www.efas.eu), where a distributed model is run with meteorological ensembles as input. We are therefore dealing with a considerably larger data set than previous analyses. We also want to regionalize the parameters themselves for other locations than the calibration gauges. The post-processing parameters are therefore estimated for each calibration station, but with a spatial penalty for deviations from neighbouring stations, depending on the expected semivariance between the calibration catchment and these stations. The estimated post-processed parameters can then be used for regionalization of the postprocessing parameters also for uncalibrated locations using top-kriging in the rtop-package (Skøien et al., 2006, 2014). We will show results from cross-validation of the methodology and although our interest is mainly in identifying exceedance probabilities for certain return levels, we will also show how the rtop package can be used for creating a set of post-processed ensembles through simulations.

A New Feedback-Based Method for Parameter Adaptation in Image Processing Routines.

PubMed

Khan, Arif Ul Maula; Mikut, Ralf; Reischl, Markus

2016-01-01

The parametrization of automatic image processing routines is time-consuming if a lot of image processing parameters are involved. An expert can tune parameters sequentially to get desired results. This may not be productive for applications with difficult image analysis tasks, e.g. when high noise and shading levels in an image are present or images vary in their characteristics due to different acquisition conditions. Parameters are required to be tuned simultaneously. We propose a framework to improve standard image segmentation methods by using feedback-based automatic parameter adaptation. Moreover, we compare algorithms by implementing them in a feedforward fashion and then adapting their parameters. This comparison is proposed to be evaluated by a benchmark data set that contains challenging image distortions in an increasing fashion. This promptly enables us to compare different standard image segmentation algorithms in a feedback vs. feedforward implementation by evaluating their segmentation quality and robustness. We also propose an efficient way of performing automatic image analysis when only abstract ground truth is present. Such a framework evaluates robustness of different image processing pipelines using a graded data set. This is useful for both end-users and experts.

A New Feedback-Based Method for Parameter Adaptation in Image Processing Routines

PubMed Central

Mikut, Ralf; Reischl, Markus

2016-01-01

The parametrization of automatic image processing routines is time-consuming if a lot of image processing parameters are involved. An expert can tune parameters sequentially to get desired results. This may not be productive for applications with difficult image analysis tasks, e.g. when high noise and shading levels in an image are present or images vary in their characteristics due to different acquisition conditions. Parameters are required to be tuned simultaneously. We propose a framework to improve standard image segmentation methods by using feedback-based automatic parameter adaptation. Moreover, we compare algorithms by implementing them in a feedforward fashion and then adapting their parameters. This comparison is proposed to be evaluated by a benchmark data set that contains challenging image distortions in an increasing fashion. This promptly enables us to compare different standard image segmentation algorithms in a feedback vs. feedforward implementation by evaluating their segmentation quality and robustness. We also propose an efficient way of performing automatic image analysis when only abstract ground truth is present. Such a framework evaluates robustness of different image processing pipelines using a graded data set. This is useful for both end-users and experts. PMID:27764213

Advanced Method to Estimate Fuel Slosh Simulation Parameters

NASA Technical Reports Server (NTRS)

Schlee, Keith; Gangadharan, Sathya; Ristow, James; Sudermann, James; Walker, Charles; Hubert, Carl

2005-01-01

The nutation (wobble) of a spinning spacecraft in the presence of energy dissipation is a well-known problem in dynamics and is of particular concern for space missions. The nutation of a spacecraft spinning about its minor axis typically grows exponentially and the rate of growth is characterized by the Nutation Time Constant (NTC). For launch vehicles using spin-stabilized upper stages, fuel slosh in the spacecraft propellant tanks is usually the primary source of energy dissipation. For analytical prediction of the NTC this fuel slosh is commonly modeled using simple mechanical analogies such as pendulums or rigid rotors coupled to the spacecraft. Identifying model parameter values which adequately represent the sloshing dynamics is the most important step in obtaining an accurate NTC estimate. Analytic determination of the slosh model parameters has met with mixed success and is made even more difficult by the introduction of propellant management devices and elastomeric diaphragms. By subjecting full-sized fuel tanks with actual flight fuel loads to motion similar to that experienced in flight and measuring the forces experienced by the tanks these parameters can be determined experimentally. Currently, the identification of the model parameters is a laborious trial-and-error process in which the equations of motion for the mechanical analog are hand-derived, evaluated, and their results are compared with the experimental results. The proposed research is an effort to automate the process of identifying the parameters of the slosh model using a MATLAB/SimMechanics-based computer simulation of the experimental setup. Different parameter estimation and optimization approaches are evaluated and compared in order to arrive at a reliable and effective parameter identification process. To evaluate each parameter identification approach, a simple one-degree-of-freedom pendulum experiment is constructed and motion is induced using an electric motor. By applying the estimation approach to a simple, accurately modeled system, its effectiveness and accuracy can be evaluated. The same experimental setup can then be used with fluid-filled tanks to further evaluate the effectiveness of the process. Ultimately, the proven process can be applied to the full-sized spinning experimental setup to quickly and accurately determine the slosh model parameters for a particular spacecraft mission. Automating the parameter identification process will save time, allow more changes to be made to proposed designs, and lower the cost in the initial design stages.

Process parameter and surface morphology of pineapple leaf electrospun nanofibers (PALF)

NASA Astrophysics Data System (ADS)

Surip, S. N.; Aziz, F. M. A.; Bonnia, N. N.; Sekak, K. A.; Zakaria, M. N.

2017-09-01

In recent times, nanofibers have attracted the attention of researchers due to their pronounced micro and nano structural characteristics that enable the development of advanced materials that have sophisticated applications. The production of nanofibers by the electrospinning process is influenced both by the electrostatic forces and the viscoelastic behavior of the polymer. Process parameters, like solution feed rate, applied voltage, nozzle-collector distance, and spinning environment, and material properties, like solution concentration, viscosity, surface tension, conductivity, and solvent vapor pressure, influence the structure and properties of electrospun nanofibers. Significant work has been done to characterize the properties of PALF nanofibers as a function of process and material parameters.

Diagnosis of dynamic process over rainband of landfall typhoon

NASA Astrophysics Data System (ADS)

Ran, Ling-Kun; Yang, Wen-Xia; Chu, Yan-Li

2010-07-01

This paper introduces a new physical parameter — thermodynamic shear advection parameter combining the perturbation vertical component of convective vorticity vector with the coupling of horizontal divergence perturbation and vertical gradient of general potential temperature perturbation. For a heavy-rainfall event resulting from the landfall typhoon 'Wipha', the parameter is calculated by using National Centres for Enviromental Prediction/National Centre for Atmospheric Research global final analysis data. The results showed that the parameter corresponds to the observed 6 h accumulative rainband since it is capable of catching hold of the dynamic and thermodynamic disturbance in the lower troposphere over the observed rainband. Before the typhoon landed, the advection of the parameter by basic-state flow and the coupling of general potential temperature perturbation with curl of Coriolis force perturbation are the primary dynamic processes which are responsible for the local change of the parameter. After the typhoon landed, the disturbance is mainly driven by the combination of five primary dynamic processes. The advection of the parameter by basic-state flow was weakened after the typhoon landed.

Optimization of processing parameters of UAV integral structural components based on yield response

NASA Astrophysics Data System (ADS)

Chen, Yunsheng

2018-05-01

In order to improve the overall strength of unmanned aerial vehicle (UAV), it is necessary to optimize the processing parameters of UAV structural components, which is affected by initial residual stress in the process of UAV structural components processing. Because machining errors are easy to occur, an optimization model for machining parameters of UAV integral structural components based on yield response is proposed. The finite element method is used to simulate the machining parameters of UAV integral structural components. The prediction model of workpiece surface machining error is established, and the influence of the path of walking knife on residual stress of UAV integral structure is studied, according to the stress of UAV integral component. The yield response of the time-varying stiffness is analyzed, and the yield response and the stress evolution mechanism of the UAV integral structure are analyzed. The simulation results show that this method is used to optimize the machining parameters of UAV integral structural components and improve the precision of UAV milling processing. The machining error is reduced, and the deformation prediction and error compensation of UAV integral structural parts are realized, thus improving the quality of machining.

Using the Multipole Resonance Probe to Stabilize the Electron Density During a Reactive Sputter Process

NASA Astrophysics Data System (ADS)

Oberberg, Moritz; Styrnoll, Tim; Ries, Stefan; Bienholz, Stefan; Awakowicz, Peter

2015-09-01

Reactive sputter processes are used for the deposition of hard, wear-resistant and non-corrosive ceramic layers such as aluminum oxide (Al2O3) . A well known problem is target poisoning at high reactive gas flows, which results from the reaction of the reactive gas with the metal target. Consequently, the sputter rate decreases and secondary electron emission increases. Both parameters show a non-linear hysteresis behavior as a function of the reactive gas flow and this leads to process instabilities. This work presents a new control method of Al2O3 deposition in a multiple frequency CCP (MFCCP) based on plasma parameters. Until today, process controls use parameters such as spectral line intensities of sputtered metal as an indicator for the sputter rate. A coupling between plasma and substrate is not considered. The control system in this work uses a new plasma diagnostic method: The multipole resonance probe (MRP) measures plasma parameters such as electron density by analyzing a typical resonance frequency of the system response. This concept combines target processes and plasma effects and directly controls the sputter source instead of the resulting target parameters.

A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters.

PubMed

Suzuki, Yasuhiro; Suzuki, Tatsuya; Minami, Hidemi; Terada, Katsuhide

2016-01-01

In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing.

Marginal Utility of Conditional Sensitivity Analyses for Dynamic Models

EPA Science Inventory

Background/Question/MethodsDynamic ecological processes may be influenced by many factors. Simulation models thatmimic these processes often have complex implementations with many parameters. Sensitivityanalyses are subsequently used to identify critical parameters whose uncertai...

An automatic alignment tool to improve repeatability of left ventricular function and dyssynchrony parameters in serial gated myocardial perfusion SPECT studies

PubMed Central

Zhou, Yanli; Faber, Tracy L.; Patel, Zenic; Folks, Russell D.; Cheung, Alice A.; Garcia, Ernest V.; Soman, Prem; Li, Dianfu; Cao, Kejiang; Chen, Ji

2013-01-01

Objective Left ventricular (LV) function and dyssynchrony parameters measured from serial gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) using blinded processing had a poorer repeatability than when manual side-by-side processing was used. The objective of this study was to validate whether an automatic alignment tool can reduce the variability of LV function and dyssynchrony parameters in serial gated SPECT MPI. Methods Thirty patients who had undergone serial gated SPECT MPI were prospectively enrolled in this study. Thirty minutes after the first acquisition, each patient was repositioned and a gated SPECT MPI image was reacquired. The two data sets were first processed blinded from each other by the same technologist in different weeks. These processed data were then realigned by the automatic tool, and manual side-by-side processing was carried out. All processing methods used standard iterative reconstruction and Butterworth filtering. The Emory Cardiac Toolbox was used to measure the LV function and dyssynchrony parameters. Results The automatic tool failed in one patient, who had a large, severe scar in the inferobasal wall. In the remaining 29 patients, the repeatability of the LV function and dyssynchrony parameters after automatic alignment was significantly improved from blinded processing and was comparable to manual side-by-side processing. Conclusion The automatic alignment tool can be an alternative method to manual side-by-side processing to improve the repeatability of LV function and dyssynchrony measurements by serial gated SPECT MPI. PMID:23211996

Process optimization of rolling for zincked sheet technology using response surface methodology and genetic algorithm

NASA Astrophysics Data System (ADS)

Ji, Liang-Bo; Chen, Fang

2017-07-01

Numerical simulation and intelligent optimization technology were adopted for rolling and extrusion of zincked sheet. By response surface methodology (RSM), genetic algorithm (GA) and data processing technology, an efficient optimization of process parameters for rolling of zincked sheet was investigated. The influence trend of roller gap, rolling speed and friction factor effects on reduction rate and plate shortening rate were analyzed firstly. Then a predictive response surface model for comprehensive quality index of part was created using RSM. Simulated and predicted values were compared. Through genetic algorithm method, the optimal process parameters for the forming of rolling were solved. They were verified and the optimum process parameters of rolling were obtained. It is feasible and effective.

Effects of process parameters in plastic, metal, and ceramic injection molding processes

NASA Astrophysics Data System (ADS)

Lee, Shi W.; Ahn, Seokyoung; Whang, Chul Jin; Park, Seong Jin; Atre, Sundar V.; Kim, Jookwon; German, Randall M.

2011-09-01

Plastic injection molding has been widely used in the past and is a dominant forming approach today. As the customer demands require materials with better engineering properties that were not feasible with polymers, powder injection molding with metal and ceramic powders has received considerable attention in recent decades. To better understand the differences in the plastic injection molding, metal injection molding, and ceramic injection molding, the effects of the core process parameters on the process performances has been studied using the state-of-the-art computer-aided engineering (CAE) design tool, PIMSolver® The design of experiments has been conducted using the Taguchi method to obtain the relative contributions of various process parameters onto the successful operations.

Effect of Voltage and Flow Rate Electrospinning Parameters on Polyacrylonitrile Electrospun Fibers

NASA Astrophysics Data System (ADS)

Bakar, S. S. S.; Fong, K. C.; Eleyas, A.; Nazeri, M. F. M.

2018-03-01

Currently, electrospinning is a very famous technique and widely used for forming polymer nanofibers. In this paper, the Polyacrylonitrile (PAN) nanofibers were prepared in concentration of 10wt% with varied processing parameters that can affect the properties of PAN fiber in term of fiber diameter and electrical conductivity was presented. Voltage of 10, 15 and 20 kV with PAN flow rate of 1 electrospun PAN fibers were then undergo pyrolysis at 800°C for 30 minutes. The resultant PAN nanofibers were then analysed by SEM, XRD and four point probe test after pyrolysis process. SEM image show continuos uniform and smooth surface fibrous structure of electrospun PAN fibers with average diameter of 1.81 μm. The fiber morphology is controlled by manipulating the processing parameters of electrospinning process. The results showed that the resistance of electrospun PAN fibers decreases as the processing parameter changes by increasing the applied voltage and flow rate of electrospinning.

Effect of spray drying processing parameters on the insecticidal activity of two encapsulated formulations of baculovirus

USDA-ARS?s Scientific Manuscript database

The aim of this work was to evaluate the effect of spray dryer processing parameters on the process yield and insecticidal activity of baculovirus to support the development of this beneficial group of microbes as biopesticides. For each of two baculoviruses [granulovirus (GV) from Pieris rapae (L....

Effects of process parameters on the molding quality of the micro-needle array

NASA Astrophysics Data System (ADS)

Qiu, Z. J.; Ma, Z.; Gao, S.

2016-07-01

Micro-needle array, which is used in medical applications, is a kind of typical injection molded products with microstructures. Due to its tiny micro-features size and high aspect ratios, it is more likely to produce short shots defects, leading to poor molding quality. The injection molding process of the micro-needle array was studied in this paper to find the effects of the process parameters on the molding quality of the micro-needle array and to provide theoretical guidance for practical production of high-quality products. With the shrinkage ratio and warpage of micro needles as the evaluation indices of the molding quality, the orthogonal experiment was conducted and the analysis of variance was carried out. According to the results, the contribution rates were calculated to determine the influence of various process parameters on molding quality. The single parameter method was used to analyse the main process parameter. It was found that the contribution rate of the holding pressure on shrinkage ratio and warpage reached 83.55% and 94.71% respectively, far higher than that of the other parameters. The study revealed that the holding pressure is the main factor which affects the molding quality of micro-needle array so that it should be focused on in order to obtain plastic parts with high quality in the practical production.

The Influence of Friction Stir Weld Tool Form and Welding Parameters on Weld Structure and Properties: Nugget Bulge in Self-Reacting Friction Stir Welds

NASA Technical Reports Server (NTRS)

Schneider, Judy; Nunes, Arthur C., Jr.; Brendel, Michael S.

2010-01-01

Although friction stir welding (FSW) was patented in 1991, process development has been based upon trial and error and the literature still exhibits little understanding of the mechanisms determining weld structure and properties. New concepts emerging from a better understanding of these mechanisms enhance the ability of FSW engineers to think about the FSW process in new ways, inevitably leading to advances in the technology. A kinematic approach in which the FSW flow process is decomposed into several simple flow components has been found to explain the basic structural features of FSW welds and to relate them to tool geometry and process parameters. Using this modelling approach, this study reports on a correlation between the features of the weld nugget, process parameters, weld tool geometry, and weld strength. This correlation presents a way to select process parameters for a given tool geometry so as to optimize weld strength. It also provides clues that may ultimately explain why the weld strength varies within the sample population.

Research on a Defects Detection Method in the Ferrite Phase Shifter Cementing Process Based on a Multi-Sensor Prognostic and Health Management (PHM) System.

PubMed

Wan, Bo; Fu, Guicui; Li, Yanruoyue; Zhao, Youhu

2016-08-10

The cementing manufacturing process of ferrite phase shifters has the defect that cementing strength is insufficient and fractures always appear. A detection method of these defects was studied utilizing the multi-sensors Prognostic and Health Management (PHM) theory. Aiming at these process defects, the reasons that lead to defects are analyzed in this paper. In the meanwhile, the key process parameters were determined and Differential Scanning Calorimetry (DSC) tests during the cure process of resin cementing were carried out. At the same time, in order to get data on changing cementing strength, multiple-group cementing process tests of different key process parameters were designed and conducted. A relational model of cementing strength and cure temperature, time and pressure was established, by combining data of DSC and process tests as well as based on the Avrami formula. Through sensitivity analysis for three process parameters, the on-line detection decision criterion and the process parameters which have obvious impact on cementing strength were determined. A PHM system with multiple temperature and pressure sensors was established on this basis, and then, on-line detection, diagnosis and control for ferrite phase shifter cementing process defects were realized. It was verified by subsequent process that the on-line detection system improved the reliability of the ferrite phase shifter cementing process and reduced the incidence of insufficient cementing strength defects.

Investigation on influence of Wurster coating process parameters for the development of delayed release minitablets of Naproxen.

PubMed

Shah, Neha; Mehta, Tejal; Aware, Rahul; Shetty, Vasant

2017-12-01

The present work aims at studying process parameters affecting coating of minitablets (3 mm in diameter) through Wurster coating process. Minitablets of Naproxen with high drug loading were manufactured using 3 mm multi-tip punches. The release profile of core pellets (published) and minitablets was compared with that of marketed formulation. The core formulation of minitablets was found to show similarity in dissolution profile with marketed formulation and hence was further carried forward for functional coating over it. Wurster processing was implemented to pursue functional coating over core formulation. Different process parameters were screened and control strategy was applied for factors significantly affecting the process. Modified Plackett Burman Design was applied for studying important factors. Based on the significant factors and minimum level of coating required for functionalization, optimized process was executed. Final coated batch was evaluated for coating thickness, surface morphology, and drug release study.

Optimisation Of Cutting Parameters Of Composite Material Laser Cutting Process By Taguchi Method

NASA Astrophysics Data System (ADS)

Lokesh, S.; Niresh, J.; Neelakrishnan, S.; Rahul, S. P. Deepak

2018-03-01

The aim of this work is to develop a laser cutting process model that can predict the relationship between the process input parameters and resultant surface roughness, kerf width characteristics. The research conduct is based on the Design of Experiment (DOE) analysis. Response Surface Methodology (RSM) is used in this work. It is one of the most practical and most effective techniques to develop a process model. Even though RSM has been used for the optimization of the laser process, this research investigates laser cutting of materials like Composite wood (veneer)to be best circumstances of laser cutting using RSM process. The input parameters evaluated are focal length, power supply and cutting speed, the output responses being kerf width, surface roughness, temperature. To efficiently optimize and customize the kerf width and surface roughness characteristics, a machine laser cutting process model using Taguchi L9 orthogonal methodology was proposed.

Investigation, sensitivity analysis, and multi-objective optimization of effective parameters on temperature and force in robotic drilling cortical bone.

PubMed

Tahmasbi, Vahid; Ghoreishi, Majid; Zolfaghari, Mojtaba

2017-11-01

The bone drilling process is very prominent in orthopedic surgeries and in the repair of bone fractures. It is also very common in dentistry and bone sampling operations. Due to the complexity of bone and the sensitivity of the process, bone drilling is one of the most important and sensitive processes in biomedical engineering. Orthopedic surgeries can be improved using robotic systems and mechatronic tools. The most crucial problem during drilling is an unwanted increase in process temperature (higher than 47 °C), which causes thermal osteonecrosis or cell death and local burning of the bone tissue. Moreover, imposing higher forces to the bone may lead to breaking or cracking and consequently cause serious damage. In this study, a mathematical second-order linear regression model as a function of tool drilling speed, feed rate, tool diameter, and their effective interactions is introduced to predict temperature and force during the bone drilling process. This model can determine the maximum speed of surgery that remains within an acceptable temperature range. Moreover, for the first time, using designed experiments, the bone drilling process was modeled, and the drilling speed, feed rate, and tool diameter were optimized. Then, using response surface methodology and applying a multi-objective optimization, drilling force was minimized to sustain an acceptable temperature range without damaging the bone or the surrounding tissue. In addition, for the first time, Sobol statistical sensitivity analysis is used to ascertain the effect of process input parameters on process temperature and force. The results show that among all effective input parameters, tool rotational speed, feed rate, and tool diameter have the highest influence on process temperature and force, respectively. The behavior of each output parameters with variation in each input parameter is further investigated. Finally, a multi-objective optimization has been performed considering all the aforementioned parameters. This optimization yielded a set of data that can considerably improve orthopedic osteosynthesis outcomes.

Mathematical Model of Nonstationary Separation Processes Proceeding in the Cascade of Gas Centrifuges in the Process of Separation of Multicomponent Isotope Mixtures

NASA Astrophysics Data System (ADS)

Orlov, A. A.; Ushakov, A. A.; Sovach, V. P.

2017-03-01

We have developed and realized on software a mathematical model of the nonstationary separation processes proceeding in the cascades of gas centrifuges in the process of separation of multicomponent isotope mixtures. With the use of this model the parameters of the separation process of germanium isotopes have been calculated. It has been shown that the model adequately describes the nonstationary processes in the cascade and is suitable for calculating their parameters in the process of separation of multicomponent isotope mixtures.

Finding Relevant Parameters for the Thin-film Photovoltaic Cells Production Process with the Application of Data Mining Methods.

PubMed

Ulaczyk, Jan; Morawiec, Krzysztof; Zabierowski, Paweł; Drobiazg, Tomasz; Barreau, Nicolas

2017-09-01

A data mining approach is proposed as a useful tool for the control parameters analysis of the 3-stage CIGSe photovoltaic cell production process, in order to find variables that are the most relevant for cell electric parameters and efficiency. The analysed data set consists of stage duration times, heater power values as well as temperatures for the element sources and the substrate - there are 14 variables per sample in total. The most relevant variables of the process have been found based on the so-called random forest analysis with the application of the Boruta algorithm. 118 CIGSe samples, prepared at Institut des Matériaux Jean Rouxel, were analysed. The results are close to experimental knowledge on the CIGSe cells production process. They bring new evidence to production parameters of new cells and further research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A holistic approach towards defined product attributes by Maillard-type food processing.

PubMed

Davidek, Tomas; Illmann, Silke; Rytz, Andreas; Blank, Imre

2013-07-01

A fractional factorial experimental design was used to quantify the impact of process and recipe parameters on selected product attributes of extruded products (colour, viscosity, acrylamide, and the flavour marker 4-hydroxy-2,5-dimethyl-3(2H)-furanone, HDMF). The study has shown that recipe parameters (lysine, phosphate) can be used to modulate the HDMF level without changing the specific mechanical energy (SME) and consequently the texture of the product, while processing parameters (temperature, moisture) impact both HDMF and SME in parallel. Similarly, several parameters, including phosphate level, temperature and moisture, simultaneously impact both HDMF and acrylamide formation, while pH and addition of lysine showed different trends. Therefore, the latter two options can be used to mitigate acrylamide without a negative impact on flavour. Such a holistic approach has been shown as a powerful tool to optimize various product attributes upon food processing.

Computational Modeling and High Performance Computing in Advanced Materials Processing, Synthesis, and Design

DTIC Science & Technology

2014-12-07

parameters of resin viscosity and preform permeability prior to resin gelation. However, there could be significant variations in these two parameters...during actual manufacturing due to differences in the resin batches, mixes, temperature, ambient conditions for viscosity ; in the preform rolls...optimal injection time and locations for given process parameters of resin viscosity and preform permeability prior to resin gelation. However, there

On selecting a prior for the precision parameter of Dirichlet process mixture models

USGS Publications Warehouse

Dorazio, R.M.

2009-01-01

In hierarchical mixture models the Dirichlet process is used to specify latent patterns of heterogeneity, particularly when the distribution of latent parameters is thought to be clustered (multimodal). The parameters of a Dirichlet process include a precision parameter ?? and a base probability measure G0. In problems where ?? is unknown and must be estimated, inferences about the level of clustering can be sensitive to the choice of prior assumed for ??. In this paper an approach is developed for computing a prior for the precision parameter ?? that can be used in the presence or absence of prior information about the level of clustering. This approach is illustrated in an analysis of counts of stream fishes. The results of this fully Bayesian analysis are compared with an empirical Bayes analysis of the same data and with a Bayesian analysis based on an alternative commonly used prior.

Surface pretreatment of plastics with an atmospheric pressure plasma jet - Influence of generator power and kinematics

NASA Astrophysics Data System (ADS)

Moritzer, E.; Leister, C.

2014-05-01

The industrial use of atmospheric pressure plasmas in the plastics processing industry has increased significantly in recent years. Users of this treatment process have the possibility to influence the target values (e.g. bond strength or surface energy) with the help of kinematic and electrical parameters. Until now, systematic procedures have been used with which the parameters can be adapted to the process or product requirements but only by very time-consuming methods. For this reason, the relationship between influencing values and target values will be examined based on the example of a pretreatment in the bonding process with the help of statistical experimental design. Because of the large number of parameters involved, the analysis is restricted to the kinematic and electrical parameters. In the experimental tests, the following factors are taken as parameters: gap between nozzle and substrate, treatment velocity (kinematic data), voltage and duty cycle (electrical data). The statistical evaluation shows significant relationships between the parameters and surface energy in the case of polypropylene. An increase in the voltage and duty cycle increases the polar proportion of the surface energy, while a larger gap and higher velocity leads to lower energy levels. The bond strength of the overlapping bond is also significantly influenced by the voltage, velocity and gap. The direction of their effects is identical with those of the surface energy. In addition to the kinematic influences of the motion of an atmospheric pressure plasma jet, it is therefore especially important that the parameters for the plasma production are taken into account when designing the pretreatment processes.

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

Moritzer, E., E-mail: elmar.moritzer@ktp.upb.de; Leister, C., E-mail: elmar.moritzer@ktp.upb.de

The industrial use of atmospheric pressure plasmas in the plastics processing industry has increased significantly in recent years. Users of this treatment process have the possibility to influence the target values (e.g. bond strength or surface energy) with the help of kinematic and electrical parameters. Until now, systematic procedures have been used with which the parameters can be adapted to the process or product requirements but only by very time-consuming methods. For this reason, the relationship between influencing values and target values will be examined based on the example of a pretreatment in the bonding process with the help ofmore » statistical experimental design. Because of the large number of parameters involved, the analysis is restricted to the kinematic and electrical parameters. In the experimental tests, the following factors are taken as parameters: gap between nozzle and substrate, treatment velocity (kinematic data), voltage and duty cycle (electrical data). The statistical evaluation shows significant relationships between the parameters and surface energy in the case of polypropylene. An increase in the voltage and duty cycle increases the polar proportion of the surface energy, while a larger gap and higher velocity leads to lower energy levels. The bond strength of the overlapping bond is also significantly influenced by the voltage, velocity and gap. The direction of their effects is identical with those of the surface energy. In addition to the kinematic influences of the motion of an atmospheric pressure plasma jet, it is therefore especially important that the parameters for the plasma production are taken into account when designing the pretreatment processes.« less

Parameter-induced uncertainty quantification of crop yields, soil N2O and CO2 emission for 8 arable sites across Europe using the LandscapeDNDC model

NASA Astrophysics Data System (ADS)

Santabarbara, Ignacio; Haas, Edwin; Kraus, David; Herrera, Saul; Klatt, Steffen; Kiese, Ralf

2014-05-01

When using biogeochemical models to estimate greenhouse gas emissions at site to regional/national levels, the assessment and quantification of the uncertainties of simulation results are of significant importance. The uncertainties in simulation results of process-based ecosystem models may result from uncertainties of the process parameters that describe the processes of the model, model structure inadequacy as well as uncertainties in the observations. Data for development and testing of uncertainty analisys were corp yield observations, measurements of soil fluxes of nitrous oxide (N2O) and carbon dioxide (CO2) from 8 arable sites across Europe. Using the process-based biogeochemical model LandscapeDNDC for simulating crop yields, N2O and CO2 emissions, our aim is to assess the simulation uncertainty by setting up a Bayesian framework based on Metropolis-Hastings algorithm. Using Gelman statistics convergence criteria and parallel computing techniques, enable multi Markov Chains to run independently in parallel and create a random walk to estimate the joint model parameter distribution. Through means distribution we limit the parameter space, get probabilities of parameter values and find the complex dependencies among them. With this parameter distribution that determines soil-atmosphere C and N exchange, we are able to obtain the parameter-induced uncertainty of simulation results and compare them with the measurements data.

'Scaling' analysis of the ice accretion process on aircraft surfaces

NASA Technical Reports Server (NTRS)

Keshock, E. G.; Tabrizi, A. H.; Missimer, J. R.

1982-01-01

A comprehensive set of scaling parameters is developed for the ice accretion process by analyzing the energy equations of the dynamic freezing zone and the already frozen ice layer, the continuity equation associated with supercooled liquid droplets entering into and impacting within the dynamic freezing zone, and energy equation of the ice layer. No initial arbitrary judgments are made regarding the relative magnitudes of each of the terms. The method of intrinsic reference variables in employed in order to develop the appropriate scaling parameters and their relative significance in rime icing conditions in an orderly process, rather than utilizing empiricism. The significance of these parameters is examined and the parameters are combined with scaling criteria related to droplet trajectory similitude.

Estimation of correlation functions by stochastic approximation.

NASA Technical Reports Server (NTRS)

Habibi, A.; Wintz, P. A.

1972-01-01

Consideration of the autocorrelation function of a zero-mean stationary random process. The techniques are applicable to processes with nonzero mean provided the mean is estimated first and subtracted. Two recursive techniques are proposed, both of which are based on the method of stochastic approximation and assume a functional form for the correlation function that depends on a number of parameters that are recursively estimated from successive records. One technique uses a standard point estimator of the correlation function to provide estimates of the parameters that minimize the mean-square error between the point estimates and the parametric function. The other technique provides estimates of the parameters that maximize a likelihood function relating the parameters of the function to the random process. Examples are presented.

Comparative Analyses of Creep Models of a Solid Propellant

NASA Astrophysics Data System (ADS)

Zhang, J. B.; Lu, B. J.; Gong, S. F.; Zhao, S. P.

2018-05-01

The creep experiments of a solid propellant samples under five different stresses are carried out at 293.15 K and 323.15 K. In order to express the creep properties of this solid propellant, the viscoelastic model i.e. three Parameters solid, three Parameters fluid, four Parameters solid, four Parameters fluid and exponential model are involved. On the basis of the principle of least squares fitting, and different stress of all the parameters for the models, the nonlinear fitting procedure can be used to analyze the creep properties. The study shows that the four Parameters solid model can best express the behavior of creep properties of the propellant samples. However, the three Parameters solid and exponential model cannot very well reflect the initial value of the creep process, while the modified four Parameters models are found to agree well with the acceleration characteristics of the creep process.

UHF Signal Processing and Pattern Recognition of Partial Discharge in Gas-Insulated Switchgear Using Chromatic Methodology

PubMed Central

Wang, Xiaohua; Li, Xi; Rong, Mingzhe; Xie, Dingli; Ding, Dan; Wang, Zhixiang

2017-01-01

The ultra-high frequency (UHF) method is widely used in insulation condition assessment. However, UHF signal processing algorithms are complicated and the size of the result is large, which hinders extracting features and recognizing partial discharge (PD) patterns. This article investigated the chromatic methodology that is novel in PD detection. The principle of chromatic methodologies in color science are introduced. The chromatic processing represents UHF signals sparsely. The UHF signals obtained from PD experiments were processed using chromatic methodology and characterized by three parameters in chromatic space (H, L, and S representing dominant wavelength, signal strength, and saturation, respectively). The features of the UHF signals were studied hierarchically. The results showed that the chromatic parameters were consistent with conventional frequency domain parameters. The global chromatic parameters can be used to distinguish UHF signals acquired by different sensors, and they reveal the propagation properties of the UHF signal in the L-shaped gas-insulated switchgear (GIS). Finally, typical PD defect patterns had been recognized by using novel chromatic parameters in an actual GIS tank and good performance of recognition was achieved. PMID:28106806

UHF Signal Processing and Pattern Recognition of Partial Discharge in Gas-Insulated Switchgear Using Chromatic Methodology.

PubMed

Wang, Xiaohua; Li, Xi; Rong, Mingzhe; Xie, Dingli; Ding, Dan; Wang, Zhixiang

2017-01-18

The ultra-high frequency (UHF) method is widely used in insulation condition assessment. However, UHF signal processing algorithms are complicated and the size of the result is large, which hinders extracting features and recognizing partial discharge (PD) patterns. This article investigated the chromatic methodology that is novel in PD detection. The principle of chromatic methodologies in color science are introduced. The chromatic processing represents UHF signals sparsely. The UHF signals obtained from PD experiments were processed using chromatic methodology and characterized by three parameters in chromatic space ( H , L , and S representing dominant wavelength, signal strength, and saturation, respectively). The features of the UHF signals were studied hierarchically. The results showed that the chromatic parameters were consistent with conventional frequency domain parameters. The global chromatic parameters can be used to distinguish UHF signals acquired by different sensors, and they reveal the propagation properties of the UHF signal in the L-shaped gas-insulated switchgear (GIS). Finally, typical PD defect patterns had been recognized by using novel chromatic parameters in an actual GIS tank and good performance of recognition was achieved.

Modulation of mitochondrial activity in HaCaT keratinocytes by the cell penetrating peptide Z-Gly-RGD(DPhe)-mitoparan.

PubMed

Richardson, Adam; Muir, Lewis; Mousdell, Sasha; Sexton, Darren; Jones, Sarah; Howl, John; Ross, Kehinde

2018-01-30

Biologically active cell penetrating peptides (CPPs) are an emerging class of therapeutic agent. The wasp venom peptide mastoparan is an established CPP that modulates mitochondrial activity and triggers caspase-dependent apoptosis in cancer cells, as does the mastoparan analogue mitoparan (mitP). Mitochondrial depolarisation and activation of the caspase cascade also underpins the action of dithranol, a topical agent for treatment of psoriasis. The effects of a potent mitP analogue on mitochondrial activity were therefore examined to assess its potential as a novel approach for targeting mitochondria for the treatment of psoriasis. In HaCaT keratinocytes treated with the mitP analogue Z-Gly-RGD(DPhe)-mitP for 24 h, a dose-dependent loss of mitochondrial activity was observed using the methyl-thiazolyl-tetrazolium (MTT) assay. At 10 μmol L -1 , MTT activity was less than 30% that observed in untreated cells. Staining with the cationic dye JC-1 suggested that Z-Gly-RGD(DPhe)-mitP also dissipated the mitochondrial membrane potential, with a threefold increase in mitochondrial depolarisation levels. However, caspase activity appeared to be reduced by 24 h exposure to Z-Gly-RGD(DPhe)-mitP treatment. Furthermore, Z-Gly-RGD(DPhe)-mitP treatment had little effect on overall cell viability. Our findings suggest Z-Gly-RGD(DPhe)-mitP promotes the loss of mitochondrial activity but does not appear to evoke apoptosis in HaCaT keratinocytes.

Cationic membrane-active peptides - anticancer and antifungal activity as well as penetration into human skin.

PubMed

Do, Nhung; Weindl, Günther; Grohmann, Lisa; Salwiczek, Mario; Koksch, Beate; Korting, Hans Christian; Schäfer-Korting, Monika

2014-05-01

Cationic antimicrobial peptides are ancient natural broad-spectrum antibiotics, and several compounds also exhibit anticancer activity. However, most applications pertain to bacterial infections, and treatment for skin cancer is less frequently considered. The cytotoxicity of melittin, cecropin A, protegrin-1 and histatin 5 against squamous skin cancer cell lines and normal human keratinocytes was evaluated and compared to established drugs. The results show that melittin clearly outperforms 5-fluorouracil regarding antitumor activity. Importantly, combined melittin and 5-fluorouracil enhanced cytotoxic effects on cancer cells and reduced toxicity on normal keratinocytes. Additionally, minimum inhibitory concentrations indicate that melittin also shows superior activity against clinical and laboratory strains of Candida albicans compared to amphotericin B. To evaluate its potential for topical applications, human skin penetration of melittin was investigated ex vivo and compared to two non-toxic cell-penetrating peptides (CPPs), low molecular weight protamine (LMWP) and penetratin. The stratum corneum prevents penetration into viable epidermis over 6 h; however, the peptides gain access to the viable skin after 24 h. Inhibition of digestive enzymes during skin penetration significantly enhances the availability of intact peptide. In conclusion, melittin may represent an innovative agent for non-melanoma skin cancer and infectious skin diseases. In order to develop a drug candidate, skin absorption and proteolytic digestion by skin enzymes need to be addressed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier.

PubMed

Bera, Swapna; Kar, Rajiv K; Mondal, Susanta; Pahan, Kalipada; Bhunia, Anirban

2016-09-06

Cell-penetrating peptides (CPPs) have shown promise in nonpermeable therapeutic drug delivery, because of their ability to transport a variety of cargo molecules across the cell membranes and their noncytotoxicity. Drosophila antennapedia homeodomain-derived CPP penetratin (RQIKIWFQNRRMKWKK), being rich in positively charged residues, has been increasingly used as a potential drug carrier for various purposes. Penetratin can breach the tight endothelial network known as the blood-brain barrier (BBB), permitting treatment of several neurodegenerative maladies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, a detailed structural understanding of penetratin and its mechanism of action is lacking. This study defines structural features of the penetratin-derived peptide, DK17 (DRQIKIWFQNRRMKWKK), in several model membranes and describes a membrane-induced conformational transition of the DK17 peptide in these environments. A series of biophysical experiments, including high-resolution nuclear magnetic resonance spectroscopy, provides the three-dimensional structure of DK17 in different membranes mimicking the BBB or total brain lipid extract. Molecular dynamics simulations support the experimental results showing preferential binding of DK17 to particular lipids at atomic resolution. The peptide conserves the structure of the subdomain spanning residues Ile6-Arg11, despite considerable conformational variation in different membrane models. In vivo data suggest that the wild type, not a mutated sequence, enters the central nervous system. Together, these data highlight important structural and functional attributes of DK17 that could be utilized in drug delivery for neurodegenerative disorders.

Empty Turnip yellow mosaic virus capsids as delivery vehicles to mammalian cells.

PubMed

Kim, Doyeong; Lee, Younghee; Dreher, Theo W; Cho, Tae-Ju

2018-05-03

Turnip yellow mosaic virus (TYMV) was able to enter animal cells when the spherical plant virus was conjugated with Tat, a cell penetrating peptide (CPP). Tat was chemically attached to the surface lysine residues of TYMV using hydrazone chemistry. Baby hamster kidney (BHK) cells were incubated with either unmodified or Tat-conjugated TYMV and examined by flow cytometry and confocal microscopic analyses. Tat conjugation was shown to be more efficient than Lipofectamine in allowing TYMV to enter the mammalian cells. Tat-assisted-transfection was also associated with less loss of cell viability than lipofection. Among the CPPs tested (Tat, R8, Pep-1 and Pen), it was observed that R8 and Pen were also effective while Pep-1 was not. We also examined if the internal space of TYMV can be used to load fluorescein dye as a model cargo. When TYMV is treated by freezing and thawing, the virus is known to convert into a structure with a 6-8 nm hole and release viral RNA. When the resultant pot-like particles were reacted with fluorescein-5-maleimide using interior sulfhydryl groups as conjugation sites, about 145 fluorescein molecules were added per particle. The fluorescein-loaded TYMV particles were conjugated with Tat and introduced into BHK cells, again with higher transfection efficiency compared to lipofection. Our studies demonstrate the potential of modified TYMV as an efficient system for therapeutic cargo delivery to mammalian cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Peptides, polypeptides and peptide-polymer hybrids as nucleic acid carriers.

PubMed

Ahmed, Marya

2017-10-24

Cell penetrating peptides (CPPs), and protein transduction domains (PTDs) of viruses and other natural proteins serve as a template for the development of efficient peptide based gene delivery vectors. PTDs are sequences of acidic or basic amphipathic amino acids, with superior membrane trespassing efficacies. Gene delivery vectors derived from these natural, cationic and cationic amphipathic peptides, however, offer little flexibility in tailoring the physicochemical properties of single chain peptide based systems. Owing to significant advances in the field of peptide chemistry, synthetic mimics of natural peptides are often prepared and have been evaluated for their gene expression, as a function of amino acid functionalities, architecture and net cationic content of peptide chains. Moreover, chimeric single polypeptide chains are prepared by a combination of multiple small natural or synthetic peptides, which imparts distinct physiological properties to peptide based gene delivery therapeutics. In order to obtain multivalency and improve the gene delivery efficacies of low molecular weight cationic peptides, bioactive peptides are often incorporated into a polymeric architecture to obtain novel 'polymer-peptide hybrids' with improved gene delivery efficacies. Peptide modified polymers prepared by physical or chemical modifications exhibit enhanced endosomal escape, stimuli responsive degradation and targeting efficacies, as a function of physicochemical and biological activities of peptides attached onto a polymeric scaffold. The focus of this review is to provide comprehensive and step-wise progress in major natural and synthetic peptides, chimeric polypeptides, and peptide-polymer hybrids for nucleic acid delivery applications.

A photo-responsive peptide- and asparagine-glycine-arginine (NGR) peptide-mediated liposomal delivery system.

PubMed

Xie, Xiangyang; Yang, Yanfang; Yang, Yang; Zhang, Hui; Li, Ying; Mei, Xingguo

2016-09-01

The conjugation of tunable peptides or materials with nanocarriers represents a promising approach for drug delivery to tumor cells. In this study, we report the development of a novel liposomal carrier system that exploits the cell surface binding synergism between photo-sensitive peptides (PSPs) and targeting ligands. The positive charges of the lysine residues on the cell-penetrating peptides (CPPs) were temporarily caged by the photolabile-protective groups (PG), thereby forming a PSP. Furthermore, this PSP enhances specific uptake into cancer cells after rapidly uncaging the PG via near-infrared (NIR) light illumination. In the circulatory system, the cell penetrability of PSP was hindered. In contrast, the asparagine-glycine-arginine (NGR) peptide moieties, selectively bind to CD13-positive tumors, were attached to the nanocarrier to facilitate the active accumulation of this liposomal carrier in tumor tissue. The dual-modified liposomes (PSP/NGR-L) were prepared by emulsification method, and the concentrations of DSPE-PEG 2000 -psCPP and DSPE-PEG 5000 -NGR in the liposomes were chosen to be 4% and 1% (molar ratio), respectively. The mean particle size of the PSP/NGR-L was about 95 nm, and the drug entrapment efficiency was more than 90%. Cellular uptake results demonstrated that the proposed PSP/NGR-L had an enhancement of cancer cell recognition and specific uptake. Furthermore, the PSP/NGR-L demonstrated a stronger antitumor efficacy in the HT-1080 tumor model in nude mice with the aid of NIR illumination.

Information Use Differences in Hot and Cold Risk Processing: When Does Information About Probability Count in the Columbia Card Task?

PubMed

Markiewicz, Łukasz; Kubińska, Elżbieta

2015-01-01

This paper aims to provide insight into information processing differences between hot and cold risk taking decision tasks within a single domain. Decision theory defines risky situations using at least three parameters: outcome one (often a gain) with its probability and outcome two (often a loss) with a complementary probability. Although a rational agent should consider all of the parameters, s/he could potentially narrow their focus to only some of them, particularly when explicit Type 2 processes do not have the resources to override implicit Type 1 processes. Here we investigate differences in risky situation parameters' influence on hot and cold decisions. Although previous studies show lower information use in hot than in cold processes, they do not provide decision weight changes and therefore do not explain whether this difference results from worse concentration on each parameter of a risky situation (probability, gain amount, and loss amount) or from ignoring some parameters. Two studies were conducted, with participants performing the Columbia Card Task (CCT) in either its Cold or Hot version. In the first study, participants also performed the Cognitive Reflection Test (CRT) to monitor their ability to override Type 1 processing cues (implicit processes) with Type 2 explicit processes. Because hypothesis testing required comparison of the relative importance of risky situation decision weights (gain, loss, probability), we developed a novel way of measuring information use in the CCT by employing a conjoint analysis methodology. Across the two studies, results indicated that in the CCT Cold condition decision makers concentrate on each information type (gain, loss, probability), but in the CCT Hot condition they concentrate mostly on a single parameter: probability of gain/loss. We also show that an individual's CRT score correlates with information use propensity in cold but not hot tasks. Thus, the affective dimension of hot tasks inhibits correct information processing, probably because it is difficult to engage Type 2 processes in such circumstances. Individuals' Type 2 processing abilities (measured by the CRT) assist greater use of information in cold tasks but do not help in hot tasks.

Information Use Differences in Hot and Cold Risk Processing: When Does Information About Probability Count in the Columbia Card Task?

PubMed Central

Markiewicz, Łukasz; Kubińska, Elżbieta

2015-01-01

Objective: This paper aims to provide insight into information processing differences between hot and cold risk taking decision tasks within a single domain. Decision theory defines risky situations using at least three parameters: outcome one (often a gain) with its probability and outcome two (often a loss) with a complementary probability. Although a rational agent should consider all of the parameters, s/he could potentially narrow their focus to only some of them, particularly when explicit Type 2 processes do not have the resources to override implicit Type 1 processes. Here we investigate differences in risky situation parameters' influence on hot and cold decisions. Although previous studies show lower information use in hot than in cold processes, they do not provide decision weight changes and therefore do not explain whether this difference results from worse concentration on each parameter of a risky situation (probability, gain amount, and loss amount) or from ignoring some parameters. Methods: Two studies were conducted, with participants performing the Columbia Card Task (CCT) in either its Cold or Hot version. In the first study, participants also performed the Cognitive Reflection Test (CRT) to monitor their ability to override Type 1 processing cues (implicit processes) with Type 2 explicit processes. Because hypothesis testing required comparison of the relative importance of risky situation decision weights (gain, loss, probability), we developed a novel way of measuring information use in the CCT by employing a conjoint analysis methodology. Results: Across the two studies, results indicated that in the CCT Cold condition decision makers concentrate on each information type (gain, loss, probability), but in the CCT Hot condition they concentrate mostly on a single parameter: probability of gain/loss. We also show that an individual's CRT score correlates with information use propensity in cold but not hot tasks. Thus, the affective dimension of hot tasks inhibits correct information processing, probably because it is difficult to engage Type 2 processes in such circumstances. Individuals' Type 2 processing abilities (measured by the CRT) assist greater use of information in cold tasks but do not help in hot tasks. PMID:26635652

Parameter extraction with neural networks

NASA Astrophysics Data System (ADS)

Cazzanti, Luca; Khan, Mumit; Cerrina, Franco

1998-06-01

In semiconductor processing, the modeling of the process is becoming more and more important. While the ultimate goal is that of developing a set of tools for designing a complete process (Technology CAD), it is also necessary to have modules to simulate the various technologies and, in particular, to optimize specific steps. This need is particularly acute in lithography, where the continuous decrease in CD forces the technologies to operate near their limits. In the development of a 'model' for a physical process, we face several levels of challenges. First, it is necessary to develop a 'physical model,' i.e. a rational description of the process itself on the basis of know physical laws. Second, we need an 'algorithmic model' to represent in a virtual environment the behavior of the 'physical model.' After a 'complete' model has been developed and verified, it becomes possible to do performance analysis. In many cases the input parameters are poorly known or not accessible directly to experiment. It would be extremely useful to obtain the values of these 'hidden' parameters from experimental results by comparing model to data. This is particularly severe, because the complexity and costs associated with semiconductor processing make a simple 'trial-and-error' approach infeasible and cost- inefficient. Even when computer models of the process already exists, obtaining data through simulations may be time consuming. Neural networks (NN) are powerful computational tools to predict the behavior of a system from an existing data set. They are able to adaptively 'learn' input/output mappings and to act as universal function approximators. In this paper we use artificial neural networks to build a mapping from the input parameters of the process to output parameters which are indicative of the performance of the process. Once the NN has been 'trained,' it is also possible to observe the process 'in reverse,' and to extract the values of the inputs which yield outputs with desired characteristics. Using this method, we can extract optimum values for the parameters and determine the process latitude very quickly.

Drug recrystallization using supercritical anti-solvent (SAS) process with impinging jets: Effect of process parameters

NASA Astrophysics Data System (ADS)

Careno, Stéphanie; Boutin, Olivier; Badens, Elisabeth

2012-03-01

The aim of this study is to improve mixing in supercritical anti-solvent process (SAS) with impinging jets in order to form finer particles of sulfathiazole, a poorly water-soluble drug. The influence of several process parameters upon the powder characteristics is studied. Parameters are jets' velocity (0.25 m s-1 to 25.92 m s-1), molar ratio solvent/CO2 (2.5% to 20%), temperature (313 K to 343 K), pressure (10 MPa to 20 MPa) and sulfathiazole concentration in the organic solution (0.5% to 1.8%). Two solvents are used: acetone and methanol. Smaller particles with a more homogeneous morphology are obtained from acetone solutions. For the smallest jets' velocity, corresponding to a non-atomized jet, the stable polymorphic form is obtained, pure or in mixture. At this velocity, pressure is the most influential parameter controlling the polymorphic nature of the powder formed. The pure stable polymorph is formed at 20 MPa. Concerning the particle size, the most influential parameters are temperature and sulfathiazole concentration. The use of impinging jets with different process parameters allows the crystallization of four polymorphs among the five known, and particle sizes are varied. This work demonstrates the studied device ability of the polymorph and the size control. A comparison with the classical SAS process shows that particle size, size distribution and morphology of particles crystallized with impinging jets are different from the ones obtained with classical SAS introduction device in similar operating conditions. Mean particle sizes are significantly smaller and size distributions are narrower with impinging jets device.

Physical parameters for proton induced K-, L-, and M-shell ionization processes

NASA Astrophysics Data System (ADS)

Shehla; Puri, Sanjiv

2016-10-01

The proton induced atomic inner-shell ionization processes comprising radiative and non-radiative transitions are characterized by physical parameters, namely, the proton ionization cross sections, X-ray emission rates, fluorescence yields and Coster-Kronig (CK) transition probabilities. These parameters are required to calculate the K/L/M shell X-ray production (XRP) cross sections and relative X-ray intensity ratios, which in turn are required for different analytical applications. The current status of different physical parameters is presented in this report for use in various applications.

Rapid permeation measurement system for the production control of monolayer and multilayer films

NASA Astrophysics Data System (ADS)

Botos, J.; Müller, K.; Heidemeyer, P.; Kretschmer, K.; Bastian, M.; Hochrein, T.

2014-05-01

Plastics have been used for packaging films for a long time. Until now the development of new formulations for film applications, including process optimization, has been a time-consuming and cost-intensive process for gases like oxygen (O2) or carbon dioxide (CO2). By using helium (He) the permeation measurement can be accelerated from hours or days to a few minutes. Therefore a manometric measuring system for tests according to ISO 15105-1 is coupled with a mass spectrometer to determine the helium flow rate and to calculate the helium permeation rate. Due to the accelerated determination the permeation quality of monolayer and multilayer films can be measured atline. Such a system can be used to predict for example the helium permeation rate of filled polymer films. Defined quality limits for the permeation rate can be specified as well as the prompt correction of process parameters if the results do not meet the specification. This method for process control was tested on a pilot line with a corotating twin-screw extruder for monolayer films. Selected process parameters were varied iteratively without changing the material formulation to obtain the best process parameter set and thus the lowest permeation rate. Beyond that the influence of different parameters on the helium permeation rate was examined on monolayer films. The results were evaluated conventional as well as with artificial neuronal networks in order to determine the non-linear correlation between all process parameters.

Optimization of the Hot Forging Processing Parameters for Powder Metallurgy Fe-Cu-C Connecting Rods Based on Finite Element Simulation

NASA Astrophysics Data System (ADS)

Li, Fengxian; Yi, Jianhong; Eckert, Jürgen

2017-12-01

Powder forged connecting rods have the problem of non-uniform density distributions because of their complex geometric shape. The densification behaviors of powder metallurgy (PM) connecting rod preforms during hot forging processes play a significant role in optimizing the connecting rod quality. The deformation behaviors of a connecting rod preform, a Fe-3Cu-0.5C (wt pct) alloy compacted and sintered by the powder metallurgy route (PM Fe-Cu-C), were investigated using the finite element method, while damage and friction behaviors of the material were considered in the complicated forging process. The calculated results agree well with the experimental results. The relationship between the processing parameters of hot forging and the relative density of the connecting rod was revealed. The results showed that the relative density of the hot forged connecting rod at the central shank changed significantly compared with the relative density at the big end and at the small end. Moreover, the relative density of the connecting rod was sensitive to the processing parameters such as the forging velocity and the initial density of the preform. The optimum forging processing parameters were determined and presented by using an orthogonal design method. This work suggests that the processing parameters can be optimized to prepare a connecting rod with uniform density distribution and can help to better meet the requirements of the connecting rod industry.

A Design of Experiment approach to predict product and process parameters for a spray dried influenza vaccine.

PubMed

Kanojia, Gaurav; Willems, Geert-Jan; Frijlink, Henderik W; Kersten, Gideon F A; Soema, Peter C; Amorij, Jean-Pierre

2016-09-25

Spray dried vaccine formulations might be an alternative to traditional lyophilized vaccines. Compared to lyophilization, spray drying is a fast and cheap process extensively used for drying biologicals. The current study provides an approach that utilizes Design of Experiments for spray drying process to stabilize whole inactivated influenza virus (WIV) vaccine. The approach included systematically screening and optimizing the spray drying process variables, determining the desired process parameters and predicting product quality parameters. The process parameters inlet air temperature, nozzle gas flow rate and feed flow rate and their effect on WIV vaccine powder characteristics such as particle size, residual moisture content (RMC) and powder yield were investigated. Vaccine powders with a broad range of physical characteristics (RMC 1.2-4.9%, particle size 2.4-8.5μm and powder yield 42-82%) were obtained. WIV showed no significant loss in antigenicity as revealed by hemagglutination test. Furthermore, descriptive models generated by DoE software could be used to determine and select (set) spray drying process parameter. This was used to generate a dried WIV powder with predefined (predicted) characteristics. Moreover, the spray dried vaccine powders retained their antigenic stability even after storage for 3 months at 60°C. The approach used here enabled the generation of a thermostable, antigenic WIV vaccine powder with desired physical characteristics that could be potentially used for pulmonary administration. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Determining Parameters of Double-Wiebe Function for Simulation of Combustion Process in Overload Diesel Engine with Common Rail Fuel Feed System

NASA Astrophysics Data System (ADS)

Kamaltdinov, V. G.; Markov, V. A.; Lysov, I. O.

2018-03-01

To analyze the peculiarities of the combustion process in an overload diesel engine with the system of Common Rail type with one-stage injection, the indicator diagram was registered. The parameters of the combustion process simulated by the double-Wiebe function were calculated as satisfactorily reconstructing the law of burning rate variation. The main parameters of the operating cycle obtained through the indicator diagram processing and the double-Wiebe function calculation differed insignificantly. And the calculated curve of the cylinder pressure differed notably only in the end of the expansion stroke. To improve the performance of the diesel engine, a two-stage fuel injection was recommended.

Optimization of process parameters for a quasi-continuous tablet coating system using design of experiments.

PubMed

Cahyadi, Christine; Heng, Paul Wan Sia; Chan, Lai Wah

2011-03-01

The aim of this study was to identify and optimize the critical process parameters of the newly developed Supercell quasi-continuous coater for optimal tablet coat quality. Design of experiments, aided by multivariate analysis techniques, was used to quantify the effects of various coating process conditions and their interactions on the quality of film-coated tablets. The process parameters varied included batch size, inlet temperature, atomizing pressure, plenum pressure, spray rate and coating level. An initial screening stage was carried out using a 2(6-1(IV)) fractional factorial design. Following these preliminary experiments, optimization study was carried out using the Box-Behnken design. Main response variables measured included drug-loading efficiency, coat thickness variation, and the extent of tablet damage. Apparent optimum conditions were determined by using response surface plots. The process parameters exerted various effects on the different response variables. Hence, trade-offs between individual optima were necessary to obtain the best compromised set of conditions. The adequacy of the optimized process conditions in meeting the combined goals for all responses was indicated by the composite desirability value. By using response surface methodology and optimization, coating conditions which produced coated tablets of high drug-loading efficiency, low incidences of tablet damage and low coat thickness variation were defined. Optimal conditions were found to vary over a large spectrum when different responses were considered. Changes in processing parameters across the design space did not result in drastic changes to coat quality, thereby demonstrating robustness in the Supercell coating process. © 2010 American Association of Pharmaceutical Scientists

Assessing the Impact of Model Parameter Uncertainty in Simulating Grass Biomass Using a Hybrid Carbon Allocation Strategy

NASA Astrophysics Data System (ADS)

Reyes, J. J.; Adam, J. C.; Tague, C.

2016-12-01

Grasslands play an important role in agricultural production as forage for livestock; they also provide a diverse set of ecosystem services including soil carbon (C) storage. The partitioning of C between above and belowground plant compartments (i.e. allocation) is influenced by both plant characteristics and environmental conditions. The objectives of this study are to 1) develop and evaluate a hybrid C allocation strategy suitable for grasslands, and 2) apply this strategy to examine the importance of various parameters related to biogeochemical cycling, photosynthesis, allocation, and soil water drainage on above and belowground biomass. We include allocation as an important process in quantifying the model parameter uncertainty, which identifies the most influential parameters and what processes may require further refinement. For this, we use the Regional Hydro-ecologic Simulation System, a mechanistic model that simulates coupled water and biogeochemical processes. A Latin hypercube sampling scheme was used to develop parameter sets for calibration and evaluation of allocation strategies, as well as parameter uncertainty analysis. We developed the hybrid allocation strategy to integrate both growth-based and resource-limited allocation mechanisms. When evaluating the new strategy simultaneously for above and belowground biomass, it produced a larger number of less biased parameter sets: 16% more compared to resource-limited and 9% more compared to growth-based. This also demonstrates its flexible application across diverse plant types and environmental conditions. We found that higher parameter importance corresponded to sub- or supra-optimal resource availability (i.e. water, nutrients) and temperature ranges (i.e. too hot or cold). For example, photosynthesis-related parameters were more important at sites warmer than the theoretical optimal growth temperature. Therefore, larger values of parameter importance indicate greater relative sensitivity in adequately representing the relevant process to capture limiting resources or manage atypical environmental conditions. These results may inform future experimental work by focusing efforts on quantifying specific parameters under various environmental conditions or across diverse plant functional types.

Thermodynamic Behavior Research Analysis of Twin-roll Casting Lead Alloy Strip Process

NASA Astrophysics Data System (ADS)

Jiang, Chengcan; Rui, Yannian

2017-03-01

The thermodynamic behavior of twin-roll casting (TRC) lead alloy strip process directly affects the forming of the lead strip, the quality of the lead strip and the production efficiency. However, there is little research on the thermodynamics of lead alloy strip at home and abroad. The TRC lead process is studied in four parameters: the pouring temperature of molten lead, the depth of molten pool, the roll casting speed, and the rolling thickness of continuous casting. Firstly, the thermodynamic model for TRC lead process is built. Secondly, the thermodynamic behavior of the TRC process is simulated with the use of Fluent. Through the thermodynamics research and analysis, the process parameters of cast rolling lead strip can be obtained: the pouring temperature of molten lead: 360-400 °C, the depth of molten pool: 250-300 mm, the roll casting speed: 2.5-3 m/min, the rolling thickness: 8-9 mm. Based on the above process parameters, the optimal parameters(the pouring temperature of molten lead: 375-390 °C, the depth of molten pool: 285-300 mm, the roll casting speed: 2.75-3 m/min, the rolling thickness: 8.5-9 mm) can be gained with the use of the orthogonal experiment. Finally, the engineering test of TRC lead alloy strip is carried out and the test proves the thermodynamic model is scientific, necessary and correct. In this paper, a detailed study on the thermodynamic behavior of lead alloy strip is carried out and the process parameters of lead strip forming are obtained through the research, which provide an effective theoretical guide for TRC lead alloy strip process.

Investigating Effects of Fused-Deposition Modeling (FDM) Processing Parameters on Flexural Properties of ULTEM 9085 using Designed Experiment.

PubMed

Gebisa, Aboma Wagari; Lemu, Hirpa G

2018-03-27

Fused-deposition modeling (FDM), one of the additive manufacturing (AM) technologies, is an advanced digital manufacturing technique that produces parts by heating, extruding and depositing filaments of thermoplastic polymers. The properties of FDM-produced parts apparently depend on the processing parameters. These processing parameters have conflicting advantages that need to be investigated. This article focuses on an investigation into the effect of these parameters on the flexural properties of FDM-produced parts. The investigation is carried out on high-performance ULTEM 9085 material, as this material is relatively new and has potential application in the aerospace, military and automotive industries. Five parameters: air gap, raster width, raster angle, contour number, and contour width, with a full factorial design of the experiment, are considered for the investigation. From the investigation, it is revealed that raster angle and raster width have the greatest effect on the flexural properties of the material. The optimal levels of the process parameters achieved are: air gap of 0.000 mm, raster width of 0.7814 mm, raster angle of 0°, contour number of 5, and contour width of 0.7814 mm, leading to a flexural strength of 127 MPa, a flexural modulus of 2400 MPa, and 0.081 flexural strain.

A hybrid artificial neural network as a software sensor for optimal control of a wastewater treatment process.

PubMed

Choi, D J; Park, H

2001-11-01

For control and automation of biological treatment processes, lack of reliable on-line sensors to measure water quality parameters is one of the most important problems to overcome. Many parameters cannot be measured directly with on-line sensors. The accuracy of existing hardware sensors is also not sufficient and maintenance problems such as electrode fouling often cause trouble. This paper deals with the development of software sensor techniques that estimate the target water quality parameter from other parameters using the correlation between water quality parameters. We focus our attention on the preprocessing of noisy data and the selection of the best model feasible to the situation. Problems of existing approaches are also discussed. We propose a hybrid neural network as a software sensor inferring wastewater quality parameter. Multivariate regression, artificial neural networks (ANN), and a hybrid technique that combines principal component analysis as a preprocessing stage are applied to data from industrial wastewater processes. The hybrid ANN technique shows an enhancement of prediction capability and reduces the overfitting problem of neural networks. The result shows that the hybrid ANN technique can be used to extract information from noisy data and to describe the nonlinearity of complex wastewater treatment processes.

Investigating Effects of Fused-Deposition Modeling (FDM) Processing Parameters on Flexural Properties of ULTEM 9085 using Designed Experiment

PubMed Central

Gebisa, Aboma Wagari

2018-01-01

Fused-deposition modeling (FDM), one of the additive manufacturing (AM) technologies, is an advanced digital manufacturing technique that produces parts by heating, extruding and depositing filaments of thermoplastic polymers. The properties of FDM-produced parts apparently depend on the processing parameters. These processing parameters have conflicting advantages that need to be investigated. This article focuses on an investigation into the effect of these parameters on the flexural properties of FDM-produced parts. The investigation is carried out on high-performance ULTEM 9085 material, as this material is relatively new and has potential application in the aerospace, military and automotive industries. Five parameters: air gap, raster width, raster angle, contour number, and contour width, with a full factorial design of the experiment, are considered for the investigation. From the investigation, it is revealed that raster angle and raster width have the greatest effect on the flexural properties of the material. The optimal levels of the process parameters achieved are: air gap of 0.000 mm, raster width of 0.7814 mm, raster angle of 0°, contour number of 5, and contour width of 0.7814 mm, leading to a flexural strength of 127 MPa, a flexural modulus of 2400 MPa, and 0.081 flexural strain. PMID:29584674

Effect of processing parameters on the corrosion behaviour of friction stir processed AA 2219 aluminum alloy

NASA Astrophysics Data System (ADS)

Surekha, K.; Murty, B. S.; Prasad Rao, K.

2009-04-01

The effect of processing parameters (rotation speed and traverse speed) on the corrosion behaviour of friction stir processed high strength precipitation hardenable AA 2219-T87 alloy was investigated. The results indicate that the rotation speed has a major influence in determining the rate of corrosion, which is attributed to the breaking down and dissolution of the intermetallic particles. Corrosion resistance of friction stir processed alloy was studied by potentiodynamic polarization, electrochemical impedance spectroscopy, salt spray and immersion tests.

CAD/CAM interface design of excimer laser micro-processing system

NASA Astrophysics Data System (ADS)

Jing, Liang; Chen, Tao; Zuo, Tiechuan

2005-12-01

Recently CAD/CAM technology has been gradually used in the field of laser processing. The excimer laser micro-processing system just identified G instruction before CAD/CAM interface was designed. However the course of designing a part with G instruction for users is too hard. The efficiency is low and probability of making errors is high. By secondary development technology of AutoCAD with Visual Basic, an application was developed to pick-up each entity's information in graph and convert them to each entity's processing parameters. Also an additional function was added into former controlling software to identify these processing parameters of each entity and realize continue processing of graphic. Based on the above CAD/CAM interface, Users can design a part in AutoCAD instead of using G instruction. The period of designing a part is sharply shortened. This new way of design greatly guarantees the processing parameters of the part is right and exclusive. The processing of complex novel bio-chip has been realized by this new function.

A general model for attitude determination error analysis

NASA Technical Reports Server (NTRS)

Markley, F. Landis; Seidewitz, ED; Nicholson, Mark

1988-01-01

An overview is given of a comprehensive approach to filter and dynamics modeling for attitude determination error analysis. The models presented include both batch least-squares and sequential attitude estimation processes for both spin-stabilized and three-axis stabilized spacecraft. The discussion includes a brief description of a dynamics model of strapdown gyros, but it does not cover other sensor models. Model parameters can be chosen to be solve-for parameters, which are assumed to be estimated as part of the determination process, or consider parameters, which are assumed to have errors but not to be estimated. The only restriction on this choice is that the time evolution of the consider parameters must not depend on any of the solve-for parameters. The result of an error analysis is an indication of the contributions of the various error sources to the uncertainties in the determination of the spacecraft solve-for parameters. The model presented gives the uncertainty due to errors in the a priori estimates of the solve-for parameters, the uncertainty due to measurement noise, the uncertainty due to dynamic noise (also known as process noise or measurement noise), the uncertainty due to the consider parameters, and the overall uncertainty due to all these sources of error.

Overview of Icing Physics Relevant to Scaling

NASA Technical Reports Server (NTRS)

Anderson, David N.; Tsao, Jen-Ching

2005-01-01

An understanding of icing physics is required for the development of both scaling methods and ice-accretion prediction codes. This paper gives an overview of our present understanding of the important physical processes and the associated similarity parameters that determine the shape of Appendix C ice accretions. For many years it has been recognized that ice accretion processes depend on flow effects over the model, on droplet trajectories, on the rate of water collection and time of exposure, and, for glaze ice, on a heat balance. For scaling applications, equations describing these events have been based on analyses at the stagnation line of the model and have resulted in the identification of several non-dimensional similarity parameters. The parameters include the modified inertia parameter of the water drop, the accumulation parameter and the freezing fraction. Other parameters dealing with the leading edge heat balance have also been used for convenience. By equating scale expressions for these parameters to the values to be simulated a set of equations is produced which can be solved for the scale test conditions. Studies in the past few years have shown that at least one parameter in addition to those mentioned above is needed to describe surface-water effects, and some of the traditional parameters may not be as significant as once thought. Insight into the importance of each parameter, and the physical processes it represents, can be made by viewing whether ice shapes change, and the extent of the change, when each parameter is varied. Experimental evidence is presented to establish the importance of each of the traditionally used parameters and to identify the possible form of a new similarity parameter to be used for scaling.

Fermentation process using specific oxygen uptake rates as a process control

DOEpatents

Van Hoek, Pim; Aristidou, Aristos; Rush, Brian J.

2016-08-30

Specific oxygen uptake (OUR) is used as a process control parameter in fermentation processes. OUR is determined during at least the production phase of a fermentation process, and process parameters are adjusted to maintain the OUR within desired ranges. The invention is particularly applicable when the fermentation is conducted using a microorganism having a natural PDC pathway that has been disrupted so that it no longer functions. Microorganisms of this sort often produce poorly under strictly anaerobic conditions. Microaeration controlled by monitoring OUR allows the performance of the microorganism to be optimized.

Fermentation process using specific oxygen uptake rates as a process control

DOEpatents

Van Hoek, Pim [Minnetonka, MN; Aristidou, Aristos [Maple Grove, MN; Rush, Brian [Minneapolis, MN

2011-05-10

Specific oxygen uptake (OUR) is used as a process control parameter in fermentation processes. OUR is determined during at least the production phase of a fermentation process, and process parameters are adjusted to maintain the OUR within desired ranges. The invention is particularly applicable when the fermentation is conducted using a microorganism having a natural PDC pathway that has been disrupted so that it no longer functions. Microorganisms of this sort often produce poorly under strictly anaerobic conditions. Microaeration controlled by monitoring OUR allows the performance of the microorganism to be optimized.

Fermentation process using specific oxygen uptake rates as a process control

DOEpatents

Hoek, Van; Pim, Aristidou [Minnetonka, MN; Aristos, Rush [Maple Grove, MN; Brian, [Minneapolis, MN

2007-06-19

Specific oxygen uptake (OUR) is used as a process control parameter in fermentation processes. OUR is determined during at least the production phase of a fermentation process, and process parameters are adjusted to maintain the OUR within desired ranges. The invention is particularly applicable when the fermentation is conducted using a microorganism having a natural PDC pathway that has been disrupted so that it no longer functions. Microorganisms of this sort often produce poorly under strictly anaerobic conditions. Microaeration controlled by monitoring OUR allows the performance of the microorganism to be optimized.

Fermentation process using specific oxygen uptake rates as a process control

DOEpatents

Van Hoek, Pim; Aristidou, Aristos; Rush, Brian

2014-09-09

Specific oxygen uptake (OUR) is used as a process control parameter in fermentation processes. OUR is determined during at least the production phase of a fermentation process, and process parameters are adjusted to maintain the OUR within desired ranges. The invention is particularly applicable when the fermentation is conducted using a microorganism having a natural PDC pathway that has been disrupted so that it no longer functions. Microorganisms of this sort often produce poorly under strictly anaerobic conditions. Microaeration controlled by monitoring OUR allows the performance of the microorganism to be optimized.

Invariant polarimetric contrast parameters of coherent light.

PubMed

Réfrégier, Philippe; Goudail, François

2002-06-01

Many applications use an active coherent illumination and analyze the variation of the polarization state of optical signals. However, as a result of the use of coherent light, these signals are generally strongly perturbed with speckle noise. This is the case, for example, for active polarimetric imaging systems that are useful for enhancing contrast between different elements in a scene. We propose a rigorous definition of the minimal set of parameters that characterize the difference between two coherent and partially polarized states. Indeed, two states of partially polarized light are a priori defined by eight parameters, for example, their two Stokes vectors. We demonstrate that the processing performance for such signal processing tasks as detection, localization, or segmentation of spatial or temporal polarization variations is uniquely determined by two scalar functions of these eight parameters. These two scalar functions are the invariant parameters that define the polarimetric contrast between two polarized states of coherent light. Different polarization configurations with the same invariant contrast parameters will necessarily lead to the same performance for a given task, which is a desirable quality for a rigorous contrast measure. The definition of these polarimetric contrast parameters simplifies the analysis and the specification of processing techniques for coherent polarimetric signals.

Investigation of selected structural parameters in Fe 95Si 5 amorphous alloy during crystallization process

NASA Astrophysics Data System (ADS)

Fronczyk, Adam

2007-04-01

In this study, we report on a crystallization behavior of the Fe 95Si 5 metallic glasses using a differential scanning cabrimetry (DSC), and X-ray diffraction. The paper presents the results of experimental investigation of Fe 95Si 5 amorphous alloy, subjected to the crystallizing process by the isothermal annealing. The objective of the experiment was to determine changes in the structural parameters during crystallization process of the examined alloy. Crystalline diameter and the lattice constant of the crystallizing phase were used as parameters to evaluate structural changes in material.

Determination of material distribution in heading process of small bimetallic bar

NASA Astrophysics Data System (ADS)

Presz, Wojciech; Cacko, Robert

2018-05-01

The electrical connectors mostly have silver contacts joined by riveting. In order to reduce costs, the core of the contact rivet can be replaced with cheaper material, e.g. copper. There is a wide range of commercially available bimetallic (silver-copper) rivets on the market for the production of contacts. Following that, new conditions in the riveting process are created because the bi-metal object is riveted. In the analyzed example, it is a small size object, which can be placed on the border of microforming. Based on the FEM modeling of the load process of bimetallic rivets with different material distributions, the desired distribution was chosen and the choice was justified. Possible material distributions were parameterized with two parameters referring to desirable distribution characteristics. The parameter: Coefficient of Mutual Interactions of Plastic Deformations and the method of its determination have been proposed. The parameter is determined based of two-parameter stress-strain curves and is a function of these parameters and the range of equivalent strains occurring in the analyzed process. The proposed method was used for the upsetting process of the bimetallic head of the electrical contact. A nomogram was established to predict the distribution of materials in the head of the rivet and the appropriate selection of a pair of materials to achieve the desired distribution.

Sensitivity of Austempering Heat Treatment of Ductile Irons to Changes in Process Parameters

NASA Astrophysics Data System (ADS)

Boccardo, A. D.; Dardati, P. M.; Godoy, L. A.; Celentano, D. J.

2018-06-01

Austempered ductile iron (ADI) is frequently obtained by means of a three-step austempering heat treatment. The parameters of this process play a crucial role on the microstructure of the final product. This paper considers the influence of some process parameters ( i.e., the initial microstructure of ductile iron and the thermal cycle) on key features of the heat treatment (such as minimum required time for austenitization and austempering and microstructure of the final product). A computational simulation of the austempering heat treatment is reported in this work, which accounts for a coupled thermo-metallurgical behavior in terms of the evolution of temperature at the scale of the part being investigated (the macroscale) and the evolution of phases at the scale of microconstituents (the microscale). The paper focuses on the sensitivity of the process by looking at a sensitivity index and scatter plots. The sensitivity indices are determined by using a technique based on the variance of the output. The results of this study indicate that both the initial microstructure and the thermal cycle parameters play a key role in the production of ADI. This work also provides a guideline to help selecting values of the appropriate process parameters to obtain parts with a required microstructural characteristic.

Optimization of the monitoring of landfill gas and leachate in closed methanogenic landfills.

PubMed

Jovanov, Dejan; Vujić, Bogdana; Vujić, Goran

2018-06-15

Monitoring of the gas and leachate parameters in a closed landfill is a long-term activity defined by national legislative worldwide. Serbian Waste Disposal Law defines the monitoring of a landfill at least 30 years after its closing, but the definition of the monitoring extent (number and type of parameters) is incomplete. In order to define and clear all the uncertainties, this research focuses on process of monitoring optimization, using the closed landfill in Zrenjanin, Serbia, as the experimental model. The aim of optimization was to find representative parameters which would define the physical, chemical and biological processes in the closed methanogenic landfill and to make this process less expensive. Research included development of the five monitoring models with different number of gas and leachate parameters and each model has been processed in open source software GeoGebra which is often used for solving optimization problems. The results of optimization process identified the most favorable monitoring model which fulfills all the defined criteria not only from the point of view of mathematical analyses, but also from the point of view of environment protection. The final outcome of this research - the minimal required parameters which should be included in the landfill monitoring are precisely defined. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of process parameters on solid self-microemulsifying particles in a laboratory scale fluid bed.

PubMed

Mukherjee, Tusharmouli; Plakogiannis, Fotios M

2012-01-01

The purpose of this study was to select the critical process parameters of the fluid bed processes impacting the quality attribute of a solid self-microemulsifying (SME) system of albendazole (ABZ). A fractional factorial design (2(4-1)) with four parameters (spray rate, inlet air temperature, inlet air flow, and atomization air pressure) was created by MINITAB software. Batches were manufactured in a laboratory top-spray fluid bed at 625-g scale. Loss on drying (LOD) samples were taken throughout each batch to build the entire moisture profiles. All dried granulation were sieved using mesh 20 and analyzed for particle size distribution (PSD), morphology, density, and flow. It was found that as spray rate increased, sauter-mean diameter (D(s)) also increased. The effect of inlet air temperature on the peak moisture which is directly related to the mean particle size was found to be significant. There were two-way interactions between studied process parameters. The main effects of inlet air flow rate and atomization air pressure could not be found as the data were inconclusive. The partial least square (PLS) regression model was found significant (P < 0.01) and predictive for optimization. This study established a design space for the parameters for solid SME manufacturing process.

Application of high-throughput mini-bioreactor system for systematic scale-down modeling, process characterization, and control strategy development.

PubMed

Janakiraman, Vijay; Kwiatkowski, Chris; Kshirsagar, Rashmi; Ryll, Thomas; Huang, Yao-Ming

2015-01-01

High-throughput systems and processes have typically been targeted for process development and optimization in the bioprocessing industry. For process characterization, bench scale bioreactors have been the system of choice. Due to the need for performing different process conditions for multiple process parameters, the process characterization studies typically span several months and are considered time and resource intensive. In this study, we have shown the application of a high-throughput mini-bioreactor system viz. the Advanced Microscale Bioreactor (ambr15(TM) ), to perform process characterization in less than a month and develop an input control strategy. As a pre-requisite to process characterization, a scale-down model was first developed in the ambr system (15 mL) using statistical multivariate analysis techniques that showed comparability with both manufacturing scale (15,000 L) and bench scale (5 L). Volumetric sparge rates were matched between ambr and manufacturing scale, and the ambr process matched the pCO2 profiles as well as several other process and product quality parameters. The scale-down model was used to perform the process characterization DoE study and product quality results were generated. Upon comparison with DoE data from the bench scale bioreactors, similar effects of process parameters on process yield and product quality were identified between the two systems. We used the ambr data for setting action limits for the critical controlled parameters (CCPs), which were comparable to those from bench scale bioreactor data. In other words, the current work shows that the ambr15(TM) system is capable of replacing the bench scale bioreactor system for routine process development and process characterization. © 2015 American Institute of Chemical Engineers.

Downstream processing from hot-melt extrusion towards tablets: A quality by design approach.

PubMed

Grymonpré, W; Bostijn, N; Herck, S Van; Verstraete, G; Vanhoorne, V; Nuhn, L; Rombouts, P; Beer, T De; Remon, J P; Vervaet, C

2017-10-05

Since the concept of continuous processing is gaining momentum in pharmaceutical manufacturing, a thorough understanding on how process and formulation parameters can impact the critical quality attributes (CQA) of the end product is more than ever required. This study was designed to screen the influence of process parameters and drug load during HME on both extrudate properties and tableting behaviour of an amorphous solid dispersion formulation using a quality-by-design (QbD) approach. A full factorial experimental design with 19 experiments was used to evaluate the effect of several process variables (barrel temperature: 160-200°C, screw speed: 50-200rpm, throughput: 0.2-0.5kg/h) and drug load (0-20%) as formulation parameter on the hot-melt extrusion (HME) process, extrudate and tablet quality of Soluplus ® -Celecoxib amorphous solid dispersions. A prominent impact of the formulation parameter on the CQA of the extrudates (i.e. solid state properties, moisture content, particle size distribution) and tablets (i.e. tabletability, compactibility, fragmentary behaviour, elastic recovery) was discovered. The resistance of the polymer matrix to thermo-mechanical stress during HME was confirmed throughout the experimental design space. In addition, the suitability of Raman spectroscopy as verification method for the active pharmaceutical ingredient (API) concentration in solid dispersions was evaluated. Incorporation of the Raman spectroscopy data in a PLS model enabled API quantification in the extrudate powders with none of the DOE-experiments resulting in extrudates with a CEL content deviating>3% of the label claim. This research paper emphasized that HME is a robust process throughout the experimental design space for obtaining amorphous glassy solutions and for tabletting of such formulations since only minimal impact of the process parameters was detected on the extrudate and tablet properties. However, the quality of extrudates and tablets can be optimized by adjusting specific formulations parameters (e.g. drug load). Copyright © 2017 Elsevier B.V. All rights reserved.

Thermal Management in Friction-Stir Welding of Precipitation-Hardening Aluminum Alloys

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

Upadhyay, Piyush; Reynolds, Anthony

2015-05-25

Process design and implementation in FSW is mostly dependent on empirical information gathered through experience. Basic science of friction stir welding and processing can only be complete when fundamental interrelationships between process control parameters and response variables and resulting weld microstructure and properties are established to a reasonable extent. It is known that primary process control parameters like tool rotation and translation rate and forge axis force have complicated and interactive relationships to the process response variables such as peak temperature, time at temperature etc. Of primary influence to the other process response parameters are temperature and its gradient atmore » the deformation and heat affected zones. Through review of pertinent works in the literature and some experimental results from boundary condition work performed in precipitation hardening aluminum alloys this paper will partially elucidate the nature and effects of temperature transients caused by variation of thermal boundaries in Friction Stir Welding.« less

Thermal Management in Friction-Stir Welding of Precipitation-Hardened Aluminum Alloys

NASA Astrophysics Data System (ADS)

Upadhyay, Piyush; Reynolds, Anthony P.

2015-05-01

Process design and implementation in friction-stir welding (FSW) is mostly dependent on empirical information. Basic science of FSW and processing can only be complete when fundamental interrelationships between the process control parameters and response variables and the resulting weld microstructure and properties are established to a reasonable extent. It is known that primary process control parameters such as tool rotation, translation rates, and forge axis force have complicated and interactive relationships to process-response variables such as peak temperature and time at temperature. Of primary influence on the other process-response parameters are temperature and its gradient in the deformation and heat-affected zones. Through a review of pertinent works in the literature and results from boundary condition experiments performed in precipitation-hardening aluminum alloys, this article partially elucidates the nature and effects of temperature transients caused by variation of thermal boundaries in FSW.

Investigation about the Chrome Steel Wire Arc Spray Process and the Resulting Coating Properties

NASA Astrophysics Data System (ADS)

Wilden, J.; Bergmann, J. P.; Jahn, S.; Knapp, S.; van Rodijnen, F.; Fischer, G.

2007-12-01

Nowadays, wire-arc spraying of chromium steel has gained an important market share for corrosion and wear protection applications. However, detailed studies are the basis for further process optimization. In order to optimize the process parameters and to evaluate the effects of the spray parameters DoE-based experiments had been carried out with high-speed camera shoots. In this article, the effects of spray current, voltage, and atomizing gas pressure on the particle jet properties, mean particle velocity and mean particle temperature and plume width on X46Cr13 wire are presented using an online process monitoring device. Moreover, the properties of the coatings concerning the morphology, composition and phase formation were subject of the investigations using SEM, EDX, and XRD-analysis. These deep investigations allow a defined verification of the influence of process parameters on spray plume and coating properties and are the basis for further process optimization.

The finite element simulation analysis research of 38CrSi cylindrical power spinning

NASA Astrophysics Data System (ADS)

Liang, Wei; Lv, Qiongying; Zhao, Yujuan; Lv, Yunxia

2018-01-01

In order to grope for the influence of the main cylindrical spinning process parameters on the spinning process, this paper combines with real tube power spinning process and uses ABAQUS finite element analysis software to simulate the tube power spinning process of 38CrSi steel materials, through the analysis of the stress, strain of the part forming process, analyzes the influence of the thickness reduction and the feed rate to the forming process, and analyzes the variation of the spinning force, finally determines the reasonable main spinning process parameters combination.

Research on the processing technology of elongated holes based on rotary ultrasonic drilling

NASA Astrophysics Data System (ADS)

Tong, Yi; Chen, Jianhua; Sun, Lipeng; Yu, Xin; Wang, Xin

2014-08-01

The optical glass is hard, brittle and difficult to process. Based on the method of rotating ultrasonic drilling, the study of single factor on drilling elongated holes was made in optical glass. The processing equipment was DAMA ultrasonic machine, and the machining tools were electroplated with diamond. Through the detection and analysis on the processing quality and surface roughness, the process parameters (the spindle speed, amplitude, feed rate) of rotary ultrasonic drilling were researched, and the influence of processing parameters on surface roughness was obtained, which will provide reference and basis for the actual processing.

Optimization of process parameters for RF sputter deposition of tin-nitride thin-films

NASA Astrophysics Data System (ADS)

Jangid, Teena; Rao, G. Mohan

2018-05-01

Radio frequency Magnetron sputtering technique was employed to deposit Tin-nitride thin films on Si and glass substrate at different process parameters. Influence of varying parameters like substrate temperature, target-substrate distance and RF power is studied in detail. X-ray diffraction method is used as a key technique for analyzing the changes in the stoichiometric and structural properties of the deposited films. Depending on the combination of deposition parameters, crystalline as well as amorphous films were obtained. Pure tin-nitride thin films were deposited at 15W RF power and 600°C substrate temperature with target-substrate distance fixed at 10cm. Bandgap value of 1.6 eV calculated for the film deposited at optimum process conditions matches well with reported values.

A fortran program for Monte Carlo simulation of oil-field discovery sequences

USGS Publications Warehouse

Bohling, Geoffrey C.; Davis, J.C.

1993-01-01

We have developed a program for performing Monte Carlo simulation of oil-field discovery histories. A synthetic parent population of fields is generated as a finite sample from a distribution of specified form. The discovery sequence then is simulated by sampling without replacement from this parent population in accordance with a probabilistic discovery process model. The program computes a chi-squared deviation between synthetic and actual discovery sequences as a function of the parameters of the discovery process model, the number of fields in the parent population, and the distributional parameters of the parent population. The program employs the three-parameter log gamma model for the distribution of field sizes and employs a two-parameter discovery process model, allowing the simulation of a wide range of scenarios. ?? 1993.

Optical components damage parameters database system

NASA Astrophysics Data System (ADS)

Tao, Yizheng; Li, Xinglan; Jin, Yuquan; Xie, Dongmei; Tang, Dingyong

2012-10-01

Optical component is the key to large-scale laser device developed by one of its load capacity is directly related to the device output capacity indicators, load capacity depends on many factors. Through the optical components will damage parameters database load capacity factors of various digital, information technology, for the load capacity of optical components to provide a scientific basis for data support; use of business processes and model-driven approach, the establishment of component damage parameter information model and database systems, system application results that meet the injury test optical components business processes and data management requirements of damage parameters, component parameters of flexible, configurable system is simple, easy to use, improve the efficiency of the optical component damage test.

Modelling of intermittent microwave convective drying: parameter sensitivity

NASA Astrophysics Data System (ADS)

Zhang, Zhijun; Qin, Wenchao; Shi, Bin; Gao, Jingxin; Zhang, Shiwei

2017-06-01

The reliability of the predictions of a mathematical model is a prerequisite to its utilization. A multiphase porous media model of intermittent microwave convective drying is developed based on the literature. The model considers the liquid water, gas and solid matrix inside of food. The model is simulated by COMSOL software. Its sensitivity parameter is analysed by changing the parameter values by ±20%, with the exception of several parameters. The sensitivity analysis of the process of the microwave power level shows that each parameter: ambient temperature, effective gas diffusivity, and evaporation rate constant, has significant effects on the process. However, the surface mass, heat transfer coefficient, relative and intrinsic permeability of the gas, and capillary diffusivity of water do not have a considerable effect. The evaporation rate constant has minimal parameter sensitivity with a ±20% value change, until it is changed 10-fold. In all results, the temperature and vapour pressure curves show the same trends as the moisture content curve. However, the water saturation at the medium surface and in the centre show different results. Vapour transfer is the major mass transfer phenomenon that affects the drying process.

Experimental design approach to the process parameter optimization for laser welding of martensitic stainless steels in a constrained overlap configuration

NASA Astrophysics Data System (ADS)

Khan, M. M. A.; Romoli, L.; Fiaschi, M.; Dini, G.; Sarri, F.

2011-02-01

This paper presents an experimental design approach to process parameter optimization for the laser welding of martensitic AISI 416 and AISI 440FSe stainless steels in a constrained overlap configuration in which outer shell was 0.55 mm thick. To determine the optimal laser-welding parameters, a set of mathematical models were developed relating welding parameters to each of the weld characteristics. These were validated both statistically and experimentally. The quality criteria set for the weld to determine optimal parameters were the minimization of weld width and the maximization of weld penetration depth, resistance length and shearing force. Laser power and welding speed in the range 855-930 W and 4.50-4.65 m/min, respectively, with a fiber diameter of 300 μm were identified as the optimal set of process parameters. However, the laser power and welding speed can be reduced to 800-840 W and increased to 4.75-5.37 m/min, respectively, to obtain stronger and better welds.

Modeling of process of forming quality parameters for surfaces of parts by diamond burnishing taking into account technological heredity

NASA Astrophysics Data System (ADS)

Nagorkin, M. N.; Fyodorov, V. P.; Kovalyova, E. V.

2018-03-01

The paper presents a methodology for quantitative assessment of the influence of technological heredity on the formation of quality parameters for surfaces of machine parts. An example of an estimation of influence factors of technological subsystems of processing by end milling processing by composite 10 and the subsequent diamond burnishing is presented.

Wind speed vector restoration algorithm

NASA Astrophysics Data System (ADS)

Baranov, Nikolay; Petrov, Gleb; Shiriaev, Ilia

2018-04-01

Impulse wind lidar (IWL) signal processing software developed by JSC «BANS» recovers full wind speed vector by radial projections and provides wind parameters information up to 2 km distance. Increasing accuracy and speed of wind parameters calculation signal processing technics have been studied in this research. Measurements results of IWL and continuous scanning lidar were compared. Also, IWL data processing modeling results have been analyzed.

300 Area treated effluent disposal facility sampling schedule

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

Loll, C.M.

1994-10-11

This document is the interface between the 300 Area Liquid Effluent Process Engineering (LEPE) group and the Waste Sampling and Characterization Facility (WSCF), concerning process control samples. It contains a schedule for process control samples at the 300 Area TEDF which describes the parameters to be measured, the frequency of sampling and analysis, the sampling point, and the purpose for each parameter.

Evaluation of laser cutting process with auxiliary gas pressure by soft computing approach

NASA Astrophysics Data System (ADS)

Lazov, Lyubomir; Nikolić, Vlastimir; Jovic, Srdjan; Milovančević, Miloš; Deneva, Heristina; Teirumenieka, Erika; Arsic, Nebojsa

2018-06-01

Evaluation of the optimal laser cutting parameters is very important for the high cut quality. This is highly nonlinear process with different parameters which is the main challenge in the optimization process. Data mining methodology is one of most versatile method which can be used laser cutting process optimization. Support vector regression (SVR) procedure is implemented since it is a versatile and robust technique for very nonlinear data regression. The goal in this study was to determine the optimal laser cutting parameters to ensure robust condition for minimization of average surface roughness. Three cutting parameters, the cutting speed, the laser power, and the assist gas pressure, were used in the investigation. As a laser type TruLaser 1030 technological system was used. Nitrogen as an assisted gas was used in the laser cutting process. As the data mining method, support vector regression procedure was used. Data mining prediction accuracy was very high according the coefficient (R2) of determination and root mean square error (RMSE): R2 = 0.9975 and RMSE = 0.0337. Therefore the data mining approach could be used effectively for determination of the optimal conditions of the laser cutting process.

Catchment process affecting drinking water quality, including the significance of rainfall events, using factor analysis and event mean concentrations.

PubMed

Cinque, Kathy; Jayasuriya, Niranjali

2010-12-01

To ensure the protection of drinking water an understanding of the catchment processes which can affect water quality is important as it enables targeted catchment management actions to be implemented. In this study factor analysis (FA) and comparing event mean concentrations (EMCs) with baseline values were techniques used to asses the relationships between water quality parameters and linking those parameters to processes within an agricultural drinking water catchment. FA found that 55% of the variance in the water quality data could be explained by the first factor, which was dominated by parameters usually associated with erosion. Inclusion of pathogenic indicators in an additional FA showed that Enterococcus and Clostridium perfringens (C. perfringens) were also related to the erosion factor. Analysis of the EMCs found that most parameters were significantly higher during periods of rainfall runoff. This study shows that the most dominant processes in an agricultural catchment are surface runoff and erosion. It also shows that it is these processes which mobilise pathogenic indicators and are therefore most likely to influence the transport of pathogens. Catchment management efforts need to focus on reducing the effect of these processes on water quality.

Optimizing pulsed Nd:YAG laser beam welding process parameters to attain maximum ultimate tensile strength for thin AISI316L sheet using response surface methodology and simulated annealing algorithm

NASA Astrophysics Data System (ADS)

Torabi, Amir; Kolahan, Farhad

2018-07-01

Pulsed laser welding is a powerful technique especially suitable for joining thin sheet metals. In this study, based on experimental data, pulsed laser welding of thin AISI316L austenitic stainless steel sheet has been modeled and optimized. The experimental data required for modeling are gathered as per Central Composite Design matrix in Response Surface Methodology (RSM) with full replication of 31 runs. Ultimate Tensile Strength (UTS) is considered as the main quality measure in laser welding. Furthermore, the important process parameters including peak power, pulse duration, pulse frequency and welding speed are selected as input process parameters. The relation between input parameters and the output response is established via full quadratic response surface regression with confidence level of 95%. The adequacy of the regression model was verified using Analysis of Variance technique results. The main effects of each factor and the interactions effects with other factors were analyzed graphically in contour and surface plot. Next, to maximum joint UTS, the best combinations of parameters levels were specified using RSM. Moreover, the mathematical model is implanted into a Simulated Annealing (SA) optimization algorithm to determine the optimal values of process parameters. The results obtained by both SA and RSM optimization techniques are in good agreement. The optimal parameters settings for peak power of 1800 W, pulse duration of 4.5 ms, frequency of 4.2 Hz and welding speed of 0.5 mm/s would result in a welded joint with 96% of the base metal UTS. Computational results clearly demonstrate that the proposed modeling and optimization procedures perform quite well for pulsed laser welding process.

Ring rolling process simulation for geometry optimization

NASA Astrophysics Data System (ADS)

Franchi, Rodolfo; Del Prete, Antonio; Donatiello, Iolanda; Calabrese, Maurizio

2017-10-01

Ring Rolling is a complex hot forming process where different rolls are involved in the production of seamless rings. Since each roll must be independently controlled, different speed laws must be set; usually, in the industrial environment, a milling curve is introduced to monitor the shape of the workpiece during the deformation in order to ensure the correct ring production. In the present paper a ring rolling process has been studied and optimized in order to obtain anular components to be used in aerospace applications. In particular, the influence of process input parameters (feed rate of the mandrel and angular speed of main roll) on geometrical features of the final ring has been evaluated. For this purpose, a three-dimensional finite element model for HRR (Hot Ring Rolling) has been implemented in SFTC DEFORM V11. The FEM model has been used to formulate a proper optimization problem. The optimization procedure has been implemented in the commercial software DS ISight in order to find the combination of process parameters which allows to minimize the percentage error of each obtained dimension with respect to its nominal value. The software allows to find the relationship between input and output parameters applying Response Surface Methodology (RSM), by using the exact values of output parameters in the control points of the design space explored through FEM simulation. Once this relationship is known, the values of the output parameters can be calculated for each combination of the input parameters. After the calculation of the response surfaces for the selected output parameters, an optimization procedure based on Genetic Algorithms has been applied. At the end, the error between each obtained dimension and its nominal value has been minimized. The constraints imposed were the maximum values of standard deviations of the dimensions obtained for the final ring.