Association between periodontal flap surgery for periodontitis and vasculogenic erectile dysfunction in Koreans.

PubMed

Lee, Jae-Hong; Choi, Jung-Kyu; Kim, Sang-Hyun; Cho, Kyung-Hyun; Kim, Young-Taek; Choi, Seong-Ho; Jung, Ui-Won

2017-04-01

The National Health Insurance Service-National Sample Cohort and medical checkup data from 2002 to 2013 were used to evaluate the association between periodontal surgery for the treatment of periodontitis (PSTP) and vasculogenic erectile dysfunction (VED). Bivariate and multivariate logistic regression analyses were applied to a longitudinal retrospective database to assess the association between PSTP and VED while adjusting for the potential confounding effects of sociodemographic factors (age, household income, insurance status, health status, residence area, and smoking status) and comorbidities (diabetes mellitus, angina pectoris, cerebral infarction, and myocardial infarction). Among the 7,148 PSTP within the 268,296 recruited subjects, the overall prevalence of VED in PSTP was 1.43% (n=102). The bivariate analysis showed that VED was significantly related to PSTP (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.38-2.06; P <0.001), and this was confirmed in the multivariate analysis after adjusting for sociodemographic factors and comorbidities (OR, 1.29; 95% CI, 1.06-1.58; P =0.002). Subjects with a history of periodontal flap surgery had a significantly higher risk of VED, after adjusting for potential confounding factors. Further studies are required to identify the key mechanisms underlying the association between severe periodontal disease and VED.

Association between periodontal flap surgery for periodontitis and vasculogenic erectile dysfunction in Koreans

PubMed Central

2017-01-01

Purpose The National Health Insurance Service-National Sample Cohort and medical checkup data from 2002 to 2013 were used to evaluate the association between periodontal surgery for the treatment of periodontitis (PSTP) and vasculogenic erectile dysfunction (VED). Methods Bivariate and multivariate logistic regression analyses were applied to a longitudinal retrospective database to assess the association between PSTP and VED while adjusting for the potential confounding effects of sociodemographic factors (age, household income, insurance status, health status, residence area, and smoking status) and comorbidities (diabetes mellitus, angina pectoris, cerebral infarction, and myocardial infarction). Results Among the 7,148 PSTP within the 268,296 recruited subjects, the overall prevalence of VED in PSTP was 1.43% (n=102). The bivariate analysis showed that VED was significantly related to PSTP (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.38–2.06; P<0.001), and this was confirmed in the multivariate analysis after adjusting for sociodemographic factors and comorbidities (OR, 1.29; 95% CI, 1.06–1.58; P=0.002). Conclusions Subjects with a history of periodontal flap surgery had a significantly higher risk of VED, after adjusting for potential confounding factors. Further studies are required to identify the key mechanisms underlying the association between severe periodontal disease and VED. PMID:28462008

Yeast prions: structure, biology, and prion-handling systems.

PubMed

Wickner, Reed B; Shewmaker, Frank P; Bateman, David A; Edskes, Herman K; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E

2015-03-01

A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis.

PubMed

Winter, Martin; Tholey, Andreas; Kristen, Arnt; Röcken, Christoph

2017-11-01

Amyloidosis is a group of diseases caused by extracellular accumulation of fibrillar polypeptide aggregates. So far, diagnosis is performed by Congo red staining of tissue sections in combination with polarization microscopy. Subsequent identification of the causative protein by immunohistochemistry harbors some difficulties regarding sensitivity and specificity. Mass spectrometry based approaches have been demonstrated to constitute a reliable method to supplement typing of amyloidosis, but still depend on Congo red staining. In the present study, we used matrix-assisted laser desorption/ionization mass spectrometry imaging coupled with ion mobility separation (MALDI-IMS MSI) to investigate amyloid deposits in formalin-fixed and paraffin-embedded tissue samples. Utilizing a novel peptide filter method, we found a universal peptide signature for amyloidoses. Furthermore, differences in the peptide composition of ALλ and ATTR amyloid were revealed and used to build a reliable classification model. Integrating the peptide filter in MALDI-IMS MSI analysis, we developed a bioinformatics workflow facilitating the identification and classification of amyloidosis in a less time and sample-consuming experimental setup. Our findings demonstrate also the feasibility to investigate the amyloid's protein composition, thus paving the way to establish classification models for the diverse types of amyloidoses and to shed further light on the complex process of amyloidogenesis. © 2017 The Authors, Proteomics Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synchrotron x-ray microdiffraction reveals intrinsic structural features of amyloid deposits in situ.

PubMed

Briki, Fatma; Vérine, Jérôme; Doucet, Jean; Bénas, Philippe; Fayard, Barbara; Delpech, Marc; Grateau, Gilles; Riès-Kautt, Madeleine

2011-07-20

Amyloidoses are increasingly recognized as a major public health concern in Western countries. All amyloidoses share common morphological, structural, and tinctorial properties. These consist of staining by specific dyes, a fibrillar aspect in electron microscopy and a typical cross-β folding in x-ray diffraction patterns. Most studies that aim at deciphering the amyloid structure rely on fibers generated in vitro or extracted from tissues using protocols that may modify their intrinsic structure. Therefore, the fine details of the in situ architecture of the deposits remain unknown. Here, we present to our knowledge the first data obtained on ex vivo human renal tissue sections using x-ray microdiffraction. The typical cross-β features from fixed paraffin-embedded samples are similar to those formed in vitro or extracted from tissues. Moreover, the fiber orientation maps obtained across glomerular sections reveal an intrinsic texture that is correlated with the glomerulus morphology. These results are of the highest importance to understanding the formation of amyloid deposits and are thus expected to trigger new incentives for tissue investigation. Moreover, the access to intrinsic structural parameters such as fiber size and orientation using synchrotron x-ray microdiffraction, could provide valuable information concerning in situ mechanisms and deposit formation with potential benefits for diagnostic and therapeutic purposes. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Comparison of the effects of extracorporeal shock wave therapy and a vacuum erectile device on penile erectile dysfunction: a randomized clinical trial.

PubMed

Qi, Tao; Ye, Lei; Wang, Bo; Zhang, Bin; Chen, Jun

2017-11-01

This randomized clinical trial (October 2012-December 2013) compared extracorporeal shock wave therapy (ESWT) and a vacuum erectile device (VED) for management of erectile dysfunction (ED). Consecutive Chinese patients (20-55 years) with ED, abnormal nocturnal penile tumescence and rigidity (NPTR), and international index of erectile function-5 items (IIEF-5) score <22 were randomized to receive ESWT or VED (twice weekly, 4 weeks). Primary outcomes were treatment efficacy and success rate 4 weeks after completion of therapy. Secondary outcomes included changes in IIEF-5 score, sex encounter profile (SEP) score, erection hardness score (EHS) and NPTR assessments 4 weeks post-therapy. All enrolled patients (n = 30 per group) completed the study. At baseline, age, IIEF-5 score, SEP score, EHS, and NPTR assessments were similar between groups. Four weeks post-therapy, IIEF-5 score increased in the ESWT (15.03 ± 3.00 vs. 11.60 ± 2.28) and VED (15.10 ± 3.06 vs. 11.53 ± 2.27) groups, as did SEP score, EHS, and NPTR measures (all P < .05). Efficacy in the ESWT and VED groups was excellent in 10% and 13.3%, respectively, and moderate in 63.3% and 53.3%, respectively. Treatment success rate in the ESWT and VED groups was 73.3% and 67.7%, respectively. VED use and ESWT have comparable efficacies in the treatment of ED in Chinese patients.

Comparison of the effects of extracorporeal shock wave therapy and a vacuum erectile device on penile erectile dysfunction: a randomized clinical trial

PubMed Central

Qi, Tao; Ye, Lei; Wang, Bo; Zhang, Bin; Chen, Jun

2017-01-01

Abstract Background: This randomized clinical trial (October 2012–December 2013) compared extracorporeal shock wave therapy (ESWT) and a vacuum erectile device (VED) for management of erectile dysfunction (ED). Methods: Consecutive Chinese patients (20–55 years) with ED, abnormal nocturnal penile tumescence and rigidity (NPTR), and international index of erectile function-5 items (IIEF-5) score <22 were randomized to receive ESWT or VED (twice weekly, 4 weeks). Primary outcomes were treatment efficacy and success rate 4 weeks after completion of therapy. Secondary outcomes included changes in IIEF-5 score, sex encounter profile (SEP) score, erection hardness score (EHS) and NPTR assessments 4 weeks post-therapy. All enrolled patients (n = 30 per group) completed the study. At baseline, age, IIEF-5 score, SEP score, EHS, and NPTR assessments were similar between groups. Results: Four weeks post-therapy, IIEF-5 score increased in the ESWT (15.03 ± 3.00 vs. 11.60 ± 2.28) and VED (15.10 ± 3.06 vs. 11.53 ± 2.27) groups, as did SEP score, EHS, and NPTR measures (all P < .05). Efficacy in the ESWT and VED groups was excellent in 10% and 13.3%, respectively, and moderate in 63.3% and 53.3%, respectively. Treatment success rate in the ESWT and VED groups was 73.3% and 67.7%, respectively. Conclusion: VED use and ESWT have comparable efficacies in the treatment of ED in Chinese patients. PMID:29095274

Spontaneous Splenic Rupture in Vascular Ehlers-Danlos Syndrome.

PubMed

Batagini, Nayara Cioffi; Gornik, Heather; Kirksey, Lee

2015-01-01

Vascular Ehlers-Danlos Syndrome (VEDS) is a rare autosomal dominant collagen vascular disorder. Different from other Ehler-Danlos Syndrome subtypes, VEDS has poor prognosis due to severe fragility of connective tissues and association with life-threatening vascular and gastrointestinal complications. Spontaneous splenic rupture is a rare but hazardous complication related to this syndrome. To date, only 2 cases have been reported in the literature. Here we present another case of this uncommon complication, occurring in a 54-year-old woman in clinical follow-up for VEDS who presented with sudden onset of abdominal pain and hypotension. © The Author(s) 2015.

Effect of agmatine on experimental vascular endothelial dysfunction.

PubMed

Nader, M A; Gamiel, N M; El-Kashef, H; Zaghloul, M S

2016-05-01

This study was designed to investigate the effect of agmatine sulfate (AG, CAS2482-00-0) in nicotine (NIC)-induced vascular endothelial dysfunction (VED) in rabbits. NIC was administered to produce VED in rabbits with or without AG for 6 weeks. Serum lipid profile, serum thiobarbituric acid reactive substances, reduced glutathione, superoxide dismutase generation, serum nitrite/nitrate, serum vascular cellular adhesion molecule-1 (VCAM-1), and aortic nuclear factor κB (NF-κB) levels were analyzed.Treatment with AG markedly improves lipid profile and prevented NIC-induced VED and oxidative stress. The mechanism of AG in improving NIC-induced VED may be due to the significant reduction in serum VCAM-1 levels and aortic NF-κB. Thus, it may be concluded that AG reduces the oxidative stress, nitric oxide production, VCAM-1 levels, and aortic NF-κB expression, thereby consequently improving the integrity of vascular endothelium. © The Author(s) 2015.

Vascular Ehlers-Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci: A case report.

PubMed

Park, Min A; Shin, So Youn; Kim, Young Jin; Park, Myung Jae; Lee, Seung Hyeun

2017-11-01

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant inherited collagen disorder caused by defects or deficiency of pro-alpha 1 chain of type III procollagen encoded by COL3A1. vEDS is characterized not only by soft tissue manifestations including hyperextensibility of skin and joint hypermobility but also by early mortality due to rupture of arteries or vital organs. Although pulmonary complications are not common, vEDS cases complicated by pneumothorax, hemothorax, or intrapulmonary hematoma have been reported. When a patient initially presents only with pulmonary complications, it is not easy for clinicians to suspect vEDS. We report a case of an 18-year-old high school student, with a past history of cryptorchidism, presenting with recurrent pneumothorax. Routine laboratory findings were unremarkable. Chest high resolution computed tomographic scan showed age-unmatched hyperinflation of both lungs, atypical cystic changes and multifocal ground glass opacities scattered in both lower lobes. His slender body shape, hyperflexible joints, and hyperextensible skin provided clue to suspicion of a possible connective tissue disorder. The histological examination of the lung lesions showed excessive capillary proliferation in the pulmonary interstitium and pleura allowing the diagnosis of pulmonary capillary hemangiomatosis (PCH)-like foci. Genetic study revealed COL3A1 gene splicing site mutation confirming his diagnosis as vEDS. Although his diagnosis vEDS is notorious for fatal vascular complication, there was no evidence of such complication at presentation. Fortunately, he has been followed up for 10 months without pulmonary or vascular complications. To the best of our knowledge, both cryptorchidism and PCH-like foci have never been reported yet as complications of vEDS, suggesting our case might be a new variant of this condition. This case emphasizes the importance of comprehensive physical examination and history-taking, and the clinical

Vascular Ehlers–Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci

PubMed Central

Park, Min A.; Shin, So Youn; Kim, Young Jin; Park, Myung Jae; Lee, Seung Hyeun

2017-01-01

Abstract Rationale: Vascular Ehlers–Danlos syndrome (vEDS) is a rare autosomal dominant inherited collagen disorder caused by defects or deficiency of pro-alpha 1 chain of type III procollagen encoded by COL3A1. vEDS is characterized not only by soft tissue manifestations including hyperextensibility of skin and joint hypermobility but also by early mortality due to rupture of arteries or vital organs. Although pulmonary complications are not common, vEDS cases complicated by pneumothorax, hemothorax, or intrapulmonary hematoma have been reported. When a patient initially presents only with pulmonary complications, it is not easy for clinicians to suspect vEDS. Patient concerns: We report a case of an 18-year-old high school student, with a past history of cryptorchidism, presenting with recurrent pneumothorax. Diagnoses: Routine laboratory findings were unremarkable. Chest high resolution computed tomographic scan showed age-unmatched hyperinflation of both lungs, atypical cystic changes and multifocal ground glass opacities scattered in both lower lobes. His slender body shape, hyperflexible joints, and hyperextensible skin provided clue to suspicion of a possible connective tissue disorder. Interventions: The histological examination of the lung lesions showed excessive capillary proliferation in the pulmonary interstitium and pleura allowing the diagnosis of pulmonary capillary hemangiomatosis (PCH)-like foci. Genetic study revealed COL3A1 gene splicing site mutation confirming his diagnosis as vEDS. Outcomes: Although his diagnosis vEDS is notorious for fatal vascular complication, there was no evidence of such complication at presentation. Fortunately, he has been followed up for 10 months without pulmonary or vascular complications. Lessons: To the best of our knowledge, both cryptorchidism and PCH-like foci have never been reported yet as complications of vEDS, suggesting our case might be a new variant of this condition. This case emphasizes the

Assessment of vascular and endothelial dysfunction in nutritional studies.

PubMed

Ray, S; Miglio, C; Eden, T; Del Rio, D

2014-09-01

Vascular and endothelial dysfunction (VED) is emerging as a potential set of early markers of cardiovascular disease risk and tests for its measurement have been widely used in clinical research. The aim of this viewpoint is to describe and discuss the current usage of these measures in well-designed nutritional trials, using the potential relationship between fruit juice intake and VED as example. A search was conducted using the NHS evidence portal including studies published in English between January 1980 and October 2013. Only 10 suitable studies were selected, which investigated the effect of fruit juice intake on VED, among which 4 interventions used flow-mediated dilatation, 2 arterial stiffness, 2 a combination of arterial stiffness and flow-mediated dilatation, 2 carotid intimal media thickness and 1 iontophoresis with laser Doppler. Despite minimal effects reported on classical CVD markers, such as lipids, 8 out of the 10 identified studies reported an effect on endothelial function following juice consumption, indicating that VED tests can be effectively used in human dietary interventions to identify relationships between bioactive compounds from fruit and CVD risk. However, paucity of available data, scarcity of compound bioavailability and metabolism information, strong heterogeneity among experimental methodologies and a number of limitations to study designs, still limit the interpretation of the results obtained through these measures. Future, well-designed studies with greater attention to consider use of VED measures are needed to strengthen the utility of VED tests in nutrition research such as those investigating the impact of polyphenol-rich juices and CVD risk. Copyright © 2014 Elsevier B.V. All rights reserved.

Current perspectives on cardiac amyloidosis

PubMed Central

Guan, Jian; Mishra, Shikha; Falk, Rodney H.

2012-01-01

Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis. PMID:22058156

Total pleural covering technique for intractable pneumothorax in patient with Ehlers-Danlos syndrome.

PubMed

Kadota, Yoshihisa; Fukui, Eriko; Kitahara, Naoto; Okura, Eiji; Ohta, Mitsunori

2016-07-01

We report a patient with vascular-type Ehlers-Danlos syndrome (vEDS) who developed pneumothorax and was treated with a total pleural covering technique (TPC). A 24-year-old man developed repeat pneumothorax with intermittent hemo-sputum. Based on unusual radiological manifestations of lung lesions and physical findings, EDS was suspected as an underlying cause of the pneumothorax. Surgical treatment was performed using a mediastinal fat pad and TPC, and no relapse was seen up to 2 years after surgery. TPC is a less invasive surgical approach for selected patients with vEDS. Accurate underlying diagnosis of vEDS and systemic evaluation of vascular complications are necessary before planning surgery.

Micromachined TWTs for THz Radiation Sources

NASA Technical Reports Server (NTRS)

Booske, John H.; vanderWeide, Daniel W.; Kory, Carol L.; Limbach, S.; Downey, Alan (Technical Monitor)

2001-01-01

The Terahertz (THz) region of the electromagnetic spectrum (about 300 - 3000 GHz in frequency or about 0.1 - 1 mm free space wavelength) has enormous potential for high-data-rate communications, spectroscopy, astronomy, space research, medicine, biology, surveillance, remote sensing, industrial process control, etc. It has been characterized as the most scientifically rich, yet under-utilized, region of the electromagnetic spectrum. The most critical roadblock to full exploitation of the THz band is lack of coherent radiation sources that are powerful (0.001 - 1.0 W continuous wave), efficient (> 1%), frequency agile (instantaneously tunable over 1% bandwidths or more), reliable, and comparatively inexpensive. To develop vacuum electron device (VED) radiation sources satisfying these requirements, fabrication and packaging approaches must be heavily considered to minimize costs, in addition to the basic interaction physics and circuit design. To minimize size of the prime power supply, beam voltage must be minimized, preferably 10 kV. Solid state sources satisfy the low voltage requirement, but are many orders of magnitude below power, efficiency, and bandwidth requirements. On the other hand, typical fast-wave VED sources in this regime (e.g., gyrotrons, FELs) tend to be large, expensive, high voltage and very high power devices unsuitable for most of the applications cited above. VEDs based on grating or inter-digital (ID) circuits have been researched and developed. However, achieving forward-wave amplifier operation with instantaneous fractional bandwidths > 1% is problematic for these devices with low-energy (< 15 kV) electron beams. Moreover, the interaction impedance is quite low unless the beam-circuit spacing is kept particularly narrow, often leading to significant beam interception. One solution to satisfy the THz source requirements mentioned above is to develop micromachined VEDs, or "micro-VEDs". Among other benefits, micro-machining technologies

Is early measles vaccination better than later measles vaccination?

PubMed

Aaby, Peter; Martins, Cesário L; Ravn, Henrik; Rodrigues, Amabelia; Whittle, Hilton C; Benn, Christine S

2015-01-01

WHO recommends delaying measles vaccination (MV) until maternal antibody has waned. However, early MV may improve child survival by reducing mortality from conditions other than measles infection. We tested whether early MV improves child survival compared with later MV. We found 43 studies comparing measles-vaccinated and measles-unvaccinated children; however, only 16 studies had specific information that MV had been provided at 4-13 months of age, many before 9 months of age. In the 10 best studies (4 randomized trials and 6 observational studies) control children did not receive MV during follow-up. In eight of these studies the vaccine efficacy against death (VED) was 60% or more. In four studies with information on MV provided both before and after 12 months of age, the all-cause mortality reduction was significantly larger for children vaccinated in infancy (VED=74%; 95% CI 51-86%) than for children vaccinated after 12 months of age (VED=29%; CI 8-46%). Prevention of measles explained little of the reduction in mortality. In five studies with information on measles infection, VED was 67% (51-78%) and when measles deaths were excluded, VED was only reduced to 65% (47-77%). One natural experiment compared MV at 4-8 months versus MV at 9-11 months of age and found significantly lower all-cause mortality with early vaccination, the difference being 39% (8-60%). Child mortality may be reduced if MV is given earlier than currently recommended by international organizations. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Interdisciplinary evaluation of dysphagia: clinical swallowing evaluation and videoendoscopy of swallowing.

PubMed

Sordi, Marina de; Mourão, Lucia Figueiredo; Silva, Ariovaldo Armando da; Flosi, Luciana Claudia Leite

2009-01-01

Patients with dysphagia have impairments in many aspects, and an interdisciplinary approach is fundamental to define diagnosis and treatment. A joint approach in the clinical and videoendoscopy evaluation is paramount. To study the correlation between the clinical assessment (ACD) and the videoendoscopic (VED) assessment of swallowing by classifying the degree of severity and the qualitative/descriptive analyses of the procedures. cross-sectional, descriptive and comparative. held from March to December of 2006, at the Otolaryngology/Dysphagia ward of a hospital in the country side of São Paulo. 30 dysphagic patients with different disorders were assessed by ACD and VED. The data was classified by means of severity scales and qualitative/ descriptive analysis. the correlation between severity ACD and VED scales pointed to a statistically significant low agreement (KAPA = 0.4) (p=0,006). The correlation between the qualitative/descriptive analysis pointed to an excellent and statistically significant agreement (KAPA=0.962) (p<0.001) concerning the entire sample. the low agreement between the severity scales point to a need to perform both procedures, reinforcing VED as a doable procedure. The descriptive qualitative analysis pointed to an excellent agreement, and such data reinforces our need to understand swallowing as a process.

What amyloidoses may tell us about normal protein folding: The Alzheimer's disease story

NASA Astrophysics Data System (ADS)

Teplow, David B.

2002-03-01

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by severe neuronal injury and death. A prominent histopathologic feature of AD is disseminated parenchymal and vascular amyloid deposition. The fibrils in these deposits are composed of the amyloid β-protein (Aβ), a peptide of 4 kDa mass. In vitro and in vivo studies of Aβ fibril formation have shown that both oligomeric and polymeric Aβ assemblies have neurotoxic activity. Understanding how these assemblies form thus could be of direct therapeutic relevance. However, the aggregation and fibril-forming propensities of Aβ have complicated structure determination. Nevertheless, careful morphologic, spectroscopic, protein chemical, and physiologic analyses of the time-dependent changes in Aβ conformation, assembly state, and biological activity which occur during fibrillogenesis have significantly advanced our understanding of this clinically important process. Here, I will discuss recent findings about the pathway(s) of Aβ folding and assembly and about key structural features of Aβ which control the associated kinetics. Interestingly, the amyloidogenic folding pathway of Aβ is in some respects the mirror image of that through which natively folded amyloidogenic proteins proceed.

Structure–Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders

PubMed Central

Rahimi, F.; Shanmugam, A.; Bitan, G.

2010-01-01

Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid β-protein (Aβ), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary

[Secondary amyloidosis in patients with rheumatoid arthritis(RA)].

PubMed

Inada, Shinichi

2002-12-01

The amyloidoses are a group of protein deposition diseases in which amyloid proteins composed of insoluble fibrils are deposited in various organs. Most cases of the secondary amyloidosis(AA amyloidosis) in which amyloid A(AA) protein is deposited followed by uncontrolled, long term RA(duration 7 to 10 years). It has been revealed that the multi-organ dysfunction associated with AA amyloidosis causes the deterioration of RA prognosis. Since the mechanism of amyloid protein deposition is still unknown, the diagnosis of AA amyloidosis is difficult and there is no fundamental therapy for it; there are only supportive therapies for the malfunction of involved organs.

Proteomics with Mass Spectrometry Imaging: Beyond Amyloid Typing.

PubMed

Lavatelli, Francesca; Merlini, Giampaolo

2018-04-01

Detection and typing of amyloid deposits in tissues are two crucial steps in the management of systemic amyloidoses. The presence of amyloid deposits is routinely evaluated through Congo red staining, whereas proteomics is now a mainstay in the identification of the deposited proteins. In article number 1700236, Winter et al. [Proteomics 2017, 17, Issue 22] describe a novel method based on MALDI-MS imaging coupled to ion mobility separation and peptide filtering, to detect the presence of amyloid in histology samples and to identify its composition, while preserving the spatial distribution of proteins in tissues. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of toothbrush hardness on in vitro wear and roughness of composite resins.

PubMed

Kyoizumi, Hideaki; Yamada, Junji; Suzuki, Toshimitsu; Kanehira, Masafumi; Finger, Werner J; Sasaki, Keiichi

2013-11-01

To investigate and compare the effects of toothbrushes with different hardness on abrasion and surface roughness of composite resins. Toothbrushes (DENT. EX Slimhead II 33, Lion Dental Products Co. Ltd., Tokyo, Japan) marked as soft, medium and hard, were used to brush 10 beam-shaped specimens of each of three composites resins (Venus [VEN], Venus Diamond [VED] and Venus Pearl [VEP]; HeraeusKulzer) with standardized calcium carbonate slurry in a multistation testing machine (2N load, 60 Hz). After each of five cycles with 10k brushing strokes the wear depth and surface roughness of the specimens were determined. After completion of 50k strokes representative samples were inspected by SEM. Data were treated with ANOVA and regression analyses (p < 0.05). Abrasion of the composite resins increased linearly with increasing number of brushing cycles (r² > 0.9). Highest wear was recorded for VEN, lowest for VED. Hard brushes produced significantly higher wear on VEN and VEP, whereas no difference in wear by toothbrush type was detected for VED. Significantly highest surface roughness was found on VED specimens (Ra > 1.5 µm), the lowest one on VEN (Ra < 0.3 µm). VEN specimens showed increased numbers of pinhole defects when brushed with hard toothbrushes, surfaces of VEP were uniformly abraded without level differences between the prepolymerized fillers and the glass filler-loaded matrix, VED showed large glass fillers protruding over the main filler-loaded matrix portion under each condition. Abrasion and surface roughness of composite resins produced by toothbrushing with dentifrice depend mainly on the type of restorative resin. Hardness grades of toothbrushes have minor effects only on abrasion and surface roughness of composite resins. No relationship was found between abrasion and surface roughness. The grade of the toothbrush used has minor effect on wear, texture and roughness of the composite resin.

Pulsed Artificial Electrojet Generation

NASA Astrophysics Data System (ADS)

Papadopoulos, K.

2008-12-01

Traditional techniques for generating low frequency signals in the ULF/ELF range (.1-100 Hz) and rely on ground based Horizontal Electric Dipole (HED) antennas. It is, furthermore, well known that a Vertical Electric Dipole (VED) is by more than 50 dB more efficient than a HED with the same dipole current moment. However, the prohibitively long length of VED antennas in the ELF/ULF range coupled with voltage limitations due to corona discharge in the atmosphere make them totally impracticable. In this paper we discuss a novel concept, inspired by the physics of the equatorial electrojet, that allows for the conversion of a ground based HED to a VED in the E-region of the equatorial ionosphere with current moment comparable to the driving HED. The paper focuses in locations near the dip-equator, where the earth's magnetic is in predominantly in the horizontal direction. The horizontal electric field associated with a pulsed HED drives a large Hall current in the ionospheric E-region, resulting in a vertical current. It is shown that the pulsed vertical current in the altitude range 80-130 km, driven by a horizontal electric field of, approximately, .1 mV/m at 100 km altitude, is of the order of kA. This results in a pulsed VED larger than 106 A-m. Such a pulsed VED will drive ELF/ULF pulses with amplitude in excess of .1 nT at a lateral range larger than few hundred kilometers. This is by three orders of magnitude larger than the one expected by a HED with comparable current moment. The paper will conclude with the description of a sneak-through technique that allows for creating pulsed electric fields in the ionosphere much larger than expected from steady state oscillatory HED antennas.

Predictive modeling of slope deposits and comparisons of two small areas in Northern Germany

NASA Astrophysics Data System (ADS)

Shary, Peter A.; Sharaya, Larisa S.; Mitusov, Andrew V.

2017-08-01

Methods for correct quantitative comparison of several terrains are important in the development and use of quantitative landscape evolution models, and they need to introduce specific modeling parameters. We introduce such parameters and compare two small terrains with respect to the link slope-valley for the description of slope deposits (colluvium) in them. We show that colluvium accumulation in small areas cannot be described by linear models and thus introduce non-linear models. Two small areas, Perdoel (0.29 ha) and Bornhöved (3.2 ha), are studied. Slope deposits in the both are mainly in dry valleys, with a total thickness Mtotal up to 2.0 m in Perdoel and up to 1.2 m in Bornhöved. Parent materials are mainly Pleistocene sands aged 30 kyr BP. Exponential models of multiple regression that use a 1-m LiDAR DEM (digital elevation model) explained 70-93% of spatial variability in Mtotal. Parameters DH12 and DV12 of horizontal and vertical distances are introduced that permit to characterize and compare conditions of colluvium formation for various terrains. The study areas differ 3.7 times by the parameter DH12 that describes a horizontal distance from thalwegs at which Mtotal diminishes 2.72 times. DH12 is greater in Bornhöved (29.7 m) than in Perdoel (8.12 m). We relate this difference in DH12 to the distinction between types of the link slope-valley: a regional type if catchment area of a region outside a given small area plays an important role, and a local type when accumulation of colluvium from valley banks within a small area is of more importance. We argue that the link slope-valley is regional in Perdoel and local in Bornhöved. Peaks of colluvium thickness were found on thalwegs of three studied valleys by both direct measurements in a trench, and model surfaces of Mtotal. A hypothesis on the formation mechanism of such peaks is discussed. The parameter DV12 describes a vertical distance from a peak of colluvium thickness along valley bottom at

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

Okada, Takuya, E-mail: okabone@gmail.com; Frank, Michael, E-mail: michael.frank@egp.aphp.fr; Pellerin, Olivier, E-mail: olivier@pellerin.as

PurposeTo evaluate the safety and efficacy of transarterial embolization of life-threatening arterial rupture in patients with vascular Ehlers–Danlos syndrome (vEDS) in a single tertiary referral center.MethodsWe retrospectively analyzed transarterial embolization for vEDS performed at our institution from 2000 to 2012. The indication of embolization was spontaneous arterial rupture or pseudoaneurysm with acute bleeding. All interventions used a percutaneous approach through a 5F or less introducer sheath. Embolic agents were microcoils and glue in 3 procedures, glue alone in 2, and microcoils alone in 2.ResultsFive consecutive vEDS patients were treated by 7 embolization procedures (4 women, mean age 29.8 years). All proceduresmore » were successfully performed. Two patients required a second procedure for newly arterial lesions at a different site from the first procedure. Four of the five patients were still alive after a mean follow-up of 19.4 (range 1–74.7) months. One patient died of multiple organ failure 2 days after procedure. Minor procedural complications were observed in 3 procedures (43 %), all directly managed during the same session. Remote arterial lesions occurred after 3 procedures (43 %); one underwent a second embolization, and the other 2 were observed conservatively. Puncture site complication was observed in only one procedure (14 %).ConclusionEmbolization for vEDS is a safe and effective method to manage life-threatening arterial rupture.« less

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type With Different Phenotypes in the Same Family.

PubMed

Cortini, Francesca; Marinelli, Barbara; Romi, Silvia; Seresini, Agostino; Pesatori, Angela Cecilia; Seia, Manuela; Montano, Nicola; Bassotti, Alessandra

2017-04-01

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain ( COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance.

Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature.

PubMed

Maraj, Bharat; Harding-Theobald, Emily; Karaki, Fatima

2018-04-26

Ehlers-Danlos syndrome refers to a spectrum of connective tissue disorders typically caused by mutations in genes responsible for the synthesis of collagen. Patients with Ehlers-Danlos syndrome often exhibit hyperflexibility of joints, increased skin elasticity, and tissue fragility. Vascular Ehlers-Danlos (vEDS) is a subtype of Ehlers-Danlos syndrome with a predilection to involve blood vessels. As such, it often manifests as vascular aneurysms and vessel rupture leading to hemorrhage. There are few reports describing primary prevention of aneurysms in the setting of undiagnosed, suspected vEDS. We present a case of a 30-year-old woman who presents with a pulsatile neck mass found to have multiple arterial aneurysms on imaging, hyperflexibility, and characteristic facial features consistent with vEDS. As described in this case, management of a suspected connective tissue disorder is a multidisciplinary approach including vascular surgery, medical therapy, and genetic testing to confirm the diagnosis. We review literature regarding the care of patients with vascular Ehlers-Danlos as it might pertain to hospitalized patients.

Vessel Enhancement and Segmentation of 4D CT Lung Image Using Stick Tensor Voting

NASA Astrophysics Data System (ADS)

Cong, Tan; Hao, Yang; Jingli, Shi; Xuan, Yang

2016-12-01

Vessel enhancement and segmentation plays a significant role in medical image analysis. This paper proposes a novel vessel enhancement and segmentation method for 4D CT lung image using stick tensor voting algorithm, which focuses on addressing the vessel distortion issue of vessel enhancement diffusion (VED) method. Furthermore, the enhanced results are easily segmented using level-set segmentation. In our method, firstly, vessels are filtered using Frangi's filter to reduce intrapulmonary noises and extract rough blood vessels. Secondly, stick tensor voting algorithm is employed to estimate the correct direction along the vessel. Then the estimated direction along the vessel is used as the anisotropic diffusion direction of vessel in VED algorithm, which makes the intensity diffusion of points locating at the vessel wall be consistent with the directions of vessels and enhance the tubular features of vessels. Finally, vessels can be extracted from the enhanced image by applying level-set segmentation method. A number of experiments results show that our method outperforms traditional VED method in vessel enhancement and results in satisfied segmented vessels.

Allele-specific siRNA knockdown as a personalized treatment strategy for vascular Ehlers-Danlos syndrome in human fibroblasts.

PubMed

Müller, Gerd A; Hansen, Uwe; Xu, Zhi; Griswold, Benjamin; Talan, Mark I; McDonnell, Nazli B; Briest, Wilfried

2012-02-01

The vascular type of the Ehlers-Danlos syndrome (vEDS) is caused by dominant-negative mutations in the procollagen type III (COL3A1) gene. Patients with this autosomal dominant disorder have a shortened life expectancy due to complications from ruptured vessels or hollow organs. We tested the effectiveness of allele-specific RNA interference (RNAi) to reduce the mutated phenotype in fibroblasts. Small-interfering RNAs (siRNAs) discriminating between wild-type and mutant COL3A1 allele were identified by a luciferase reporter gene assay and in primary fibroblasts from a normal donor and a patient with vEDS. The best discriminative siRNA with the mutation at position 10 resulted in >90% silencing of the mutant allele without affecting the wild-type allele. Transmission and immunogold electron microscopy of extracted extracellular matrices from untreated fibroblasts of the patient with vEDS revealed structurally abnormal fibrils. After siRNA treatment, collagen fibrils became similar to fibrils from fibroblasts of normal and COL3A1 haploinsufficient donors. In addition, it was shown that expression of mutated COL3A1 activates the unfolded protein response and that reduction of the amount of mutated protein by siRNA reduces cellular stress. Taken together, the results provide evidence that allele-specific siRNAs are able to reduce negative effects of mutated COL3A1 proteins. Thus, the application of allele-specific RNAi may be a promising direction for future personalized therapies to reduce the severity of vEDS.

Pretargeting immunotherapy: a novel treatment approach for systemic amyloidosis.

PubMed

Wall, Jonathan S; Foster, James S; Martin, Emily B; Kennel, Stephen J

2017-09-01

The amyloidoses are a complex group of disorders characterized by the deposition of proteinaceous amyloid fibrils in vital organs. The deposits are nonimmunogenic and may be composed of one of more than 35 proteins. We have developed a two-stage immunotherapeutic approach using peptides that recognize most, if not all, amyloid deposits to facilitate amyloid clearance. In the first embodiment, we have developed a bifunctional peptope to enhance and expand the utility of currently available antibodies. In the second, we have generated peptide-reactive antibodies that can be targeted to the amyloid deposits by peptides thereby providing alternative reagents for immunotherapy of amyloidosis. These technologies provide tools for treating the many forms of amyloid disease, restoring organ function and enhancing patient survival.

Roselle supplementation prevents nicotine-induced vascular endothelial dysfunction and remodelling in rats.

PubMed

Si, Lislivia Yiang-Nee; Kamisah, Yusof; Ramalingam, Anand; Lim, Yi Cheng; Budin, Siti Balkis; Zainalabidin, Satirah

2017-07-01

Vascular endothelial dysfunction (VED) plays an important role in the initiation of cardiovascular diseases. Roselle, enriched with antioxidants, demonstrates high potential in alleviating hypertension. This study was undertaken to investigate the effects of roselle supplementation of VED and remodelling in a rodent model with prolonged nicotine administration. Male Sprague-Dawley rats (n = 6 per group) were administered with 0.6 mg/kg nicotine for 28 days to induce VED. The rats were given either aqueous roselle (100 mg/kg) or normal saline orally 30 min prior to nicotine injection daily. One additional group of rats served as control. Thoracic aorta was isolated from rats to measure vascular reactivity, vascular remodelling and oxidative stress. Roselle significantly lowered aortic sensitivity to phenylephrine-induced vasoconstriction (Endo-(+) C max = 234.5 ± 3.9%, Endo-(-) C max = 247.6 ± 5.2%) compared with untreated nicotine group (Endo-(+) C max = 264.5 ± 6.9%, Endo-(-) C max = 276.5 ± 6.8%). Roselle also improved aortic response to endothelium-dependent vasodilator, acetylcholine (Endo-(+) R max = 73.2 ± 2.1%, Endo-(-) R max = 26.2 ± 0.8%) compared to nicotine group (Endo-(+) R max = 57.8 ± 1.7%, Endo-(-) R max = 20.9 ± 0.8%). In addition, roselle prevented an increase in intimal media thickness and elastic lamellae proliferation to preserve vascular architecture. Moreover, we also observed a significantly lowered degree of oxidative stress in parallel with increased antioxidant enzymes in aortic tissues of the roselle-treated group. This study demonstrated that roselle prevents VED and remodelling, and as such it has high nutraceutical value as supplement to prevent cardiovascular diseases.

Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines.

PubMed

Sipe, Jean D; Benson, Merrill D; Buxbaum, Joel N; Ikeda, Shu-Ichi; Merlini, Giampaolo; Saraiva, Maria J M; Westermark, Per

2016-12-01

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July-7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form of amyloidosis is uniquely characterized by the chemical identity of the amyloid fibril protein that deposits in the extracellular spaces of tissues and organs and gives rise to the disease syndrome. The fibril proteins are designated as protein A followed by a suffix that is an abbreviation of the parent or precursor protein name. To date, there are 36 known extracellular fibril proteins in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII and AApoCIII derived from apolipoprotein CIII, have been added. AApoCII amyloidosis and AApoCIII amyloidosis are hereditary systemic amyloidoses. Intracellular protein inclusions displaying some of the properties of amyloid, "intracellular amyloid" have been reported. Two proteins which were previously characterized as intracellular inclusions, tau and α-synuclein, are now recognized to form extracellular

Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition

PubMed Central

Biolo, Andreia; Ramamurthy, Sujata; Connors, Lawreen H.; O'Hara, Carl J.; Meier-Ewert, Hans K.; Hoo, Pamela T. Soo; Sawyer, Douglas B.; Seldin, David S.; Sam, Flora

2009-01-01

Background Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix (ECM) disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition, has an accelerated clinical course and a worse prognosis compared to non-light chain cardiac amyloidoses i.e., forms associated with wild-type or mutated transthyretin (TTR). We therefore tested the hypothesis that determinants of proteolytic activity of the ECM, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP vs. TTR. Methods / Results We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, i.e. senile systemic amyloidois (SSA, involving wild-type TTR) or mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and −9, TIMP-1, −2 and −4, brain natriuretic peptide (BNP) values and echocardiography were determined. AL-CMP and SSA-ATTR groups had similar degrees of increased left ventricular wall thickness (LVWT). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the SSA-ATTR group. BNP, MMPs and TIMPs were not correlated with the degree of LVWT but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in SSA or ATTR hearts. Conclusions Despite comparable LVWT with TTR-related cardiac amyloidosis, AL-CMP patients have higher BNP, MMPs and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and ECM proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non

A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine-enhanced disease.

PubMed

Shibata, Takehiko; Ato, Manabu

2017-11-01

Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-γ levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-γ, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.

Six uneventful pregnancy outcomes in an extended vascular Ehlers-Danlos syndrome family.

PubMed

Baas, Annette F; Spiering, Wilko; Moll, Frans L; Page-Christiaens, Lieve; Beenakkers, Ingrid C M; Dooijes, Dennis; Vonken, Evert-Jan P A; van der Smagt, Jasper J; Knoers, Nine V; Koenen, Steven V; van Herwaarden, Joost A; Sieswerda, Gertjan Tj

2017-02-01

Vascular Ehlers-Danlos Syndrome (vEDS) is caused by heterozygous mutations in COL3A1 and is characterized by fragile vasculature and hollow organs, with a high risk of catastrophic events at a young age. During pregnancy and delivery, maternal mortality rates up until 25% have been reported. However, recent pedigree analysis reported a substantial lower pregnancy-related mortality rate of 4.9%. Here, we describe an extended vEDS family with multiple uneventful pregnancy outcomes. In the proband, a 37-year-old woman, DNA-analysis because of an asymptomatic iliac artery dissection revealed a pathogenic mutation in COL3A1 (c.980G>A; p. Gly327Asp). She had had three uneventful vaginal deliveries. At the time of diagnosis, her 33-year-old niece was 25 weeks pregnant. She had had one uneventful vaginal delivery. Targeted DNA-analysis revealed that she was carrier of the COL3A1 mutation. Ultrasound detected an aneurysm in the abdominal aorta with likely a dissection. An uneventful elective cesarean section was performed at a gestational age of 37 weeks. The 40-year-old sister of our proband had had one uneventful vaginal delivery and an active pregnancy wish. Cascade DNA-screening showed her to carry the COL3A1 mutation. Computed Tomography Angiography (CTA) of her aorta revealed a type B dissection with the most proximal entry tear just below the superior mesenteric artery. Pregnancy was therefore discouraged. This familial case illustrates the complexity and challenges of reproductive decision-making in a potentially lethal condition as vEDS, and highlights the importance of a multidisciplinary approach. Moreover, it suggests that previous pregnancy-related risks of vEDS may be overestimated. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Verbal Emotional Disclosure of Traumatic Experiences in Adolescents: The Role of Social Risk Factors

PubMed Central

Pérez, Silvia; Peñate, Wenceslao; Bethencourt, Juan M.; Fumero, Ascensión

2017-01-01

It is well-known that traumatic events and adverse life situations are very important in both physical and psychological health. Prevalence studies suggested that adolescents experience at least one potentially traumatic event before reaching age 18. The paradigm of research centered on expressive writing has evidenced the beneficial effects that the emotional disclosure of previous traumas produces on physical health and psychological adjustment. The aims of the study are threefold: determining the prevalence of adverse or traumatic events; examining the extent to which psychopathological symptoms developed in those exposed to traumatic events; and exploring an verbal emotional disclosure (VED) paradigm in which variations on time spent talking about traumatic experiences to others resulted in a reduction of the psychological impact of trauma in a sample of Spanish adolescents. 422 volunteer adolescents participated, 226 boys and 192 girls, from 10 to 19 years old, all of them living in Tenerife. The mean age was 14.8 years (SD = 1.83). All of them completed the instruments used to assess the psychological impact of traumatic experiences and VED. The main results indicated that 77% of the participants had suffered a traumatic situation. The participants who have been exposed to traumatic events scored significantly higher in measures of post-traumatic stress, disorder, intrusive thoughts, avoidance behaviors, anxiety and depression, compared to those without trauma. Furthermore, results show a decrease in symptomatology scores as a function of time spent disclosing emotional experiences to others, particularly when disclosure occurred several times. In conclusion, stressful events or traumatic experiences and their concomitant emotional effects are highly prevalent in adolescents, and repeated VED to others appears to ameliorate their impact. VED shows greater therapeutic benefits when adolescents narrate the experience on several occasions and in an extensive way

In-situ formation of Ni4Ti3 precipitate and its effect on pseudoelasticity in selective laser melting additive manufactured NiTi-based composites

NASA Astrophysics Data System (ADS)

Gu, Dongdong; Ma, Chenglong

2018-05-01

Selective laser melting (SLM) additive manufacturing technology was applied to synthesize NiTi-based composites via using ball-milled Ti, Ni, and TiC mixed powder. By transmission electron microscope (TEM) characterization, it indicated that the B2 (NiTi) matrix was obtained during SLM processing. In spite of more Ti content (the Ti/Ni ratio >1), a mass of Ni-rich intermetallic compounds containing Ni4Ti3 with nanostructure features and eutectic Ni3Ti around in-situ Ti6C3.75 dendrites were precipitated. Influence of the applied laser volume energy density (VED) on the morphology and content of Ni4Ti3 precipitate was investigated. Besides, nanoindentation test of the matrix was performed in order to assess pseudoelastic recovery behavior of SLM processed NiTi-based composites. At a relatively high VED of 533 J/mm3, the maximum pseudoelastic recovery was obtained due to the lowest content of Ni4Ti3 precipitates. Furthermore, the precipitation mechanism of in-situ Ni4Ti3 was present based on the redistribution of titanium element and thermodynamics analysis, and then the relationship of Ni4Ti3 precipitate, VED and pseudoelastic recovery behavior was also revealed.

Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease

PubMed Central

Varadharaj, Saradhadevi; Kelly, Owen J.; Khayat, Rami N.; Kumar, Purnima S.; Ahmed, Naseer; Zweier, Jay L.

2017-01-01

In vascular diseases, including hypertension and atherosclerosis, vascular endothelial dysfunction (VED) occurs secondary to altered function of endothelial nitric oxide synthase (eNOS). A novel redox regulated pathway was identified through which eNOS is uncoupled due to S-glutathionylation of critical cysteine residues, resulting in superoxide free radical formation instead of the vasodilator molecule, nitric oxide. In addition, the redox sensitive cofactor tetrahydrobiopterin, BH4, is also essential for eNOS coupling. Antioxidants, either individually or combined, can modulate eNOS uncoupling by scavenging free radicals or impairing specific radical generating pathways, thus preventing oxidative stress and ameliorating VED. Epidemiological evidence and dietary guidelines suggest that diets high in antioxidants, or antioxidant supplementation, could preserve vascular health and prevent cardiovascular diseases (CVDs). Therefore, the purpose of this review is to highlight the possible role of dietary antioxidants in regulating eNOS function and uncoupling which is critical for maintenance of vascular health with normal blood flow/circulation and prevention of VED. We hypothesize that a conditioned dietary approach with suitable antioxidants may limit systemic oxidation, maintain a beneficial ratio of reduced to oxidized glutathione, and other redox markers, and minimize eNOS uncoupling serving to prevent CVD and possibly other chronic diseases. PMID:29164133

Fulminant myocardial bleeding: another clinical course of vascular Ehlers-Danlos Syndrome.

PubMed

Tokue, Masahide; Hara, Hidehiko; Kurosawa, Kenji; Nakamura, Masato

2017-09-23

Vascular Ehlers-Danlos Syndrome (vEDS) is a dominantly inherited connective tissue disorder characterised by colon rupture and arterial aneurysm, dissection and rupture. A patient was diagnosed with vEDS after a spontaneous colon rupture when he was brought to our institute because of sudden chest pain. An ECG revealed wide regional ST elevation, which was initially suggestive of acute myocarditis. On the second day, haemodynamics suddenly deteriorated because of a rapid accumulation of bloody pericardial effusion, and the patient died. Autopsy revealed an excessive spontaneous myocardial haemorrhage owing to fragility, which suggested an underlying disease-vEDS. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

NASA Astrophysics Data System (ADS)

Bucciantini, Monica; Giannoni, Elisa; Chiti, Fabrizio; Baroni, Fabiana; Formigli, Lucia; Zurdo, Jesús; Taddei, Niccolò; Ramponi, Giampietro; Dobson, Christopher M.; Stefani, Massimo

2002-04-01

A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.

Estimation of skin concentrations of topically applied lidocaine at each depth profile.

PubMed

Oshizaka, Takeshi; Kikuchi, Keisuke; Kadhum, Wesam R; Todo, Hiroaki; Hatanaka, Tomomi; Wierzba, Konstanty; Sugibayashi, Kenji

2014-11-20

Skin concentrations of topically administered compounds need to be considered in order to evaluate their efficacies and toxicities. This study investigated the relationship between the skin permeation and concentrations of compounds, and also predicted the skin concentrations of these compounds using their permeation parameters. Full-thickness skin or stripped skin from pig ears was set on a vertical-type diffusion cell, and lidocaine (LID) solution was applied to the stratum corneum (SC) in order to determine in vitro skin permeability. Permeation parameters were obtained based on Fick's second law of diffusion. LID concentrations at each depth of the SC were measured using tape-stripping. Concentration-depth profiles were obtained from viable epidermis and dermis (VED) by analyzing horizontal sections. The corresponding skin concentration at each depth was calculated based on Fick's law using permeation parameters and then compared with the observed value. The steady state LID concentrations decreased linearly as the site became deeper in SC or VED. The calculated concentration-depth profiles of the SC and VED were almost identical to the observed profiles. The compound concentration at each depth could be easily predicted in the skin using diffusion equations and skin permeation data. Thus, this method was considered to be useful for promoting the efficient preparation of topically applied drugs and cosmetics. Copyright © 2014 Elsevier B.V. All rights reserved.

Carotid stiffness change over the cardiac cycle by ultrafast ultrasound imaging in healthy volunteers and vascular Ehlers-Danlos syndrome.

PubMed

Mirault, Tristan; Pernot, Mathieu; Frank, Michael; Couade, Mathieu; Niarra, Ralph; Azizi, Michel; Emmerich, Joseph; Jeunemaître, Xavier; Fink, Mathias; Tanter, Mickaël; Messas, Emmanuel

2015-09-01

Arterial stiffness is related to age and collagen properties of the arterial wall and can be indirectly evaluated by the pulse wave velocity (PWV). Ultrafast ultrasound imaging, a unique ultrahigh frame rate technique (>10, 000 images/s), recently emerged enabling direct measurement of carotid PWV and its variation over the cardiac cycle. Our goal was to characterize the carotid diastolic-systolic arterial stiffening using ultrafast ultrasound imaging in healthy individuals and in vascular Ehlers-Danlos syndrome (vEDS), in which collagen type III is defectuous. Ultrafast ultrasound imaging was performed on common carotids of 102 healthy individuals and 37 consecutive patients with vEDS. Results are mean ± standard deviation. Carotid ultrafast ultrasound imaging PWV in healthy individuals was 5.6 ± 1.2 in early systole and 7.3 ± 2.0  m/s in end systole, and correlated with age (r = 0.48; P < 0.0001 and r = 0.68; P < 0.0001, respectively). Difference between early and end-systole PWV increased with age independently of blood pressure (r = 0.54; P < 0.0001). In patients with vEDS, ultrafast ultrasound imaging PWV was 6.0 ± 1.5 in early systole and 6.7 ± 1.5  m/s in end systole. Carotid stiffness change over the cardiac cycle was lower than in healthy people (0.021 vs. 0.057  m/s per mmHg; P = 0.0035). Ultrafast ultrasound imaging can evaluate carotid PWV and its variation over the cardiac cycle. This allowed to demonstrate the age-induced increase of the arterial diastolic-systolic stiffening in healthy people and a lower stiffening in vEDS, both characterized by arterial complications. We believe that this easy-to-use technique could offer the opportunity to go beyond the diastolic PWV to better characterize arterial stiffness change with age or other collagen alterations.

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

PubMed Central

Chiarelli, Nicola; Carini, Giulia; Zoppi, Nicoletta; Ritelli, Marco

2018-01-01

Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures. To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome.

PubMed

Chiarelli, Nicola; Carini, Giulia; Zoppi, Nicoletta; Ritelli, Marco; Colombi, Marina

2018-01-01

Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures. To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of

Amyloidosis: Insights from Proteomics.

PubMed

Dogan, Ahmet

2017-01-24

Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometry-based proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified. Proteomic assays have been extensively used for clinical management of patients with amyloidosis, providing unprecedented diagnostic and biological information. They have shed light on the pathogenesis of different amyloid types and have led to identification of numerous new amyloid types, including ALECT2 amyloidosis, which is now recognized as one of the most common causes of systemic amyloidosis in North America.

Inhibitory effect of propolis on the development of AA amyloidosis.

PubMed

Harata, Daichi; Tsuchiya, Yuya; Miyoshi, Tomoyuki; Yanai, Tokuma; Suzuki, Kazuhiko; Murakami, Tomoaki

2018-04-01

In the several types of amyloidoses, participation of oxidative stresses in the pathogenesis and the effect of antioxidants on amyloidosis have been reported. Meanwhile, the relationship between oxidative stresses and pathogenesis of amyloid A (AA) amyloidosis is still unclear. In this study, we used an antioxidant, Brazilian propolis, to investigate the inhibitory effects on AA amyloidosis. The results showed that AA deposition was inhibited by administration of propolis. Increased expression of antioxidant markers was detected in molecular biological examinations of mice treated with propolis. Although serum amyloid A (SAA) levels were strongly correlated with the immunoreactive area of AA deposits in the control group, the correlation was weaker in the propolis-treated groups. In addition, there were no changes in SAA levels between the control group and the propolis-treated groups. The results indicate that propolis, an antioxidant, may induce inhibitory effects against AA amyloidosis.

Medical abortions performed by specialists in private practice.

PubMed

Pay, Aase Serine Devold; Aabø, Runa Sigrid; Økland, Inger; Janbu, Torunn; Iversen, Ole-Erik; Løkeland, Mette

2018-05-29

I Norge utføres abort kun i offentlige sykehus. I 2010 besluttet Helse- og omsorgsdepartementet å iverksette et toårig prøveprosjekt som ga avtalespesialister i fødselshjelp og kvinnesykdommer adgang til å tilby medikamentell abort før utgangen av 9. svangerskapsuke. Prøveprosjektet ble igangsatt 1.3.2015 og varte til 31.3.2017. I denne artikkelen presenterer vi de første erfaringene, herunder hvordan behandlingstilbudet ble mottatt av kvinnene. Gravide med en svangerskapsvarighet < 63 dager ultrasonografisk vurdert, som oppsøkte avtalespesialist for medikamentell abort, ble fortløpende inkludert i prosjektet (n = 476). Kvinnene inntok 200 mg mifepriston peroralt på legekontoret, 36-48 timer senere satte de selv 800 µg misoprostol vaginalt hjemme. Informasjon ble innhentet ved spørreskjema på den første konsultasjonen, under aborten og ved etterkontrollen 2-4 uker etter aborten. Under aborten rapporterte 66 % (296/450) moderat eller sterk smerte og 79 % (358/451) moderat eller sterk blødning. De fleste opplevde det som trygt å være hjemme. 96 % (390/406) ville valgt medikamentell abort hos avtalespesialist ved en eventuell senere abort, og 97 % (392/405) ville anbefalt behandlingstilbudet til andre i samme situasjon. Kvinnene i studien opplevde abortbehandling hos avtalespesialist som trygt. Tilbudet gir større valgfrihet til gravide som ønsker abort, og pasientene er tilfredse.

Introducing cholera vaccination in Asia, Africa and Haiti: a meeting report.

PubMed

Hall, Robert H; Sack, David A

2015-01-15

Orally-administered cholera vaccine (OCV) has been increasingly examined as an additional tool to intervene against endemic and epidemic cholera. In 2013, short- and long-term field experience with OCV under nine distinctive field settings was reported from India, Bangladesh, Vietnam, Guinea, Haiti, and Thailand. Lead investigators from each of these projects presented their findings at a symposium chaired by Drs. David A. Sack and Robert H. Hall at the Vaccines for Enteric Diseases (VED) Conference in Bangkok on November 7, 2013. The objective of the symposium was to describe the unique features of each setting and project, share field experience of implementing cholera vaccination, discuss results, and identify constraints to the wider use of OCV. The VED provided a forum where >200 attendees engaged with this exciting and potentially decisive new development in the cholera field. Copyright © 2014. Published by Elsevier Ltd.. All rights reserved.

Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models.

PubMed

Grimm, Fabian A; Lehmler, Hans-Joachim; He, Xianran; Robertson, Larry W; Duffel, Michael W

2015-02-25

Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein's tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Modulating Inhibitors of Transthyretin Fibrillogenesis via Sulfation: Polychlorinated Biphenyl Sulfates as Models1

PubMed Central

Grimm, Fabian A.; Lehmler, Hans-Joachim; He, Xianran; Robertson, Larry W.; Duffel, Michael W.

2015-01-01

Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein’s tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors. PMID:25595224

Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

PubMed

Liu, Gai; Gaines, Jennifer C; Robbins, Kevin J; Lazo, Noel D

2012-10-11

The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation. How these compounds affect the kinetics of self-assembly studied by thioflavin T (ThT) fluorescence is not understood primarily because their presence interferes with ThT fluorescence. Here, we show that by plotting peak intensities from nuclear magnetic resonance (NMR) against incubation time, kinetic profiles in the presence of the polyphenol can be obtained from which kinetic parameters of self-assembly can be easily determined. In applying this technique to the self-assembly of the islet amyloid polypeptide in the presence of curcumin, a biphenolic compound found in turmeric, we show that the kinetic profile is atypical in that it shows a prenucleation period during which there is no observable decrease in NMR peak intensities.

Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation.

PubMed

Sant'Anna, Ricardo; Almeida, Maria Rosário; Varejāo, Nathalia; Gallego, Pablo; Esperante, Sebastian; Ferreira, Priscila; Pereira-Henriques, Alda; Palhano, Fernando L; de Carvalho, Mamede; Foguel, Debora; Reverter, David; Saraiva, Maria João; Ventura, Salvador

2017-03-24

More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T 4 ) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T 4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies.

[Behavioural problems and personality change related to cerebral amyloid angiopathy].

PubMed

Gahr, Maximilian; Connemann, Bernhard J; Schönfeldt-Lecuona, Carlos

2012-11-01

Cerebral amyloid angiopathy (CAA) belongs to the group of amyloidoses that are characterized by the deposition of insoluble and tissue-damaging amyloid proteins. Spontaneous intracerebral hemorrhage is the common clinical presentation of CAA resulting from the degenerative effect of beta amyloid on the cerebral vascular system. Though CAA is rather a neurological disease psychiatric symptoms can occur and even dominate the clinical picture. A case report is presented in order to illustrate the association between CAA and psychiatric symptoms. We report the case of a 54-year-old female patient with radiologic references to a probable CAA and mild cognitive impairment who developed behavioural difficulties and personality change that necessitated a psychiatric treatment. Psychiatric symptoms were most likely due to CAA. CAA can be associated with psychiatric symptoms and hence should be considered in the treatment of elderly patients with behavioural problems or personality changes. Diagnostic neuroimaging and examination of cerebrospinal fluid is recommended. © Georg Thieme Verlag KG Stuttgart · New York.

[Macular choroidal blood flow in concurrent age-related macular degeneration and primary open-angle glaucoma].

PubMed

Panova, I E; Ermak, E M; Shaimova, T A; Shaimova, V A

2016-01-01

Ocular circulation disorders are an important factor in the development of primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). To date, however, there have been no studies on choroidal blood flow peculiarities in case of concurrent AMD and POAG. to determine distinctive features of choroidal blood flow characteristic of concurrent AMD and POAG and to assess their role in disease pathogenesis. Macular choroidal blood flow, including blood supply, was assessed in 54 patients (102 eyes) by means of Doppler ultrasound. Three groups were formed: group 1 - 38 eyes with both AMD and POAG; group 2 - 41 eyes with AMD and no signs of optic nerve pathology; and group 3 - 23 eyes with POAG and no signs of AMD. Groups 1 and 2 were subdivided into two subgroups each: А - atrophic AMD and B - macular drusen. The mean patient age was 78.7±8.4 years. The following parameters of choroidal blood flow were of interest: peak systolic velocity (Vps), end diastolic velocity (Ved), time-averaged maximum velocity (Vtamax), and resistance index (RI). Groups 1, 3, and 2A had an evident choroidal hypoperfusion in the macular area (decreased Vtamax) with uncompensated perfusion deficit, despite autoregulation efforts (decreased Vps, Ved, decreased or normal RI). Group 2B demonstrated a significantly higher rate of choroidal hyperperfusion (increased Vps, Ved, Vtamax, and RI). Concurrent AMD and POAG are notable for choroidal hypoperfusion in the macular area that leads to inadequate trophism of the neurosensory retina and can aggravate the course of AMD contributing to progression of its atrophic form.

Phylogenetic conservatism in plant phenology

USGS Publications Warehouse

Davies, T. Jonathan; Wolkovich, Elizabeth M.; Kraft, Nathan J. B.; Salamin, Nicolas; Allen, Jenica M.; Ault, Toby R.; Betancourt, Julio L.; Bolmgren, Kjell; Cleland, Elsa E.; Cook, Benjamin I.; Crimmins, Theresa M.; Mazer, Susan J.; McCabe, Gregory J.; Pau, Stephanie; Regetz, Jim; Schwartz, Mark D.; Travers, Steven E.

2013-01-01

Synthesis. Closely related species tend to resemble each other in the timing of their life-history events, a likely product of evolutionarily conser ved responses to environmental cues. The search for the underlying drivers of phenology must therefore account for species’ shared evolutionary histories.

In vitro disintegration of goat brain cystatin fibrils using conventional and gemini surfactants: Putative therapeutic intervention in amyloidoses.

PubMed

Bhat, Waseem Feeroze; Bhat, Imtiyaz Ahmad; Bhat, Sheraz Ahmad; Bano, Bilqees

2016-12-01

Many protein misfolding diseases in mammalian system are characterised by the accumulation of protein aggregates in amyloid fibrillar forms. Several therapeutic approaches include reduction in the production of the amyloidogenic form of proteins, increase in the clearance rate of misfolded or aggregated proteins, and direct inhibition of the self-assembly process have been explained. One of the possible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating the formed fibrils. In this work, we have studied the effect of conventional surfactants; sodium dodecylsulphate (SDS), cetyl trimethylammonium bromide (CTAB) and dicationic gemini (16-4-16) surfactant on the disintegration of the goat brain cystatin (GBC) fibrils above their critical micelle concentrations (CMC) using ThT fluorescence, CD, TEM, Congo red and turbidity approaches. The results obtained are significant and showing the best disintegrating potency on GBC fibrils with gemini surfactant. The outcome from this work will aid in the development and/or design of potential inhibitory agents against amyloid deposits associated with amyloid diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Community College Journal for Research and Planning.

ERIC Educational Resources Information Center

Carter, Edith H., Ed.

1981-01-01

This journal, designed as a forum for the exchange of ideas among research and planning professionals, offers articles of research studies and practices. After Timothy Lightfield highlights upcoming professional association events, Janice S. Ancarrow's article, "The National Vocational Education Data Reporting and Accounting System (VEDS): Its…

A Culture-Based Model for Strategic Implementation of Virtual Education Delivery

ERIC Educational Resources Information Center

Burn, Janice; Thongprasert, Nalinee

2005-01-01

This study was designed to examine the critical success factors for implementing Virtual Education Delivery (VED) in Thailand, and to identify ways to facilitate such adoption and lead to effective outcomes. The study incorporated an analysis of three specific factors related to Thai culture: high power distance "Bhun Khun", uncertainty…

Process Optimization and Microstructure Characterization of Ti6Al4V Manufactured by Selective Laser Melting

NASA Astrophysics Data System (ADS)

junfeng, Li; zhengying, Wei

2017-11-01

Process optimization and microstructure characterization of Ti6Al4V manufactured by selective laser melting (SLM) were investigated in this article. The relative density of sampled fabricated by SLM is influenced by the main process parameters, including laser power, scan speed and hatch distance. The volume energy density (VED) was defined to account for the combined effect of the main process parameters on the relative density. The results shown that the relative density changed with the change of VED and the optimized process interval is 55˜60J/mm3. Furthermore, compared with laser power, scan speed and hatch distance by taguchi method, it was found that the scan speed had the greatest effect on the relative density. Compared with the microstructure of the cross-section of the specimen at different scanning speeds, it was found that the microstructures at different speeds had similar characteristics, all of them were needle-like martensite distributed in the β matrix, but with the increase of scanning speed, the microstructure is finer and the lower scan speed leads to coarsening of the microstructure.

A Consensus Method for the Prediction of ‘Aggregation-Prone’ Peptides in Globular Proteins

PubMed Central

Tsolis, Antonios C.; Papandreou, Nikos C.; Iconomidou, Vassiliki A.; Hamodrakas, Stavros J.

2013-01-01

The purpose of this work was to construct a consensus prediction algorithm of ‘aggregation-prone’ peptides in globular proteins, combining existing tools. This allows comparison of the different algorithms and the production of more objective and accurate results. Eleven (11) individual methods are combined and produce AMYLPRED2, a publicly, freely available web tool to academic users (http://biophysics.biol.uoa.gr/AMYLPRED2), for the consensus prediction of amyloidogenic determinants/‘aggregation-prone’ peptides in proteins, from sequence alone. The performance of AMYLPRED2 indicates that it functions better than individual aggregation-prediction algorithms, as perhaps expected. AMYLPRED2 is a useful tool for identifying amyloid-forming regions in proteins that are associated with several conformational diseases, called amyloidoses, such as Altzheimer's, Parkinson's, prion diseases and type II diabetes. It may also be useful for understanding the properties of protein folding and misfolding and for helping to the control of protein aggregation/solubility in biotechnology (recombinant proteins forming bacterial inclusion bodies) and biotherapeutics (monoclonal antibodies and biopharmaceutical proteins). PMID:23326595

Homogenization and Linear Thermeoelasticity.

DTIC Science & Technology

1981-08-01

this report) UNCLASSIFIED [7F-- D-EASSIFICATION/ OWNGRADING SCHEDU LE 16. DISTRIBUTION STATEMENT (of this Report) APPRO)VED FOR PUBLIC RELEASE...analogues of Yi and G for Xi and as in (1.27), 18 + Y.4’ (def.) (2.14) 11 = 1o 1’ 1+ where denotes the Y-average f dy y1 we introduce A VIand H1 to

[The Contribution of Vascular Capacity and Blood Volume to Maintain Stable Blood Circulation during General Anesthesia].

PubMed

Shigemi, Kenji

2016-05-01

To maintain proper cardiac preload is one of the most effective procedures for the systemic circulation remaining stable. In particular, the balance between vascular capacity and total blood volume must be maintained within appropriate range by the administration of fluids, blood and/or vasoactive drugs with mean circulatory filling pressure (Pmcf), central venous pressure (CVP) or stroke volume variation (SVV). End-diastolic left ventricular volume (Ved) is theoretically the best index of cardiac preload; however, without transesophageal echocardbalanceiogram we cannot directly monitor Ved during anesthesia. The infused fluid volume remaining in intravascular space, the vascular capacity controlled by autonomic nervous system and/or vasoactive agents, and the unstressed blood volume properly mobilized to excess blood volume are the crucial factors to maintain cardiac output The knowledge of vascular physiology contribute the decision making to manipulate such factors to control blood circulation during general anesthesia. For example, CVP is usually maintained in the narrow range and seems to be stable; however, it must be changed just after the circulatory disturbances, such as acute bleeding, blood transfusion, and fluid infusion, and followed by gradual returning to initial value, because of the solid mechanism to preserve cardiac output

Modeling of a viscoelastic damper and its application in structural control

PubMed Central

Ibrahim, Zainah; Ghodsi, S. S.; Khatibi, Hamed

2017-01-01

Conventional seismic rehabilitation methods may not be suitable for some buildings owing to their high cost and time-consuming foundation work. In recent years, viscoelastic dampers (VEDs) have been widely used in many mid- and high-rise buildings. This study introduces a viscoelastic passive control system called rotary rubber braced damper (RRBD). The RRBD is an economical, lightweight, and easy-to-assemble device. A finite element model considering nonlinearity, large deformation, and material damage is developed to conduct a parametric study on different damper sizes under pushover cyclic loading. The fundamental characteristics of this VED system are clarified by analyzing building structures under cyclic loading. The result show excellent energy absorption and stable hysteresis loops in all specimens. Additionally, by using a sinusoidal shaking table test, the effectiveness of the RRBD to manage the response displacement and acceleration of steel frames is considered. The RRBD functioned at early stages of lateral displacement, indicating that the system is effective for all levels of vibration. Moreover, the proposed damper shows significantly better performance in terms of the column compression force resulting from the brace action compared to chevron bracing (CB). PMID:28570657

Modeling of a viscoelastic damper and its application in structural control.

PubMed

Mehrabi, M H; Suhatril, Meldi; Ibrahim, Zainah; Ghodsi, S S; Khatibi, Hamed

2017-01-01

Conventional seismic rehabilitation methods may not be suitable for some buildings owing to their high cost and time-consuming foundation work. In recent years, viscoelastic dampers (VEDs) have been widely used in many mid- and high-rise buildings. This study introduces a viscoelastic passive control system called rotary rubber braced damper (RRBD). The RRBD is an economical, lightweight, and easy-to-assemble device. A finite element model considering nonlinearity, large deformation, and material damage is developed to conduct a parametric study on different damper sizes under pushover cyclic loading. The fundamental characteristics of this VED system are clarified by analyzing building structures under cyclic loading. The result show excellent energy absorption and stable hysteresis loops in all specimens. Additionally, by using a sinusoidal shaking table test, the effectiveness of the RRBD to manage the response displacement and acceleration of steel frames is considered. The RRBD functioned at early stages of lateral displacement, indicating that the system is effective for all levels of vibration. Moreover, the proposed damper shows significantly better performance in terms of the column compression force resulting from the brace action compared to chevron bracing (CB).

Design Methodology and Experimental Verification of Serpentine/Folded Waveguide TWTs

DTIC Science & Technology

2016-03-17

FW), oscillation, serpentine, stopband, traveling -wave tube (TWT), vacuum electronics. I. INTRODUCTION DEVELOPMENT of high-power broadband vacuum elec...tron devices (VEDs) beyond Ka-band using conventional coupled-cavity and helix traveling -wave tube (TWT) RF cir- cuit fabrication techniques is...between the two positions is simply ks times the relative distance along the waveguide axis. However, from the beam–wave interaction standpoint, the

Missile Manufacturing Technology Conference Held at Hilton Head Island, South Carolina on 22-26 September 1975. Panel Presentations: Guidance

DTIC Science & Technology

1975-01-01

Instead of the current three. Some de - tail on each component follows. II. POTENTIAL MANUFACTURING TECHNOLOGY PROJECTS Gyro Because of the...ranges of environment. With Imbedded microprocessors. It Is possible that parameters, once de - fined, can be placed within the microprocessor memory...Project cost: $53,000 Estimated duration of the project Is nine months. Benefits: Benefits to be de :ved from this project are a reduction

Amyloidosis: Pathogenesis and New Therapeutic Options

PubMed Central

Merlini, Giampaolo; Seldin, David C.; Gertz, Morie A.

2011-01-01

The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. The most common type, immunoglobulin light chain amyloidosis (AL), is caused by clonal plasma cells that produce misfolded light chains. The purpose of this review is to provide up-to-date information on diagnosis and treatment options for AL amyloidosis. Early, accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dominated by the extent of cardiac involvement, and cardiac staging directs the choice of therapy. Treatment for AL amyloidosis is highly individualized, determined on the basis of age, organ dysfunction, and regimen toxicities, and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy is effective in almost two thirds of patients. Novel agents are also active, and trials are ongoing to establish their optimal use. Treatment algorithms will continue to be refined through controlled trials. Advances in basic research have led to the identification of new drug targets and therapeutic approaches, which will be integrated with chemotherapy in the future. PMID:21483018

A Hydrophobic Gold Surface Triggers Misfolding and Aggregation of the Amyloidogenic Josephin Domain in Monomeric Form, While Leaving the Oligomers Unaffected

PubMed Central

Apicella, Alessandra; Soncini, Monica; Deriu, Marco Agostino; Natalello, Antonino; Bonanomi, Marcella; Dellasega, David; Tortora, Paolo; Regonesi, Maria Elena; Casari, Carlo Spartaco

2013-01-01

Protein misfolding and aggregation in intracellular and extracellular spaces is regarded as a main marker of the presence of degenerative disorders such as amyloidoses. To elucidate the mechanisms of protein misfolding, the interaction of proteins with inorganic surfaces is of particular relevance, since surfaces displaying different wettability properties may represent model systems of the cell membrane. Here, we unveil the role of surface hydrophobicity/hydrophilicity in the misfolding of the Josephin domain (JD), a globular-shaped domain of ataxin-3, the protein responsible for the spinocerebellar ataxia type 3. By means of a combined experimental and theoretical approach based on atomic force microscopy, Fourier transform infrared spectroscopy and molecular dynamics simulations, we reveal changes in JD morphology and secondary structure elicited by the interaction with the hydrophobic gold substrate, but not by the hydrophilic mica. Our results demonstrate that the interaction with the gold surface triggers misfolding of the JD when it is in native-like configuration, while no structural modification is observed after the protein has undergone oligomerization. This raises the possibility that biological membranes would be unable to affect amyloid oligomeric structures and toxicity. PMID:23527026

The role of novel chitin-like polysaccharides in Alzheimer disease.

PubMed

Castellani, Rudy J; Perry, George; Smith, Mark A

2007-12-01

While controversy over the role of carbohydrates in amyloidosis has existed since the initial recognition of amyloid, current understanding of the role of polysaccharides in the pathogenesis of amyloid deposition of Alzheimer disease and other amyloidoses is limited to studies of glyco-conjugates such as heparin sulfate proteoglycan. We hypothesized that polysaccharides may play a broader role in light of 1) the impaired glucose utilization in Alzheimer disease; 2) the demonstration of amylose in the Alzheimer disease brain; 3) the role of amyloid in Alzheimer disease pathogenesis. Specifically, as with glucose polymers (amyloid), we wanted to explore whether glucosamine polymers such as chitin were being synthesized and deposited as a result of impaired glucose utilization and aberrant hexosamine pathway activation. To this end, using calcofluor histochemistry, we recently demonstrated that amyloid plaques and blood vessels affected by amyloid angiopathy in subjects with sporadic and familial Alzheimer disease elicit chitin-type characteristics. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the Alzheimer disease brain could provide a scaffolding for amyloid-beta deposition. As such, glucosamine may facilitate the process of amyloidosis, and /or provide neuroprotection in the Alzheimer disease brain.

Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

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

Gonzalez-Montalban, Nuria; Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Bellaterra, 08193 Barcelona; Ciber de Bioingenieria, Biomateriales y Nanomedicina

The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-likemore » structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone {beta}-galactosidase fusion protein are clearly toxic for mammalian cells but the {beta}-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death.« less

The Effect of Consolidating Two-Level Reparable Inventories on Aggregate Inventory Requirements and Mission Capability.

DTIC Science & Technology

1995-09-01

Wright-Patterson Air Force_Ejase, Ohio "DISTRIBUTION STATMENT A Appr°ved for P0^ relea80; Distribution unlimited Accesion For AFTT/GLM/LAL/95S-2...Two-Level Maintenance is one element in the LL architecture . Other elements that address the need for the reliable, high velocity transportation of...of these studies has changed to reflect the [Defense] Department’s increasing concern with readiness and sustainability . Their recommendations

Abstracts of AF Materials Laboratory Reports

DTIC Science & Technology

1975-09-01

NO: TITLE: AUTHOR(S): CONTRACT NO; CONTRACTOR: AFML-TR-73-307 200,397 IMPROVED AUTOMATED TAPE LAYING MACHINE M. Poullos, W. J. Murray, D.L...AUTOMATED IMPROVED AUTOMATED TAPE LAYING MACHINE AUTOMATION AUTOMATION OF COATING PROCESSES FOR GAS TURBINE DLADcS AND VANES 203222/111 203072...IMP90VE0 TAPE LAYING MACHINE IMPP)VED AUTOMATED TAPE LAYING MACHINE A STUDY O^ THE STRESS-STRAIN TEHAVIOR OF GRAPHITE

Systems to Detect Bacterial Contamination of Banked Blood in a Rapid, Non-Invasive Low Technology Manner. Phase 1.

DTIC Science & Technology

1994-08-25

Department of the Army position, policy or decision unless so designated by other documentation. 94-30800 IIV III !111 IiI I ’ I foron Appr •vedREPORT...copyrighted material is quoted, permission has been obtained to use such material. Where material from documents designated for limited distribution is...Laser Scanning Densitometry for quantitation of the color changes. (6) Narrative: a. Eperimental Methods: 1. Bacteria: Ten bacterial species

Exploration of resistive targets within shallow marine environments using the circular electrical dipole and the differential electrical dipole methods: a time-domain modelling study

NASA Astrophysics Data System (ADS)

Haroon, Amir; Mogilatov, Vladimir; Goldman, Mark; Bergers, Rainer; Tezkan, Bülent

2016-05-01

Two novel transient controlled source electromagnetic methods called circular electrical dipole (CED) and differential electrical dipole (DED) are theoretically analysed for applications in shallow marine environments. 1-D and 3-D time-domain modelling studies are used to investigate the detectability and applicability of the methods when investigating resistive layers/targets representing hydrocarbon-saturated formations. The results are compared to the conventional time-domain horizontal electrical dipole (HED) and vertical electrical dipole (VED) sources. The applied theoretical modelling studies demonstrate that CED and DED have higher signal detectability towards resistive targets compared to TD-CSEM, but demonstrate significantly poorer signal amplitudes. Future CED/DED applications will have to solve this issue prior to measuring. Furthermore, the two novel methods have very similar detectability characteristics towards 3-D resistive targets embedded in marine sediments as VED while being less susceptible towards non-verticality. Due to the complex transmitter design of CED/DED the systems are prone to geometrical errors. Modelling studies show that even small transmitter inaccuracies have strong effects on the signal characteristics of CED making an actual marine application difficult at the present time. In contrast, the DED signal is less affected by geometrical errors in comparison to CED and may therefore be more adequate for marine applications.

Assessment of Ganga river ecosystem at Haridwar, Uttarakhand, India with reference to water quality indices

NASA Astrophysics Data System (ADS)

Bhutiani, R.; Khanna, D. R.; Kulkarni, Dipali Bhaskar; Ruhela, Mukesh

2016-06-01

The river Ganges is regarded as one of the most holy and sacred rivers of the world from time immemorial. The evaluation of river water quality is a critical element in the assessment of water resources. The quality/potability of water that is consumed defines the base line of protection against many diseases and infections. The present study aimed to calculate Water Quality Index (WQI) by the analysis of sixteen physico-chemical parameters on the basis of River Ganga index of Ved Prakash, weighted arithmetic index and WQI by National sanitation foundation (NSF) to assess the suitability of water for drinking, irrigation purposes and other human uses. These three water quality indices have been used to assess variation in the quality of the River Ganga at monitored locations over an 11-year period. Application of three different indexes to assess the water quality over a period of 11 years shows minor variations in water quality. Index values as per River Ganga Index by Ved Prakash et al. from 2000 to 2010 ranged between medium to good, Index values as per NSF Index for years 2000-2010 indicate good water quality, while Index values as per the weighted arithmetic index method for the study period indicate poor water quality.

Renal amyloidosis: current views on pathogenesis and impact on diagnosis.

PubMed

Herrera, Guillermo A; Teng, Jiamin; Turbat-Herrera, Elba A

2011-01-01

The amyloidoses constitute a group of diseases in which misfolding of extracellular proteins plays a fundamental role. The aggregation of normally soluble proteins into insoluble unbranching fibrils is the basic underlying pathology in amyloidosis. The process of amyloid formation generates toxic insoluble (in saline) protein aggregates that are deposited in tissues in the form of β- pleated sheets of fibrillary material. The amyloidoses are considered to be part of the so-called protein storage diseases (protein thesauroses). In addition, due to the unusual protein folding associated with amyloid, this group of diseases has been referred to as conformational and protein folding disorders. For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in recent years its pathogenesis, particularly that of renal amyloidosis, has been carefully dissected in the research laboratory using in vitro and, to a lesser extent, in vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an 'inert' substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. Although there are more than two dozen recognized amyloid precursor proteins (and new ones being added to the list) that can be involved in the genesis of amyloid fibrils, the pathophysiologic mechanisms that occur in the renal mesangium are likely to be very similar, if not the same, regardless of the type of amyloidosis. Likewise, the same is true of amyloid formation in the renal vasculature. Mesangial cells are essentially smooth muscle cells and the events that take place in the mesangium and vasculature

A Program for Clinical Care in Physical Trauma.

DTIC Science & Technology

1981-03-01

effects obser- ved in intravenous feeding after injury;(2) The use of isotopes of nitrogen and hydrogen in substrate research in man;(3) The patho...Tactical Problems Addressed and Summary of Findings 1. Caloric Support for Protein Synthesis and Intravenous Feeding Findings: The addition of calorie...12, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24) 2. Peripheral versus Central Vein Infusion Sites for Intravenous Feeding in the Wounded, Starved, or

Development and Validation of Methods for Applying Pharmacokinetic Data in Risk Assessment. Volume 3. Tetrachloroethylene

DTIC Science & Technology

1990-12-01

Armstrong Aerospace Medical Research Laboratory, Wright Paterson Air Force Base, and Drs. Melvin Andersen and Michael Cargas , formerly with the Harry G...based on the arterial blood concentration surrogate were more III-1-10 similar to those de ’!ved in the traditional manner than were the estimates based on...pharmacokinetic modeling. Prepared by Office of Risk Analysis, Oak Ridge National L-ioratory, Oak Pidge, Tenn.zsee. Prepared under Contract No. DE -ACO5-84

Towards Tailored Interphase Formation Utilizing Surface-Active Benzylsulfonium Salts as Cationic Initiators

DTIC Science & Technology

1994-07-15

34,AR V3 APR edrtion may be ved until eha uv’ed. CURITY" Sf ’’ NO F G .. Towsrds Talared lnterphae F .- wmon qjdM to 0 Surfzce-Actlve BenzyWM*irn Sa, -l...min with nltrog, purge. Solution "C NMR were preformed on a Bruker AC-200 wle so state ’C CPMAS, A b f • and "Sl CPMAS were run on a Bnker \\4SL.-400

Comparison of vessel enhancement algorithms applied to time-of-flight MRA images for cerebrovascular segmentation.

PubMed

Phellan, Renzo; Forkert, Nils D

2017-11-01

Vessel enhancement algorithms are often used as a preprocessing step for vessel segmentation in medical images to improve the overall segmentation accuracy. Each algorithm uses different characteristics to enhance vessels, such that the most suitable algorithm may vary for different applications. This paper presents a comparative analysis of the accuracy gains in vessel segmentation generated by the use of nine vessel enhancement algorithms: Multiscale vesselness using the formulas described by Erdt (MSE), Frangi (MSF), and Sato (MSS), optimally oriented flux (OOF), ranking orientations responses path operator (RORPO), the regularized Perona-Malik approach (RPM), vessel enhanced diffusion (VED), hybrid diffusion with continuous switch (HDCS), and the white top hat algorithm (WTH). The filters were evaluated and compared based on time-of-flight MRA datasets and corresponding manual segmentations from 5 healthy subjects and 10 patients with an arteriovenous malformation. Additionally, five synthetic angiographic datasets with corresponding ground truth segmentation were generated with three different noise levels (low, medium, and high) and also used for comparison. The parameters for each algorithm and subsequent segmentation were optimized using leave-one-out cross evaluation. The Dice coefficient, Matthews correlation coefficient, area under the ROC curve, number of connected components, and true positives were used for comparison. The results of this study suggest that vessel enhancement algorithms do not always lead to more accurate segmentation results compared to segmenting nonenhanced images directly. Multiscale vesselness algorithms, such as MSE, MSF, and MSS proved to be robust to noise, while diffusion-based filters, such as RPM, VED, and HDCS ranked in the top of the list in scenarios with medium or no noise. Filters that assume tubular-shapes, such as MSE, MSF, MSS, OOF, RORPO, and VED show a decrease in accuracy when considering patients with an AVM

Extending color primary set in spectral vector error diffusion by multilevel halftoning

NASA Astrophysics Data System (ADS)

Norberg, Ole; Nyström, Daniel

2013-02-01

Ever since its origin in the late 19th century, a color reproduction technology has relied on a trichromatic color reproduction approach. This has been a very successful method and also fundamental for the development of color reproduction devices. Trichromatic color reproduction is sufficient to approximate the range of colors perceived by the human visual system. However, tricromatic systems only have the ability to match colors when the viewing illumination for the reproduction matches that of the original. Furthermore, the advancement of digital printing technology has introduced printing systems with additional color channels. These additional color channels are used to extend the tonal range capabilities in light and dark regions and to increase color gamut. By an alternative approach the addition color channels can also be used to reproduce the spectral information of the original color. A reproduced spectral match will always correspond to original independent of lighting situation. On the other hand, spectral color reproductions also introduce a more complex color processing by spectral color transfer functions and spectral gamut mapping algorithms. In that perspective, spectral vector error diffusion (sVED) look like a tempting approach with a simple workflow where the inverse color transfer function and halftoning is performed simultaneously in one single operation. Essential for the sVED method are the available color primaries, created by mixing process colors. Increased numbers of as well as optimal spectral characteristics of color primaries are expected to significantly improve the color accuracy of the spectral reproduction. In this study, sVED in combination with multilevel halftoning has been applied on a ten channel inkjet system. The print resolution has been reduced and the underlying physical high resolution of the printer has been used to mix additional primaries. With ten ink channels and halfton cells built-up by 2x2 micro dots where each

Long-Lived Digital Data Collections Enabling Research and Education in the 21st Century

DTIC Science & Technology

2005-09-01

Collections: Enabling Research and Education in the 21st Century40 LoNG-LiVED DiGiTAL DATA CoLLECTioNS AND LARGE FACiLiTiES Workshop participants drew...Long-Lived Digital Data Collections: Enabling Research and Education in the 21st Century NSB-05-40 Report Documentation Page Form...COVERED - 4. TITLE AND SUBTITLE Long-Lived Digital Data Collections Enabling Research and Education in the 21st Century 5a. CONTRACT NUMBER 5b

A Multidisciplinary Study of Ciguatoxin and Related Low Molecular Weight Toxins from Marine Source

DTIC Science & Technology

1986-08-01

viscera (liver and intestines) of guinea pigs, and the fruit of the avocado . Authentic ClX ws not available at the time the experiments outlined below...iully Treatmet of the tissues with attract~s from tilapiao, kale,. guines, pig viscera and avocado produced respnes slimilar to those ctain’ved with...all ultimately caused death. Avocado extract differad only in the anmumt necessary to procduce these effects, 80 - 100 ug/kg in two animals. Copy .c

Compendium of the ULF/ELF Electromagnetic Fields Generated above a Sea of Finite Depth by Submerged Harmonic Dipoles

DTIC Science & Technology

1980-01-01

CATALOG NUMBER Tech. Report No. E715-1 4. TTE (ln tlitts LTYPE RPOT’ QcOIJj. Compendium of the ULF/ELF Electromagnetic Fields nccnicat Generated above...sidi if noeess’ry arid Identify hy bulock mriifi.rnb) ULF/ELF Electromagnetic Fields VMD, VED, HED, HMD Submerged Dipoles Undersea /Air Communication...a whole, it appears that the vertical electric component produced by th HED in the plane of the dipole (• =0) should be the most useful for undersea

Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease.

PubMed

Laurine, Emmanuelle; Grégoire, Catherine; Fändrich, Marcus; Engemann, Sabine; Marchal, Stéphane; Thion, Laurent; Mohr, Michel; Monsarrat, Bernard; Michel, Bernard; Dobson, Christopher M; Wanker, Erich; Erard, Monique; Verdier, Jean-Michel

2003-12-19

Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6']bibenzothiazolyl-2,2'-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

Human-murine transthyretin heterotetramers are kinetically stable and non-amyloidogenic. A lesson in the generation of transgenic models of diseases involving oligomeric proteins.

PubMed

Reixach, Natàlia; Foss, Ted R; Santelli, Eugenio; Pascual, Jaime; Kelly, Jeffery W; Buxbaum, Joel N

2008-01-25

The transthyretin amyloidoses appear to be caused by rate-limiting tetramer dissociation and partial monomer unfolding of the human serum protein transthyretin, resulting in aggregation and extracellular deposition of amorphous aggregates and amyloid fibrils. Mice transgenic for few copies of amyloid-prone human transthyretin variants, including the aggressive L55P mutant, failed to develop deposits. Silencing the murine transthyretin gene in the presence of the L55P human gene resulted in enhanced tissue deposition. To test the hypothesis that the murine protein interacted with human transthyretin, preventing the dissociation and partial unfolding required for amyloidogenesis, we produced recombinant murine transthyretin and human/murine transthyretin heterotetramers and compared their structures and biophysical properties to recombinant human transthyretin. We found no significant differences between the crystal structures of murine and human homotetramers. Murine transthyretin is not amyloidogenic because the native homotetramer is kinetically stable under physiologic conditions and cannot dissociate into partially unfolded monomers, the misfolding and aggregation precursor. Heterotetramers composed of murine and human subunits are also kinetically stable. These observations explain the lack of transthyretin deposition in transgenics carrying a low copy number of human transthyretin genes. The incorporation of mouse subunits into tetramers otherwise composed of human amyloid-prone transthyretin subunits imposes kinetic stability, preventing dissociation and subsequent amyloidogenesis.

Design of Visco-Elastic Dampers for RC Frame for Site-Specific Earthquake

NASA Astrophysics Data System (ADS)

Kamatchi, P.; Rama Raju, K.; Ravisankar, K.; Iyer, Nagesh R.

2016-12-01

Number of Reinforced Concrete (RC) framed buildings have got damaged at Ahmedabad city, India located at about 240 km away from epicenter during January 2001, 7.6 moment magnitude (Mw) Bhuj earthquake. In the present study, two dimensional nonlinear time history dynamic analyses of a typical 13 storey frame assumed to be located at Ahmedabad is carried out with the rock level and surface level site-specific ground motion for scenario earthquake of Mw 7.6 from Bhuj. Artificial ground motions are generated using extended finite source stochastic model with seismological parameters reported in literature for 2001 Bhuj earthquake. Surface level ground motions are obtained for a typical soil profile of 100 m depth reported in literature through one dimensional equivalent linear wave propagation analyses. From the analyses, failure of frame is observed for surface level ground motions which indicates that, in addition to the in-adequacy of the cross sections and reinforcement of the RC members of the frame chosen, the rich energy content of the surface level ground motion near the fundamental time period of the frame has also contributed for the failure of frame. As a part of retrofitting measure, five Visco-elastic Dampers (VED) in chevron bracing are added to frame. For the frame considered in the present study, provision of VED is found to be effective to mitigate damage for the soil site considered.

Determinants of the development of mitral regurgitation in pacing-induced heart failure.

PubMed

Takagaki, Masami; McCarthy, Patrick M; Goormastic, Marlene; Ochiai, Yoshie; Doi, Kazuyoshi; Kopcak, Michael W; Tabata, Tomotsugu; Cardon, Lisa A; Thomas, James D; Fukamachi, Kiyotaka

2003-01-01

The pacing-induced heart failure model provides an opportunity to assess the structural and functional determinants of mitral regurgitation (MR) in dilated cardiomyopathy. This study aimed to evaluate MR to better understand the multitude of factors contributing to its development. Heart failure was induced by rapid ventricular pacing (230 beats/min) in 40 mongrel dogs. Left ventricular (LV) size and MR were evaluated echocardiographically. LV contractility was analyzed using a conductance catheter. MR increased to mild in 12 animals (regurgitant orifice area, 0.06+/-0.05 cm(2)), moderate in 15 (0.14+/-0.07 cm(2)), and severe in 13 (0.34+/-0.16 cm(2)). The grade of MR had an inverse relationships with E(max) (the slope of the end-systolic pressure-volume relationship, p<0.01) and dE/dt (the slope of the maximum rate of change of pressure-end-diastolic volume [V(ED)] relationship, p<0.01) and positive relationships with V(ED) and end-diastolic cross-sectional areas and lengths (p<0.05) by univariate analysis. The dE/dt had an independently significant (p<0.01) relationship by multivariable logistic regression. Many factors influence the development of MR and because of its similarity to the clinical situation, this model can be used to investigate MR and heart failure, as well as new surgical therapies.

Administration and Stenographic Career Ladders, AFS 702x0/A/B/C and 702X1.

DTIC Science & Technology

1980-04-01

MEN mIIIIIIIII hhhllllhlhhl UNITED STATES AIR FORCE _Si -j𔃽.- 0 ADMINISTRATION AND5$TENOGRAPHIC -CAREER LADDERS AIS 702XO/ A /B/C AND 702X1 -J AFPT- 9...7J2-389 ( ,/ " ’ _ LA. -IAPRI 180 This document has n a :’.-pro+ved1 + ,for pil s’ s ;i - , OqCUPATIONAL ANALYSIS PROGRAM USAF OCCUPATIONAL...79 APPENDIX A O--------------------------------------------- 80 Acc22~C~For 1 -* ii L PREFACE This report presents the results of a detailed Air

Controlled Growth of Parallel Oriented ZnO Nanostructural Arrays on Ga2O3 Nanowires

DTIC Science & Technology

2008-11-01

Controlled Growth of Parallel Oriented ZnO Nanostructural Arrays on Ga2O3 Nanowires Lena Mazeina,* Yoosuf N. Picard, and Sharka M. Prokes Electronics...Manuscript ReceiVed NoVember 6, 2008 ABSTRACT: Novel hierarchical ZnO- Ga2O3 nanostructures were fabricated via a two stage growth process. Nanowires of Ga2O3 ...nanobrushes (NBs) with Ga2O3 as the core and ZnO as the branches self-assembling symmetrically in six equiangular directions around the core

Operational Test Director Guide. Change 4.

DTIC Science & Technology

1982-09-20

usable by the people invol - ved; the testers, the data collectors, and the evaluators. Sample formats are available to the OTD in (Change 1) 10-4 4 a...to & educe the e6jeetA o the timiting 6aetoxA. FoL exampte, "Avai- * abte ta/getA do not tepiteaent iteaLL~tic thkeatA. Howevek, 3-3 CLASSIFICATION...related test equipment and special tools. (e) (*) Completed NAVSUP Form 1250, with part number and APL number (or nomenclature of parent equipment), for

Visual Electricity Demonstrator

NASA Astrophysics Data System (ADS)

Lincoln, James

2017-09-01

The Visual Electricity Demonstrator (VED) is a linear diode array that serves as a dynamic alternative to an ammeter. A string of 48 red light-emitting diodes (LEDs) blink one after another to create the illusion of a moving current. Having the current represented visually builds an intuitive and qualitative understanding about what is happening in a circuit. In this article, I describe several activities for this device and explain how using this technology in the classroom can enhance the understanding and appreciation of physics.

Hybrid model analysis of intra-aortic balloon pump performance as a function of ventricular and circulatory parameters.

PubMed

Ferrari, Gianfranco; Khir, Ashraf W; Fresiello, Libera; Di Molfetta, Arianna; Kozarski, Maciej

2011-09-01

We investigated the effects of the intra-aortic balloon pump (IABP) on endocardial viability ratio (EVR), cardiac output (CO), end-systolic (V(es)) and end-diastolic (V(ed)) ventricular volumes, total coronary blood flow (TCBF), and ventricular energetics (external work [EW], pressure-volume area [PVA]) under different ventricular (E(max) and diastolic stiffness) and circulatory (arterial compliance) parameters. We derived a hybrid model from a computational model, which is based on merging computational and hydraulic submodels. The lumped parameter computational submodel consists of left and right hearts and systemic, pulmonary, and coronary circulations. The hydraulic submodel includes part of the systemic arterial circulation, essentially a silicone rubber tube representing the aorta, which contains a 40-mL IAB. EVR, CO, V(es), and V(ed), TCBF and ventricular energetics (EW, PVA) were analyzed against the ranges of left ventricular E(max) (0.3-0.5-1 mm Hg/cm(3)) and diastolic stiffness V(stiffness) (≈0.08 and ≈0.3 mm Hg/cm(3), obtained by changing diastolic stiffness constant) and systemic arterial compliance (1.8-2.5 cm(3)/mm Hg). All experiments were performed comparing the selected variables before and during IABP assistance. Increasing E(maxl) from 0.5 to 2 mm Hg/cm(3) resulted in IABP assistance producing lower percentage changes in the selected variables. The changes in ventricular diastolic stiffness strongly influence both absolute value of EVR and its variations during IABP (71 and 65% for lower and higher arterial compliance, respectively). V(ed) and V(es) changes are rather small but higher for lower E(max) and higher V(stiffness). Lower E(max) and higher V(stiffness) resulted in higher TCBF and CO during IABP assistance (∼35 and 10%, respectively). The use of this hybrid model allows for testing real devices in realistic, stable, and repeatable circulatory conditions. Specifically, the presented results show that IABP performance is dependent

Optical properties of soot particles: measurement - model comparison

NASA Astrophysics Data System (ADS)

Forestieri, S.; Lambe, A. T.; Lack, D.; Massoli, P.; Cross, E. S.; Dubey, M.; Mazzoleni, C.; Olfert, J.; Freedman, A.; Davidovits, P.; Onasch, T. B.; Cappa, C. D.

2013-12-01

Soot, a product of incomplete combustion, plays an important role in the earth's climate system through the absorption and scattering of solar radiation. In order to accurately model the direct radiative impact of black carbon (BC), the refractive index and shape dependent scattering and absorption characteristics must be known. At present, the assumed shape remains highly uncertain because BC particles are fractal-like, being agglomerates of smaller (20-40 nm) spherules, yet traditional optical models such as Mie theory typically assume a spherical particle morphology. To investigate the ability of various optical models to reproduce observed BC optical properties, we measured light absorption and extinction coefficients of methane and ethylene flame soot particles. Optical properties were measured by multiple instruments: absorption by a dual cavity ringdown photoacoustic spectrometer (CRD-PAS), absorption and scattering by a 3-wavelength photoacoustic/nephelometer spectrometer (PASS-3) and extinction and scattering by a cavity attenuated phase shift spectrometer (CAPS). Soot particle mass was quantified using a centrifugal particle mass analyzer (CPMA) and mobility size was measured with a scanning mobility particle sizer (SMPS). Measurements were made for nascent soot particles and for collapsed soot particles following coating with dioctyl sebacate or sulfuric acid and thermal denuding to remove the coating. Wavelength-dependent refractive indices for the sampled particles were derived by fitting the observed absorption and extinction cross-sections to spherical particle Mie theory and Rayleigh-Debye-Gans theory. The Rayleigh-Debye-Gans approximation assumes that the absorption properties of soot are dictated by the individual spherules and neglects interaction between them. In general, Mie theory reproduces the observed absorption and extinction cross-sections for particles with volume equivalent diameters (VED) < ~160 nm, but systematically predicts lower

Medical Store Management: An Integrated Economic Analysis of a Tertiary Care Hospital in Central India

PubMed Central

Mahatme, MS; Dakhale, GN; Hiware, SK; Shinde, AT; Salve, AM

2012-01-01

Economic analysis plays a pivotal role in the management of medical store. The main objectives of this study were to consider always better control-vital, essential and desirable (ABC-VED) analysis with economic order quantity (EOQ), comparison of indexed cost and the actual cost, and to assess the expenditure for the forthcoming years. Based on cost and criticality, a matrix of nine groups by combining ABC and VED analysis was formulated. Drug categories were narrowed down for prioritization to direct supervisory monitoring. The subgroups AE and AV of the categories category I and II should be ordered based on EOQ. The difference between the actual annual drug expenditure (ADE) and the derived indexed cost using the cost inflation index (CII) was calculated. Linear regression was used to assess the expenditure for the forth coming years. The total ADE for the financial year of 2010–2011 was Rs. 1,91,44,253 which was only 7.68% of annual hospital expenditure. Using the inflation index, the indexed cost of acquisition of ADE for year 2010–2011 was Rs. 1,95,10,387. The difference between the two was estimated to be 2.11%. Thus, the CII justifies the demand of increased budget for next year and prompts us for cautious use of drugs. By taking into consideration the ADE of last 10 years, we have forecasted the budget for forthcoming years which will help significantly for making policies according to the available budget. PMID:22754264

Medical store management: an integrated economic analysis of a tertiary care hospital in central India.

PubMed

Mahatme, Ms; Dakhale, Gn; Hiware, Sk; Shinde, At; Salve, Am

2012-04-01

Economic analysis plays a pivotal role in the management of medical store. The main objectives of this study were to consider always better control-vital, essential and desirable (ABC-VED) analysis with economic order quantity (EOQ), comparison of indexed cost and the actual cost, and to assess the expenditure for the forthcoming years. Based on cost and criticality, a matrix of nine groups by combining ABC and VED analysis was formulated. Drug categories were narrowed down for prioritization to direct supervisory monitoring. The subgroups AE and AV of the categories category I and II should be ordered based on EOQ. The difference between the actual annual drug expenditure (ADE) and the derived indexed cost using the cost inflation index (CII) was calculated. Linear regression was used to assess the expenditure for the forth coming years. The total ADE for the financial year of 2010-2011 was Rs. 1,91,44,253 which was only 7.68% of annual hospital expenditure. Using the inflation index, the indexed cost of acquisition of ADE for year 2010-2011 was Rs. 1,95,10,387. The difference between the two was estimated to be 2.11%. Thus, the CII justifies the demand of increased budget for next year and prompts us for cautious use of drugs. By taking into consideration the ADE of last 10 years, we have forecasted the budget for forthcoming years which will help significantly for making policies according to the available budget.

Women, Peace And Security: A Diverse Future In The USAF Is A Better Future

DTIC Science & Technology

2016-02-16

development of recruiting, such as to ensure millennials consider military service a viable option. The third recommendation suggests the development...strong leaders have knowledge of history, politics, cultures, religion , economics, and much more. But key to this mix of “smarts” is a drive for...continues+to+decline &source=bl&ots=bF5rXk2Lrh&sig=-GYN4htwJqzA1ac6C23cLFfB-- Y &hl=en&sa=X&ved=0ahUKEwjexaz7zfXKAhXMKyYKHXSTBfYQ6AEIIDAB#v=onepage&q

Hazardous Materials Management System. A Guide for Local Emergency Managers.

DTIC Science & Technology

1981-07-01

UDE OIL OCA EM~GENY ~A~iGRS𔄀. PERFORMING ORG. REPORT NUMBER F O . . . S . C O N T R A T l C R .Y N U BE R ) (i MYRAJ/LEE a&PENELOPE G./ROE *OCP41-79...out of, through, and within the area. Estimate the frequencies of shipments and the types and quanti ti es of ma teri al s i nvol ved. F (NOTE: Rer...reactions 4. Double- replacement reactions S . Oxidation- reduction reactions - Page 44 - B. Rate of Chemical Reactions I. Nature of material 2. Subdivision of

Flying Qualities of Relaxed Static Stability Aircraft. Volume 2. Ramifications of Flight-Essential/Critical Heavily-Augmented Airplane Characteristics on Flying Qualities

DTIC Science & Technology

1982-09-01

root variation am is perwltte4 to becout sort uaatlvs ( eeg ., cog. Wereeeixuly w~ved further fotowrd of the neutral potat). % w~a e t-period dh~a~a fs Cc...deg-sec) unit impulse. For sueh an input the pit~ch att.It~ tdc responses in !A’gure 11 appear with the same response shapes as those deacribed...this pair approaches the clewaical tm -degree-of-froedo. phugoid mode dwereint Z’ V/gZuAT &rglo I n this classic phugoid (Ref erence 22) the angle of

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

Wall, Jonathan; Martin, Emily B.; Richey, Tina

Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We havemore » exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique for prognostication, patient stratification, and monitoring response to therapy.« less

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade.

PubMed

Chiti, Fabrizio; Dobson, Christopher M

2017-06-20

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

New and Evolving Concepts Regarding the Prognosis and Treatment of Cardiac Amyloidosis.

PubMed

Perlini, Stefano; Mussinelli, Roberta; Salinaro, Francesco

2016-12-01

Systemic amyloidoses are rare and proteiform diseases, caused by extracellular accumulation of insoluble misfolded fibrillar proteins. Prognosis is dictated by cardiac involvement, which is especially frequent in light chain (AL) and in transthyretin variants (ATTR, both mutated, (ATTRm), and wild-type, (ATTRwt)). Recently, ATTRwt has emerged as a potentially relevant cause of a heart failure with preserved ejection fraction (HFpEF). Cardiac amyloidosis is an archetypal example of restrictive cardiomyopathy, with signs and symptoms of global heart failure and diastolic dysfunction. Independent of the aetiology, cardiac amyloidosis is associated with left ventricular concentric "hypertrophy" (i.e. increased wall thickness), preserved (or mildly depressed) ejection fraction, reduced midwall fractional shortening and global longitudinal function, as well as evident diastolic dysfunction, up to an overly restrictive pattern of the left ventricular filling. Cardiac biomarkers such as troponins and natriuretic peptides are very robust and widely accepted diagnostic as well as prognostic tools. Owing to its dismal prognosis, accurate and early diagnosis is mandatory and potentially life-saving. Although pathogenesis is still not completely understood, direct cardiomyocyte toxicity of the amyloidogenic precursor proteins and/or oligomer aggregates adds on tissue architecture disruption caused by amyloid deposition. The clarification of mechanisms of cardiac damage is offering new potential therapeutic targets, and several treatment options with a relevant impact on prognosis are now available.

Insulin amyloid structures and their influence on neural cells.

PubMed

Bystrenova, Eva; Bednarikova, Zuzana; Barbalinardo, Marianna; Valle, Francesco; Gazova, Zuzana; Biscarini, Fabio

2018-01-01

Peptide aggregation into oligomers and fibrillar architectures is a hallmark of severe neurodegenerative pathologies, diabetes mellitus or systemic amyloidoses. The polymorphism of amyloid forms and their distribution are both effectors that potentially modulate the disease, thus it is important to understand the molecular basis of protein amyloid disorders through the interaction of the different amyloid forms with neural cells and tissues. Here we explore the effect of amyloid fibrils on the human neuroblastoma (SH-SY5Y) cell line in vitro. We control the kinetic of fibrillization of insulin at low pH and higher temperature. We use a multiscale characterization via fluorescence microscopy and multimodal scanning probe microscopy to correlate the number of cells and their morphology, with the finer details of the insulin deposits. Our results show that insulin aggregates deposited on neuroblastoma cell cultures lead to a progressive modification and decreased number of cells that correlates with the degree of fibrillization. SPM unravels that the aggregates strongly interact with the cell membrane, forming a stiff encase that possibly leads to an increased cell membrane stiffness and deficit in the metabolic exchanges between the cells and their environment. The presence of fibrils does not affect the number of cells at 24h whereas drop down to 60% is observed after 48h of incubation. Copyright © 2017 Elsevier B.V. All rights reserved.

Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure.

PubMed

Yang, Mu; Liu, Yingye; Dai, Jian; Li, Lin; Ding, Xin; Xu, Zhe; Mori, Masayuki; Miyahara, Hiroki; Sawashita, Jinko; Higuchi, Keiichi

2018-04-04

During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2 -/- ) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2 -/- mice compared with wild type (WT) mice. During APR, Apoa2 -/- mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2 -/- mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2 -/- mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2 -/- mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2 -/- mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles.

Proteins with neomorphic moonlighting functions in disease.

PubMed

Jeffery, Constance J

2011-07-01

One gene can encode multiple protein functions because of RNA splice variants, gene fusions during evolution, promiscuous enzyme activities, and moonlighting protein functions. In addition to these types of multifunctional proteins, in which both functions are considered "normal" functions of a protein, some proteins have been described in which a mutation or conformational change imparts a second function on a protein that is not a "normal" function of the protein. We propose to call these new functions "neomorphic moonlighting functions". The most common examples of neomorphic moonlighting functions are due to conformational changes that impart novel protein-protein interactions resulting in the formation of protein aggregates in Alzheimers, Parkinsons disease, and the systemic amyloidoses. Other changes that can result in a neomorphic moonlighting function include a mutation in SMAD4 that causes the protein to bind to new promoters and thereby alter gene transcription patterns, mutations in two isocitrate dehydrogenase isoforms that impart a new catalytic activity, and mutations in dihydrolipoamide dehydrogenase that activate a hidden protease activity. These neomorphic moonlighting functions were identified because of their connection to disease. In the cases described herein, the new functions cause cancers or severe neurological impairment, although in most cases the mechanism by which the new function leads to disease is unknown. Copyright © 2011 Wiley Periodicals, Inc.

Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis

DOE PAGES

Wall, Jonathan; Martin, Emily B.; Richey, Tina; ...

2015-04-27

Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We havemore » exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique for prognostication, patient stratification, and monitoring response to therapy.« less

A comparative study on the aggregating effects of guanidine thiocyanate, guanidine hydrochloride and urea on lysozyme aggregation

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

Emadi, Saeed, E-mail: emadi@iasbs.ac.ir; Behzadi, Maliheh

Highlights: • Lysozyme aggregated in guanidine thiocyanate (1.0 and 2.0 M). • Lysozyme aggregated in guanidine hydrochloride (4 and 5 M). • Lysozyme did not aggregated at any concentration (0.5–5 M) of urea. • Unfolding pathway is more important than unfolding per se in aggregation. - Abstract: Protein aggregation and its subsequent deposition in different tissues culminate in a diverse range of diseases collectively known as amyloidoses. Aggregation of hen or human lysozyme depends on certain conditions, namely acidic pH or the presence of additives. In the present study, the effects on the aggregation of hen egg-white lysozyme via incubationmore » in concentrated solutions of three different chaotropic agents namely guanidine thiocyanate, guanidine hydrochloride and urea were investigated. Here we used three different methods for the detection of the aggregates, thioflavin T fluorescence, circular dichroism spectroscopy and atomic force microscopy. Our results showed that upon incubation with different concentrations (0.5, 1.0, 2.0, 3.0, 4.0, 5.0 M) of the chemical denaturants, lysozyme was aggregated at low concentrations of guanidine thiocyanate (1.0 and 2.0 M) and at high concentrations of guanidine hydrochloride (4 and 5 M), although no fibril formation was detected. In the case of urea, no aggregation was observed at any concentration.« less

Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics

PubMed Central

Paul, Ashim; Kalita, Sourav; Kalita, Sujan; Sukumar, Piruthivi; Mandal, Bhubaneswar

2017-01-01

Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis. PMID:28054630

Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics

NASA Astrophysics Data System (ADS)

Paul, Ashim; Kalita, Sourav; Kalita, Sujan; Sukumar, Piruthivi; Mandal, Bhubaneswar

2017-01-01

Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted β, γ and δ -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized α/β, α/γ and α/δ hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of α/β and α/γ BSBHps, but not of α/δ analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis.

Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways.

PubMed

Gharibyan, Anna L; Zamotin, Vladimir; Yanamandra, Kiran; Moskaleva, Olesya S; Margulis, Boris A; Kostanyan, Irina A; Morozova-Roche, Ludmilla A

2007-02-02

Among the newly discovered amyloid properties, its cytotoxicity plays a key role. Lysozyme is a ubiquitous protein involved in systemic amyloidoses in vivo and forming amyloid under destabilising conditions in vitro. We characterized both oligomers and fibrils of hen lysozyme by atomic force microscopy and demonstrated their dose (5-50 microM) and time-dependent (6-48 h) effect on neuroblastoma SH-SY5Y cell viability. We revealed that fibrils induce a decrease of cell viability after 6 h due to membrane damage shown by inhibition of WST-1 reduction, early lactate dehydrogenase release, and propidium iodide intake; by contrast, oligomers activate caspases after 6 h but cause the cell viability to decline only after 48 h, as shown by fluorescent-labelled annexin V binding to externalized phosphatidylserine, propidium iodide DNA staining, lactate dehydrogenase release, and by typical apoptotic shrinking of cells. We conclude that oligomers induce apoptosis-like cell death, while the fibrils lead to necrosis-like death. As polymorphism is a common property of an amyloid, we demonstrated that it is not a single uniform species but rather a continuum of cross-beta-sheet-containing amyloids that are cytotoxic. An abundance of lysozyme highlights a universal feature of this phenomenon, indicating that amyloid toxicity should be assessed in all clinical applications involving proteinaceous materials.

A Model for the Management of Technical Risk in New Technology Development Programs

DTIC Science & Technology

1989-09-01

Heppenheimer , T. A . "Requiem for a Heavy-weight," Air and Snace/Smithsonian, 4: 50-55-- June/July 1989). 91. Jane’s Information Group, Inc. Jane’s...8217-- A MODEL FOR THE MANAGEMENT OF TECHNICAL RISK IN NEW TECHNOLOGY DEVELOPMENT PROGRAMS THESIS Peter B. King Captain, USA~F A FIT /G SM /L SR /89...S-22 1 DISI~1UT0N TAEMEN𔃻 A , S’o11 _44110h, eea;EL ECTE EApproVed 0 ulcrl~;DC2 0 1989 Dis-,irbuticf Unlimited D DEPARTMENT OF THE AIR FORCE-- - AIR

Characterization of CTLA-4 Structure and Expression on Human T Cells

DTIC Science & Technology

1993-10-01

prevents induction of anergy in T-cell plastic B cells. J. Immunol. 143:2714. clones. Nature 356:607. 7. Selvakumar , A., B. K. Mohanraj, R . L. Eddy, T... r ~n~~1 Form Approved ,, "൘ rmi OCUMENTATION PAGE orm Ap.r•ved Onorraoe is estimated Ic Ae.C.. I e 1C.;W fp$ei . ý’~t.cr.cenq Ile Urn* fo 1’ e...associated antigen," CTLA-4 (13). The genes for the geninterestid to the r 5 iacids o both human and mouse CI’IA-4 share a similar exon and J3

Continued Development and Implementation of the Universal Network Interface Device (UNID) II in the Digital Engineering Laboratory Network (DELNET). Volume 2.

DTIC Science & Technology

1984-12-01

PACKET LO-ATED IN TABLE LCNTTB. INPUT < THE INDUT IS A TWO CHARACTER ASCII VALUE INDICATING THE TABLE REQUIRING EVALUATION . > PROCESSING THIS PROCEDURE...INTO OHANYE A (2). I NPUT THE INPUT IS AN INTEGER VA UE INDICATING’ THE TAlN’LE LOCATI’ OF THE FRAmE TO BE EVALUATED . PROC--SSING THIS PROCEDURE LOU-S AT...GOOD AEXICdLFCL ~N IS NuT rC:L I VED LY THE END OF THE WAIT PER ICOH, I r I S fx>Sit-..) ACAI N UPION IriL NE.XT CflLL THRJOH THIS IRROCEDURE. A [ RAMC OF

Immunoglobulin light chains, glycosaminoglycans and amyloid.

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

Stevens, F. J.; Kisilevsky, R.; Biosciences Division

2000-03-01

Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as g2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the g peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normalmore » protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue o shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans.« less

Distinct Annular Oligomers Captured along the Assembly and Disassembly Pathways of Transthyretin Amyloid Protofibrils

PubMed Central

Pires, Ricardo H.; Karsai, Árpád; Saraiva, Maria J.; Damas, Ana M.; Kellermayer, Miklós S. Z.

2012-01-01

Background Defects in protein folding may lead to severe degenerative diseases characterized by the appearance of amyloid fibril deposits. Cytotoxicity in amyloidoses has been linked to poration of the cell membrane that may involve interactions with amyloid intermediates of annular shape. Although annular oligomers have been detected in many amyloidogenic systems, their universality, function and molecular mechanisms of appearance are debated. Methodology/Principal Findings We investigated with high-resolution in situ atomic force microscopy the assembly and disassembly of transthyretin (TTR) amyloid protofibrils formed of the native protein by pH shift. Annular oligomers were the first morphologically distinct intermediates observed in the TTR aggregation pathway. Morphological analysis suggests that they can assemble into a double-stack of octameric rings with a 16±2 nm diameter, and displaying the tendency to form linear structures. According to light scattering data coupled to AFM imaging, annular oligomers appeared to undergo a collapse type of structural transition into spheroid oligomers containing 8–16 monomers. Disassembly of TTR amyloid protofibrils also resulted in the rapid appearance of annular oligomers but with a morphology quite distinct from that observed in the assembly pathway. Conclusions/Significance Our observations indicate that annular oligomers are key dynamic intermediates not only in the assembly but also in the disassembly of TTR protofibrils. The balance between annular and more compact forms of aggregation could be relevant for cytotoxicity in amyloidogenic disorders. PMID:22984597

Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin.

PubMed

Teixeira, Cristina A; Almeida, Maria do Rosário; Saraiva, Maria João

2016-09-01

Transthyretin (TTR)-related amyloidoses are diseases characterized by extracellular deposition of amyloid fibrils and aggregates in tissues composed of insoluble misfolded TTR that becomes toxic. Previous studies have demonstrated the ability of small compounds in preventing and reversing TTR V30M deposition in transgenic mice gastrointestinal (GI) tract as well as lowering biomarkers associated with cellular stress and apoptotic mechanisms. In the present study we aimed to study TTR V30M aggregates effect in autophagy, a cellular mechanism crucial for cell survival that has been implicated in the development of several neurodegenerative diseases. We were able to demonstrate in cell culture that TTR V30M aggregates cause a partial impairment of the autophagic machinery as shown by p62 accumulation, whereas early steps of the autophagic flux remain unaffected as shown by autophagosome number evaluation and LC3 turnover assay. Our studies performed in TTR V30M transgenic animals demonstrated that tauroursodeoxycholic acid (TUDCA) and curcumin effectively reverse p62 accumulation in the GI tract pointing to the ability of both compounds to modulate autophagy additionally to mitigate apoptosis. Overall, our in vitro and in vivo studies establish an association between TTR V30M aggregates and autophagy impairment and suggest the use of autophagy modulators as an additional and alternative therapeutic approach for the treatment of TTR V30M-related amyloidosis. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

PubMed Central

Frank, Michael; Albuisson, Juliette; Ranque, Brigitte; Golmard, Lisa; Mazzella, Jean-Michael; Bal-Theoleyre, Laurence; Fauret, Anne-Laure; Mirault, Tristan; Denarié, Nicolas; Mousseaux, Elie; Boutouyrie, Pierre; Fiessinger, Jean-Noël; Emmerich, Joseph; Messas, Emmanuel; Jeunemaitre, Xavier

2015-01-01

Vascular Ehlers–Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions–deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions–deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22–39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3–5, with extreme median ages at first major complication of 23–47 years. Patients of groups 3–5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care. PMID:25758994

Axisymmetric charge-conservative electromagnetic particle simulation algorithm on unstructured grids: Application to microwave vacuum electronic devices

NASA Astrophysics Data System (ADS)

Na, Dong-Yeop; Omelchenko, Yuri A.; Moon, Haksu; Borges, Ben-Hur V.; Teixeira, Fernando L.

2017-10-01

We present a charge-conservative electromagnetic particle-in-cell (EM-PIC) algorithm optimized for the analysis of vacuum electronic devices (VEDs) with cylindrical symmetry (axisymmetry). We exploit the axisymmetry present in the device geometry, fields, and sources to reduce the dimensionality of the problem from 3D to 2D. Further, we employ 'transformation optics' principles to map the original problem in polar coordinates with metric tensor diag (1 ,ρ2 , 1) to an equivalent problem on a Cartesian metric tensor diag (1 , 1 , 1) with an effective (artificial) inhomogeneous medium introduced. The resulting problem in the meridian (ρz) plane is discretized using an unstructured 2D mesh considering TEϕ-polarized fields. Electromagnetic field and source (node-based charges and edge-based currents) variables are expressed as differential forms of various degrees, and discretized using Whitney forms. Using leapfrog time integration, we obtain a mixed E - B finite-element time-domain scheme for the full-discrete Maxwell's equations. We achieve a local and explicit time update for the field equations by employing the sparse approximate inverse (SPAI) algorithm. Interpolating field values to particles' positions for solving Newton-Lorentz equations of motion is also done via Whitney forms. Particles are advanced using the Boris algorithm with relativistic correction. A recently introduced charge-conserving scatter scheme tailored for 2D unstructured grids is used in the scatter step. The algorithm is validated considering cylindrical cavity and space-charge-limited cylindrical diode problems. We use the algorithm to investigate the physical performance of VEDs designed to harness particle bunching effects arising from the coherent (resonance) Cerenkov electron beam interactions within micro-machined slow wave structures.

[The relevance of multiple sclerosis drugs in private health insurance (PHI)].

PubMed

Wild, F

2015-06-01

The development of expenses and prescriptions in the pharmacotherapy for multiple sclerosis (MS) is examined on the basis of prescription data of 14 PHI firms. The drugs for the treatment of MS are among the most top-selling drugs in the PHI. From 2007 to 2012, the expenses increase 2.33-fold. The main cause is the increas of the prescription figures. In 2012, about 8,400 privately insured persons receive an MS drug. The prevalence of MS is 2.3 times higher in women than in men Impro ved diagnostic possibilities and expensive new drugs will lead to a dynamic cost de velopment in the next years.

Influence of Angiotensin-Converting-Enzyme Gene Polymorphism on Echocardiographic Data of Patients with Ischemic Heart Failure.

PubMed

Duque, Gustavo Salgado; Silva, Dayse Aparecida da; Albuquerque, Felipe Neves de; Schneider, Roberta Siuffo; Gimenez, Alinne; Pozzan, Roberto; Rocha, Ricardo Mourilhe; Albuquerque, Denilson Campos de

2016-11-01

pacientes com IC de etiologia isquêmica de uma população do Rio de Janeiro e sua associação com achados ecocardiográficos. Avaliação genética do polimorfismo I/D da ECA associada a análise de dados clínicos, laboratoriais e ecocardiográficos de 99 pacientes. Foram encontrados 53 alelos I, 145 alelos D, quanto aos genótipos da ECA: 49,5% DD, 47,48% DI, 3,02% II. O tratamento medicamentoso foi otimizado com 98% usando betabloqueadores e 84,8%, IECA ou bloqueador do receptor de angiotensina. Achados ecocardiográficos: diferença entre os diâmetros diastólicos do ventrículo esquerdo (ΔVED): 2,98±8,94 (DD) vs. 0,68±8,12 (DI) vs. -11,0±7,00 (II), p=0,018; piora evolutiva do diâmetro sistólico do VE (VES): 65,3 % DD vs. 19,0 % DI vs. 0,0 % II, p=0,01; do diâmetro diastólico do VE (VED): 65,3 % DD vs. 46,8 % DI vs. 0,0 % II, p=0,03; e da fração de ejeção do VE (FEVE): 67,3 % DD vs. 40,4 % DI vs. 33,3 % II, p=0,024. Correlação com alelo D: ΔFEVE, ΔVES, ΔVED. Foram identificados mais pacientes com piora evolutiva da FEVE e dos diâmetros cavitários do VE no genótipo DD, seguido do DI, sendo o II o de melhor evolução. O mesmo padrão foi observado na ΔVED.

NASA Tech Helps Better Understand Our Home Planet

NASA Image and Video Library

2018-04-20

NASA’s Earth observations are critical for understanding our home planet and how it is changing. For Earth Day NASA is spotlighting some of the agency’s work with the latest technologies that have the potential to transform how we see our Blue Marble. Join us as we speak with NASA Ames scientist Ved Chirayath, who has developed cameras that can image marine environments below the ocean’s surface; Shayna Skolnik, founder and CEO of Navteca, a company that’s working to bring NASA Earth data to life through virtual reality; and Brian Campbell, senior education and outreach specialist for ICESat-2 satellite, which is set to launch this fall to measure polar ice and other important Earth features.

The natural and social-economic resourses of the Republic of Komi

NASA Astrophysics Data System (ADS)

Fridman, Anton; Yakovleva, Maya; Kuchkina, Ekaterina; Lyaskovskiy, Sergey; Ievlev, Nikolay

2013-04-01

North-West of Russian Federation, include 11 subjects of Russian Federation. One of the most interesting regions is republic of Komi.. The native population of North - korely, rusichi, komi, ved', permyaki and other peoples are living here. Main characteristics of region are pollution-free territory, low population concentration, material wealth and huge forest and water resources. Flora and fauna are also interesting. Successful fishing and hunting are possible because of great variety of animals and fish. There are 240 protected natural areas in Republic of Komi (information on the 1st January 2010). All these features let organize scientific expeditions, tourists' routes helping to know unique nature and ethnical culture of North.

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

PubMed Central

Shin, Thuzar M; Isas, J Mario; Hsieh, Chia-Ling; Kayed, Rakez; Glabe, Charles G; Langen, Ralf; Chen, Jeannie

2008-01-01

Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE) cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases. PMID:18939994

Transbronchial biopsies safely diagnose amyloid lung disease

PubMed Central

Govender, Praveen; Keyes, Colleen M.; Hankinson, Elizabeth A.; O’Hara, Carl J.; Sanchorawala, Vaishali; Berk, John L.

2018-01-01

Background Autopsy identifies lung involvement in 58–92% of patients with the most prevalent forms of systemic amyloidoses. In the absence of lung biopsies, amyloid lung disease often goes unrecognized. Report of a death following transbronchial biopsies in a patient with systemic amyloidosis cautioned against the procedure in this patient cohort. We reviewed our experience with transbronchial biopsies in patients with amyloidosis to determine the safety and utility of bronchoscopic lung biopsies. Methods We identified patients referred to the Amyloidosis Center at Boston Medical Center with lung amyloidosis diagnosed by transbronchial lung biopsies (TBBX). Amyloid typing was determined by immunohistochemistry or mass spectrometry. Standard end organ assessments, including pulmonary function test (PFT) and chest tomography (CT) imaging, and extra-thoracic biopsies established the extent of disease. Results Twenty-five (21.7%) of 115 patients with lung amyloidosis were diagnosed by TBBX. PFT classified 33.3% with restrictive physiology, 28.6% with obstructive disease, and 9.5% mixed physiology; 9.5% exhibited isolated diffusion defects while 19% had normal pulmonary testing. Two view chest or CT imaging identified focal opacities in 52% of cases and diffuse interstitial disease in 48%. Amyloid type and disease extent included 68% systemic AL disease, 16% localized (lung limited) AL disease, 12% ATTR disease, and 4% AA amyloidosis. Fluoroscopy was not used during biopsy. No procedure complications were reported. Conclusions Our case series of 25 patients supports the use of bronchoscopic transbronchial biopsies for diagnosis of parenchymal lung amyloidosis. Normal PFTs do not rule out the histologic presence of amyloid lung disease. PMID:28393574

Quantification of Transthyretin Kinetic Stability in Human Plasma Using Subunit Exchange

PubMed Central

2015-01-01

The transthyretin (TTR) amyloidoses are a group of degenerative diseases caused by TTR aggregation, requiring rate-limiting tetramer dissociation. Kinetic stabilization of TTR, by preferential binding of a drug to the native tetramer over the dissociative transition state, dramatically slows the progression of familial amyloid polyneuropathy. An established method for quantifying the kinetic stability of recombinant TTR tetramers in buffer is subunit exchange, in which tagged TTR homotetramers are added to untagged homotetramers at equal concentrations to measure the rate at which the subunits exchange. Herein, we report a subunit exchange method for quantifying the kinetic stability of endogenous TTR in human plasma. The subunit exchange reaction is initiated by the addition of a substoichiometric quantity of FLAG-tagged TTR homotetramers to endogenous TTR in plasma. Aliquots of the subunit exchange reaction, taken as a function of time, are then added to an excess of a fluorogenic small molecule, which immediately arrests further subunit exchange. After binding, the small molecule reacts with the TTR tetramers, rendering them fluorescent and detectable in human plasma after subsequent ion exchange chromatography. The ability to report on the extent of TTR kinetic stabilization resulting from treatment with oral tafamidis is important, especially for selection of the appropriate dose for patients carrying rare mutations. This method could also serve as a surrogate biomarker for the prediction of the clinical outcome. Subunit exchange was used to quantify the stabilization of WT TTR from senile systemic amyloidosis patients currently being treated with tafamidis (20 mg orally, once daily). TTR kinetic stability correlated with the tafamidis plasma concentration. PMID:24661308

[Adult hepatoblastoma. A case report].

PubMed

Goikoetxea Urdiain, A; Sánchez Acedo, P; Mateo Retuerta, J; Tarifa Castilla, A; Zazpe Ripa, C; Herrera Cabezón, J

2016-01-01

Adult hepatoblastoma is a rare pathology. Its pathogeny is not well understood and prognosis is very bad. We pre-sent a case of adult hepatoblastoma treated in our centre. A 65 year-old male, without previous hepatopathy, who consulted due to right hypochondrial pain with a subacute evolution. The pathological diagnosis was adult epithelial hepatoblastoma, with free surgical margins. The patient recei-ved a second surgical intervention 5 months later due to early recurrence and died 10 months after the diagnosis due to a new massive recurrence. His definitive diagnosis is histological. Radical surgery is the only treatment that increases survival, but recurrence is frequent. There are no well-defined patterns of adjuvant chemotherapy nor is there any trans-plant experience.

Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense.

PubMed

Hirakura, Yutaka; Carreras, Isabel; Sipe, Jean D; Kagan, Bruce L

2002-03-01

Serum amyloid A (SAA) is a family of closely related apolipoproteins associated with high density lipoprotein (HDL). Subclasses of SAA isoforms are differentially expressed constitutively and during inflammation. During states of infection or inflammation, levels of HDL bound, acute phase isoforms of SAA rise as much as 1000-fold in the serum, suggesting that it might play a role in host defense. Following recurrent or chronic inflammation, an N-terminal peptide fragment of SAA known as amyloid A (AA) assembles into fibrils causing extensive damage to spleen, liver, and kidney, and rapidly progressing to death. In the present paper, we report the novel finding that a recombinant acute phase isoform variant of human SAA 1.1 (SAAp) readily forms ion-channels in planar lipid bilayer membranes at physiologic concentrations. These channels are voltage-independent, poorly selective, and are relatively long-lived This type of channel would place a severe metabolic strain on various kinds of cells. Expression of human SAA 1.1 in bacteria induces lysis of bacterial cells, while expression of the constitutive isoform (human SAA4) does not. Secondary structural analysis of the SAA isoforms in dicates a strong hydrophobicity of the N-terminal of the acute phase isoform relative to the constitutive SAA4 isoform, which may be responsible for the bactericidal activity of the former, in keeping with the notion that SAA 1 targets cell membranes and forms channels in them. Channel formation may thus be related to a host defense role of acute phase SAA isoforms and may also be the mechanism of end organ damage in AA and other amyloidoses.

Systemic amyloidosis: novel therapies and role of biomarkers.

PubMed

Nuvolone, Mario; Merlini, Giampaolo

2017-05-01

Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future. © The

Disorder in milk proteins: caseins, intrinsically disordered colloids.

PubMed

Redwan, Elrashdy M; Xue, Bin; Almehdar, Hussein A; Uversky, Vladimir N

2015-01-01

This article opens a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. The focus of this introductory article on caseins is symbolic, since caseins were among the first recognized functional unfolded proteins and since they are definitely the most disordered, the most abundant, and the most studied of all milk proteins. In eutherian milks, the casein family includes at least three and usually four major members (αs1-, αs2-, β-, and κ-caseins) that are unrelated in sequence. However, in some species, two different αS2-casein genes are active, and therefore the total number of caseins can be as high as five. These proteins have found a number of uses in food industry. The functional repertoire of caseins ranges from nutritional function to involvement in the improving and/or maintaining cardiovascular health, to crucial contribution to the milk capacity to transport calcium phosphate, to serve as molecular chaperones, and to protect the mother's mammary gland against amyloidoses and ectopic calcification. An intricate feature of caseins is their ability to assemble to colloidal protein particles, casein micelles, serving to sequester and transport amorphous calcium phosphate. These and many other functions of caseins are obviously dependent on their intrinsically disordered nature and are controlled by various posttranslational modifications. Since various aspects of casein structure and function are rather well studied and since several recent reviews emphasized the functional roles of caseins' intrinsic disorder, the major goal of this article is to show how intrinsic disorder is encoded in the amino acid sequences of these proteins.

Multifaced Roles of the αvβ3 Integrin in Ehlers–Danlos and Arterial Tortuosity Syndromes’ Dermal Fibroblasts

PubMed Central

Zoppi, Nicoletta; Chiarelli, Nicola; Ritelli, Marco; Colombi, Marina

2018-01-01

The αvβ3 integrin, an endothelial cells’ receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize a fibrillar network of FN, which is preferentially bound on the entire cell surface to its canonical α5β1 integrin receptor, whereas the αvβ3 integrin is present only in rare patches in focal contacts. We report on the preferential recruitment of the αvβ3 integrin, due to the lack of FN–ECM and its canonical integrin receptor, in dermal fibroblasts from Ehlers–Danlos syndromes (EDS) and arterial tortuosity syndrome (ATS), which are rare multisystem connective tissue disorders. We review our previous findings that unraveled different biological mechanisms elicited by the αvβ3 integrin in fibroblasts derived from patients affected with classical (cEDS), vascular (vEDS), hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and ATS. In cEDS and vEDS, respectively, due to defective type V and type III collagens, αvβ3 rescues patients’ fibroblasts from anoikis through a paxillin-p60Src-mediated cross-talk with the EGF receptor. In hEDS and HSD, without a defined molecular basis, the αvβ3 integrin transduces to the ILK-Snail1-axis inducing a fibroblast-to-myofibroblast-transition. In ATS cells, the deficiency of the dehydroascorbic acid transporter GLUT10 leads to redox imbalance, ECM disarray together with the activation of a non-canonical αvβ3 integrin-TGFBRII signaling, involving p125FAK/p60Src/p38MAPK. The characterization of these different biological functions triggered by αvβ3 provides insights into the multifaced nature of this integrin, at least in cultured dermal fibroblasts, offering future perspectives for research in this field. PMID:29587413

A Low Cost Traveling Wave Tube for Wireless Communications

NASA Technical Reports Server (NTRS)

Vancil, Bernard Kenneth; Wintucky, Edwin G.; Williams, W. D. (Technical Monitor)

2002-01-01

Demand for high data rate wireless communications is pushing up amplifier power, bandwidth and frequency requirements. Some systems are using vacuum electron devices again because solid-state power amplifiers are not able to efficiently meet the new requirements. The traveling wave tube is the VED of choice because of its excellent broadband capability as well as high power efficiency and frequency. But TWTs are very expensive on a per watt basis below about 200 watts of output power. We propose a new traveling wave tube that utilizes cathode ray tube construction technology and electrostatic focusing. We believe the tube can be built in quantity for under $1,000 each. We discuss several traveling wave tube slow wave circuits that lend themselves to the new construction. We will present modeling results and data on prototype devices.

An evaluation of the accuracy of some radar wind profiling techniques

NASA Technical Reports Server (NTRS)

Koscielny, A. J.; Doviak, R. J.

1983-01-01

Major advances in Doppler radar measurement in optically clear air have made it feasible to monitor radial velocities in the troposphere and lower stratosphere. For most applications the three dimensional wind vector is monitored rather than the radial velocity. Measurement of the wind vector with a single radar can be made assuming a spatially linear, time invariant wind field. The components and derivatives of the wind are estimated by the parameters of a linear regression of the radial velocities on functions of their spatial locations. The accuracy of the wind measurement thus depends on the locations of the radial velocities. The suitability is evaluated of some of the common retrieval techniques for simultaneous measurement of both the vertical and horizontal wind components. The techniques considered for study are fixed beam, azimuthal scanning (VAD) and elevation scanning (VED).

Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology?

PubMed

Sidorova, Tatiana N; Mace, Lisa C; Wells, K Sam; Yermalitskaya, Liudmila V; Su, Pei-Fang; Shyr, Yu; Atkinson, James B; Fogo, Agnes B; Prinsen, Joseph K; Byrne, John G; Petracek, Michael R; Greelish, James P; Hoff, Steven J; Ball, Stephen K; Glabe, Charles G; Brown, Nancy J; Barnett, Joey V; Murray, Katherine T

2014-12-02

Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ-specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated. Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation-specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium-specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension. PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Proteolysis suppresses spontaneous prion generation in yeast.

PubMed

Okamoto, Atsushi; Hosoda, Nao; Tanaka, Anri; Newnam, Gary P; Chernoff, Yury O; Hoshino, Shin-Ichi

2017-12-08

Prions are infectious proteins that cause fatal neurodegenerative disorders including Creutzfeldt-Jakob and bovine spongiform encephalopathy (mad cow) diseases. The yeast [ PSI + ] prion is formed by the translation-termination factor Sup35, is the best-studied prion, and provides a useful model system for studying such diseases. However, despite recent progress in the understanding of prion diseases, the cellular defense mechanism against prions has not been elucidated. Here, we report that proteolytic cleavage of Sup35 suppresses spontaneous de novo generation of the [ PSI + ] prion. We found that during yeast growth in glucose media, a maximum of 40% of Sup35 is cleaved at its N-terminal prion domain. This cleavage requires the vacuolar proteases PrA-PrB. Cleavage occurs in a manner dependent on translation but independently of autophagy between the glutamine/asparagine-rich (Q/N-rich) stretch critical for prion formation and the oligopeptide-repeat region required for prion maintenance, resulting in the removal of the Q/N-rich stretch from the Sup35 N terminus. The complete inhibition of Sup35 cleavage, by knocking out either PrA ( pep4 Δ) or PrB ( prb1 Δ), increased the rate of de novo formation of [ PSI + ] prion up to ∼5-fold, whereas the activation of Sup35 cleavage, by overproducing PrB, inhibited [ PSI + ] formation. On the other hand, activation of the PrB pathway neither cleaved the amyloid conformers of Sup35 in [ PSI + ] strains nor eliminated preexisting [ PSI + ]. These findings point to a mechanism antagonizing prion generation in yeast. Our results underscore the usefulness of the yeast [ PSI + ] prion as a model system to investigate defense mechanisms against prion diseases and other amyloidoses. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: "in vivo" evidence from FAP mice models.

PubMed

Ferreira, Nelson; Saraiva, Maria João; Almeida, Maria Rosário

2012-01-01

optimized derivatives, in the treatment of TTR-related amyloidoses.

Predicting participation in and successful outcome of a penile rehabilitation programme using a phosphodiesterase type 5 inhibitor with a vacuum erection device after radical prostatectomy.

PubMed

Kimura, Masaki; Caso, Jorge R; Bañez, Lionel L; Koontz, Bridget F; Gerber, Leah; Senocak, Cagri; Donatucci, Craig F; Vujaskovic, Zeljko; Moul, Judd W; Polascik, Thomas J

2012-12-01

Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The role of the vacuum erection device (VED) has increased with its use in combined therapy with a phosphodiesterase type 5 inhibitor (PDE5i) for penile rehabilitation after radical prostatectomy (RP) and radiotherapy. The advantages of the VED are non-invasive, cost-effective, and a possibility of preventing shrinkage of penis length. Albeit current widespread use of penile rehabilitation programmes for post-RP erectile dysfunction, independent predictors for the rehabilitation participants, as well as for its treatment success have not been fully investigated. In the present study, we have added several new predictors for rehabilitation participation, e.g. African-Americans and higher preoperative sexual function. Conversely, higher preoperative PSA concentrations and the presence of positive surgical margins were predictors for avoidance of rehabilitation. Notably, there was a primary surgeon difference, which had a trend for predicting outcome of the rehabilitation among the participants, implying their surgical technique and follow-up might influence success of the rehabilitation. • To investigate baseline demographic and clinicopathological characteristics of men who participate in our penile rehabilitation programme after radical prostatectomy (RP). • To determine predictors for participation in rehabilitation, as well as successful rehabilitation outcome using multivariable logistic regression analyses. • We analysed data on 2345 consecutive patients who underwent RP between 2001 and 2009 in our institution. • The decision to participate in penile rehabilitation using phosphodiesterase type 5 inhibitor (PDE5i) with a vacuum erection device (VED) was based on the patient's choice after post-RP discussions. • Rehabilitation success was defined using the following criteria: (i) patients who continued the penile rehabilitation programme and

Implications of Weak Link Effects on Thermal Characteristics of Transition-Edge Sensors

NASA Technical Reports Server (NTRS)

Bailey, C. N.; Adams, J. S.; Bandler, S. R.; Brekosky, R. P.; Chevenak, J. A.; Eckart, M. E.; Finkbeiner, F. M.; Kelley, R. L.; Kally, D. P.; Kilbourne, C. A.;

Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods.

PubMed

Smith, Trevor R F; Schultheis, Katherine; Broderick, Kate E

2017-11-02

Respiratory syncytial virus (RSV) is a massive medical burden on a global scale. Infants, children and the elderly represent the vulnerable populations. Currently there is no approved vaccine to protect against the disease. Vaccine development has been hindered by several factors including vaccine enhanced disease (VED) associated with formalin-inactivated RSV vaccines, inability of target populations to raise protective immune responses after vaccination or natural viral infection, and a lack of consensus concerning the most appropriate virus-associated target antigen. However, with recent advances in the molecular understanding of the virus, and design of highly characterized vaccines with enhanced immunogenicity there is new belief a RSV vaccine is possible. One promising approach is nucleic acid-based vaccinology. Both DNA and mRNA RSV vaccines are showing promising results in clinically relevant animal models, supporting their transition into humans. Here we will discuss this strategy to target RSV, and the ongoing studies to advance the nucleic acid vaccine platform as a viable option to protect vulnerable populations from this important disease.

Unfoldomics of human diseases: linking protein intrinsic disorder with diseases

PubMed Central

Uversky, Vladimir N; Oldfield, Christopher J; Midic, Uros; Xie, Hongbo; Xue, Bin; Vucetic, Slobodan; Iakoucheva, Lilia M; Obradovic, Zoran; Dunker, A Keith

2009-01-01

Background Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary and/or secondary structure yet fulfills key biological functions. The recent recognition of IDPs and IDRs is leading to an entire field aimed at their systematic structural characterization and at determination of their mechanisms of action. Bioinformatics studies showed that IDPs and IDRs are highly abundant in different proteomes and carry out mostly regulatory functions related to molecular recognition and signal transduction. These activities complement the functions of structured proteins. IDPs and IDRs were shown to participate in both one-to-many and many-to-one signaling. Alternative splicing and posttranslational modifications are frequently used to tune the IDP functionality. Several individual IDPs were shown to be associated with human diseases, such as cancer, cardiovascular disease, amyloidoses, diabetes, neurodegenerative diseases, and others. This raises questions regarding the involvement of IDPs and IDRs in various diseases. Results IDPs and IDRs were shown to be highly abundant in proteins associated with various human maladies. As the number of IDPs related to various diseases was found to be very large, the concepts of the disease-related unfoldome and unfoldomics were introduced. Novel bioinformatics tools were proposed to populate and characterize the disease-associated unfoldome. Structural characterization of the members of the disease-related unfoldome requires specialized experimental approaches. IDPs possess a number of unique structural and functional features that determine their broad involvement into the pathogenesis of various diseases. Conclusion Proteins associated with various human diseases are enriched in intrinsic disorder. These disease-associated IDPs and IDRs are real, abundant, diversified, vital, and dynamic. These proteins and regions comprise the disease-related unfoldome, which covers a significant part

Brain Enhancing Ingredients from Āyurvedic Medicine: Quintessential Example of Bacopa monniera, a Narrative Review

PubMed Central

Singh, Hemant K.

2013-01-01

Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years. PMID:23389306

Two models of inventory control with supplier selection in case of multiple sourcing: a case of Isfahan Steel Company

NASA Astrophysics Data System (ADS)

Rabieh, Masood; Soukhakian, Mohammad Ali; Mosleh Shirazi, Ali Naghi

2016-06-01

Selecting the best suppliers is crucial for a company's success. Since competition is a determining factor nowadays, reducing cost and increasing quality of products are two key criteria for appropriate supplier selection. In the study, first the inventories of agglomeration plant of Isfahan Steel Company were categorized through VED and ABC methods. Then the models to supply two important kinds of raw materials (inventories) were developed, considering the following items: (1) the optimal consumption composite of the materials, (2) the total cost of logistics, (3) each supplier's terms and conditions, (4) the buyer's limitations and (5) the consumption behavior of the buyers. Among diverse developed and tested models—using the company's actual data within three pervious years—the two new innovative models of mixed-integer non-linear programming type were found to be most suitable. The results of solving two models by lingo software (based on company's data in this particular case) were equaled. Comparing the results of the new models to the actual performance of the company revealed 10.9 and 7.1 % reduction in total procurement costs of the company in two consecutive years.

Brain enhancing ingredients from Āyurvedic medicine: quintessential example of Bacopa monniera, a narrative review.

PubMed

Singh, Hemant K

2013-02-06

Āyurveda, the science (ved) of life (ayu), owing its origin to Veda, the oldest recorded wisdom of human civilization written in 3500 BCE, contains extensive knowledge of various diseases and their therapeutic approaches. It essentially relied on nature and the immune system of an individual, and therapeutic interventions were introduced only to augment the immune system. Āyurveda had eight specialties, including psycho-neuroscience (a combination of psychology, clinical psychology and psychiatry) and a unique promotive therapy encompassing nutrition, rejuvenation and geriatrics. The symptoms of various brain disorders, including memory disorder, were well defined. The goal of Āyurveda was to help an individual to achieve his cherished goal of leading a healthy life of 100 years. To achieve this, great emphasis was laid on nutrition, diet and a good conduct by the two great exponents of Āyurveda viz. Carak and Suśruta. By following these regimens, an individual could lead a less stressful life free from emotional disturbances. Both Carak and Suśruta had believed that these in combination with rasayana (rejuvenating) plants could enable an individual to lead a healthy life of 100 years.

Low cost mobile explosive/drug detection devices

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

Gozani, T.; Bendahan, J.

1999-06-10

Inspection technologies based on Thermal Neutron Analysis (TNA) and/or Fast Neutron Analysis (FNA) are the basis for relatively compact and low-cost, material-sensitive devices for a wide variety of inspection needs. The TNA allows the use of either isotropic neutron sources such as a {sup 252}Cf, or electronic neutron generators such as the d-T sealed neutron generator tubes. The latter could be used in a steady state mode or in slow (>{mu}s) pulsing mode, to separate the thermal neutron capture signatures following the pulse from the combination of the FNA plus TNA signatures during the pulse. Over the years, Ancore Corporationmore » has built and is continuing to develop a variety of inspection devices based on its TNA and FNA technologies: SPEDS--an explosive detection device for small parcels, portable electronics, briefcases and other similar carry-on items; MDS - a system for the detection or confirmation of buried mines; VEDS - a system for the detection of varied amounts of explosives and/or drugs concealed in passenger vehicles, pallets, lightly loaded trucks or containers, etc.; ACD - a device to clear alarms from a primary, non-specific explosive detection system for passenger luggage. The principle and performance of these devices will be shown and discussed.« less

Evaluation of the effect of D-amino acid incorporation into amyloid-reactive peptides.

PubMed

Martin, Emily B; Williams, Angela; Richey, Tina; Wooliver, Craig; Stuckey, Alan; Foster, James S; Kennel, Stephen J; Wall, Jonathan S

2017-12-11

Systemic amyloidoses comprise diseases characterized by the deposition of proteinaceous material known as amyloid. Currently, without performing multiple biopsies, there is no way to ascertain the extent of amyloid deposition in patients-a critical piece of information that informs prognosis and therapeutic strategies. We have developed pan-amyloid-targeting peptides for imaging amyloid and recently have adapted these for use as pre-targeting agents in conjunction with immunotherapy. Incorporation of D-amino acids in these peptides may enhance serum half-life, which is an important characteristic of effective peptide therapeutics. Herein, we assess the effects of partial incorporation of D-amino acids into the amyloidophilic peptide p5 on in vivo amyloid reactivity. Peptides, referred to as AQA p5 (d) , aqa p5, and AQA p5, were radiolabeled with iodine-125 and the tissue biodistribution (% injected dose/gram) measured in healthy mice at multiple time points post-injection. Microscopic distribution of the peptides was further visualized using microautoradiography (ARG). Peptides aqa p5 and AQA p5 were injected into healthy and amyloid-laden mice and evaluated by using SPECT/CT imaging at 1, 4 and 24 h post injection. Biodistribution data and ARG revealed persistent retention of [ 125 I] AQA p5 (d) in the liver and kidneys of healthy mice for at least 24 h. In contrast, peptides [ 125 I] aqa p5 and [ 125 I] AQA p5 did not bind these organs and was significantly lower than [ 125 I] AQA p5 (d) at 24 h post injection (p < 0.0001). SPECT/CT imaging of amyloid-laden mice revealed accumulation of both [ 125 I] aqa p5 and [ 125 I] AQA p5 in amyloid-affected organs; whereas, in healthy mice, [ 125 I] aqa p5 was observed in the kidneys and liver at early time points, and free radioiodide liberated during catabolism of [ 125 I] AQA p5 was seen in the stomach and thyroid. Autoradiography confirmed that both [ 125 I] aqa p5 and [ 125 I] AQA p5 peptides specifically bound

Vascular Ehlers–Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family

PubMed Central

Jørgensen, Agnete; Fagerheim, Toril; Rand-Hendriksen, Svend; Lunde, Per I; Vorren, Torgrim O; Pepin, Melanie G; Leistritz, Dru F; Byers, Peter H

2015-01-01

Vascular Ehlers–Danlos Syndrome (vEDS), also known as EDS type IV, is considered to be an autosomal dominant disorder caused by sequence variants in COL3A1, which encodes the chains of type III procollagen. We identified a family in which there was marked clinical variation with the earliest death due to extensive aortic dissection at age 15 years and other family members in their eighties with no complications. The proband was born with right-sided clubfoot but was otherwise healthy until he died unexpectedly at 15 years. His sister, in addition to signs consistent with vascular EDS, had bilateral frontal and parietal polymicrogyria. The proband and his sister each had two COL3A1 sequence variants, c.1786C>T, p.(Arg596*) in exon 26 and c.3851G>A, p.(Gly1284Glu) in exon 50 on different alleles. Cells from the compound heterozygote produced a reduced amount of type III procollagen, all the chains of which had abnormal electrophoretic mobility. Biallelic sequence variants have a significantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1. PMID:25205403

Realism Assessment of Sonic Boom Simulators

NASA Technical Reports Server (NTRS)

Sullivan, Brenda M.; Davies, Patrica; Hodgdon, Kthleen K.; Salamone, Joseph A., III; Pilon, Anthony

2008-01-01

Developments in small supersonic aircraft design are predicted to result in low-intensity sonic booms. Booms generated by current aircraft are similar to those that led to the ban on commercial supersonic fli ght over the US, so are unsuitable for parametric studies of psychoac oustic response to low-intensity booms. Therefore, simulators have be en used to study the impact of predicted low-intensity sonic booms. H owever, simulators have been criticized because, when simulating conv entional-level booms, the sounds were observed to be unrealistic by p eople experienced in listening to sonic booms. Thus, two studies were conducted to measure the perceived realism of three sonic boom simul ators. Experienced listeners rated the realism of conventional sonic boom signatures when played in these simulators. The effects on percei ved realism of factors such as duration of post-boom noise, exclusion of very low frequency components, inclusion of ground reflections, a nd type of simulator were examined. Duration of post-boom noise was f ound to have a strong effect on perceived realism, while type of simu lator had a weak effect. It was determined that post-boom noise had t o be at least 1.5 seconds long for the sound to be rated very realist ic. Loudness level did not affect realism for the range of sounds pla yed in the tests (80-93 dB ASEL).

Specificity of Atmosphere Correction of Satellite Ocean Color Data in Far-Eastern Region

NASA Astrophysics Data System (ADS)

Trusenkova, O.; Kachur, V.; Aleksanin, A. I.

2016-02-01

It was carried out an error analysis of satellite reflectance coefficients (Rrs) of MODIS/AQUA colour data for two atmospheric correction algorithms (NIR, MUMM) in the Far-Eastern region. Some sets of unique data of in situ and satellite measurements have been analysed. A set has some measurements with ASD spectroradiometer for each satellite pass. The measurement allocations were selected so the Chlorophyll-a concentration has high variability. Analysis of arbitrary set demonstrated that the main error component is systematic error, and it has simple relations on Rrs values. The reasons of such error behavior are considered. The most probable explanation of the large errors of oceanic color parameters in the Far-Eastern region is the ability of high concentrations of continental aerosol. A comparison of satellite and in situ measurements at AERONET stations of USA and South Korea regions has been made. It was shown that for NIR-correction of the atmosphere influence the error values in these two regions have differences up to 10 times for almost the same water turbidity and relatively good accuracy of computation of aerosol optical thickness. The study was supported by grant Russian Scientific Foundation No. 14-50-00034, by grant of Russian Foundation of Basic Research No.15-35-21032-mol-a-ved, and by Program of Basic Research "Far East" of Far Eastern Branch of Russian Academy of Sciences.

Combination therapy for erectile dysfunction: an update review.

PubMed

Dhir, Rohit R; Lin, Hao-Cheng; Canfield, Steven E; Wang, Run

2011-05-01

The introduction of oral phosphodiesterase-5 inhibitors (PDE5Is) in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE5Is are currently first-line monotherapy for erectile dysfunction (ED). However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE5I monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE5I therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE5I plus vacuum erectile device (VED), intraurethral medication, intracavernosal injection (ICI), androgen supplement, α-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management.

Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome.

PubMed

Byers, Peter H; Belmont, John; Black, James; De Backer, Julie; Frank, Michael; Jeunemaitre, Xavier; Johnson, Diana; Pepin, Melanie; Robert, Leema; Sanders, Lynn; Wheeldon, Nigel

2017-03-01

Vascular Ehlers Danlos syndrome (vEDS) is an uncommon genetic disorders characterized by arterial aneurysm, dissection and rupture, bowel rupture, and rupture of the gravid uterus. The frequency is estimated as 1/50,000-1/200,000 and results from pathogenic variants in COL3A1, which encodes the chains of type III procollagen, a major protein in vessel walls and hollow organs. Initial diagnosis depends on the recognitions of clinical features, including family history. Management is complex and requires multiple specialists who can respond to and manage the major complications. A summary of recommendations for management include: Identify causative variants in COL3A1 prior to application of diagnosis, modulate life style to minimize injury, risk of vessel/organ rupture, identify and create care team, provide individual plans for emergency care ("vascular EDS passport") with diagnosis and management plan for use when traveling, centralize management at centers of excellence (experience) when feasible, maintain blood pressure in the normal range and treat hypertension aggressively, surveillance of vascular tree by doppler ultrasound, CTA (low radiation alternatives) or MRA if feasible on an annual basis. These recommendations represent a consensus of an international group of specialists with a broad aggregate experience in the care of individuals with vascular EDS that will need to be assessed on a regular basis as new information develops. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Activated carbon-supported CuO nanoparticles: a hybrid material for carbon dioxide adsorption

NASA Astrophysics Data System (ADS)

Boruban, Cansu; Esenturk, Emren Nalbant

2018-03-01

Activated carbon-supported copper(II) oxide (CuO) nanoparticles were synthesized by simple impregnation method to improve carbon dioxide (CO2) adsorption capacity of the support. The structural and chemical properties of the hybrid material were characterized by scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction (https://www.google.com.tr/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&cad=rja&uact=8&ved=0CCsQFjAC&url=http%3A%2F%2Fwww.intertek.com%2Fanalytical-laboratories%2Fxrd%2F&ei=-5WZVYSCHISz7Aatqq-IAw&usg=AFQjCNFBlk-9wqy49foh8tskmbD-GGbG9g&sig2=eKrhYjO75rl_Id2sLGpq4w&bvm=bv.96952980,d.bGg) (XRD), X-ray photoelectron spectroscopy (XPS), atomic absorption spectroscopy (AAS), and Brunauer-Emmett-Teller (BET) analyses. The analyses showed that CuO nanoparticles are well-distributed on the activated carbon surface. The CO2 adsorption behavior of the activated carbon-supported CuO nanoparticles was observed by thermogravimetric analysis (TGA), temperature programmed desorption (TPD), Fourier transform infrared (FTIR), and BET analyses. The results showed that CuO nanoparticle loading on activated carbon led to about 70% increase in CO2 adsorption capacity of activated carbon under standard conditions (1 atm and 298 K). The main contributor to the observed increase is an improvement in chemical adsorption of CO2 due to the presence of CuO nanoparticles on activated carbon.

Fatigue test results of the rotating steel blades of steam turbine K-25-0.6 GEO with ion-plasma coating

NASA Astrophysics Data System (ADS)

Kachalin, G. V.; Mednikov, A. F.; Tkhabisimov, A. B.; Arkad'ev, D. A.; Temkin, S. G.; Senina, N. A.

2016-12-01

Fatigue test results of the rotating steel blades of the fourth stage of the K-25-0.6 low pressure cylinder Geo steam turbine manufactured in the Kaluga Turbine Plant (hereinafter, KTP) with the ion-plasma coating were presented. Coating formation was carried out at the National Research University (MPEI) on the Gefest vacuum pilot plant by the magnetron sputtering method. Characteristics of the obtained coating were analyzed with the use of the scientific-research equipment of the National Research University (MPEI). Fatigue tests of the rotating blades and determination of the fatigue strength of the material with the ion-plasma coating were carried out on the electrodynamic vibration machines VEDS-400A in the KTP structural laboratory. The following characteristics were obtained after tests: Ti-TiN composition, 10-11 μm thickness, 1200 HV 0.05 microhardness. Fatigue tests showed that destruction, regardless of availability or nonavailability of the coating, took place by cross-section in the root zone both on the leading and trailing edges of the blade, i.e., in the most stressed zones. It was found out that the maximum stresses during tests were revealed in the root section along the trailing edge on the blade pressure side, and the less stresses were on the leading edge. Fatigue strength of the working blades after coating formation increased by 12% minimum. Results of the fatigue tests prove the previously obtained data concerning 10-12% increase of the fatigue strength of the blade steel with the ion-plasma coating and allow claiming that the process of their formation exerts the positive influence on the fatigue characteristics of the blade materials.

Towards the mid-infrared optical biopsy

NASA Astrophysics Data System (ADS)

Seddon, Angela B.; Benson, Trevor M.; Sujecki, Slawomir; Abdel-Moneim, Nabil; Tang, Zhuoqi; Furniss, David; Sojka, Lukasz; Stone, Nick; Jayakrupakar, Nallala; Lloyd, Gavin R.; Lindsay, Ian; Ward, Jon; Farries, Mark; Moselund, Peter M.; Napier, Bruce; Lamrini, Samir; Møller, Uffe; Kubat, Irnis; Petersen, Christian R.; Bang, Ole

2016-03-01

We are establishing a new paradigm in mid-infrared molecular sensing, mapping and imaging to open up the midinfrared spectral region for in vivo (i.e. in person) medical diagnostics and surgery. Thus, we are working towards the mid-infrared optical biopsy (`opsy' look at, bio the biology) in situ in the body for real-time diagnosis. This new paradigm will be enabled through focused development of devices and systems which are robust, functionally designed, safe, compact and cost effective and are based on active and passive mid-infrared optical fibers. In particular, this will enable early diagnosis of external cancers, mid-infrared detection of cancer-margins during external surgery for precise removal of diseased tissue, in one go during the surgery, and mid-infrared endoscopy for early diagnosis of internal cancers and their precision removal. The mid-infrared spectral region has previously lacked portable, bright sources. We set a record in demonstrating extreme broad-band supercontinuum generated light 1.4 to 13.3 microns in a specially engineered, high numerical aperture mid-infrared optical fiber. The active mid-infrared fiber broadband supercontinuum for the first time offers the possibility of a bright mid-infrared wideband source in a portable package as a first step for medical fiber-based systems operating in the mid-infrared. Moreover, mid-infrared molecular mapping and imaging is potentially a disruptive technology to give improved monitoring of the environment, energy efficiency, security, agriculture and in manufacturing and chemical processing. This work is in part supported by the European Commission: Framework Seven (FP7) Large-Scale Integrated Project MINERVA: MId-to-NEaR- infrared spectroscopy for improVed medical diAgnostics (317803; www.minerva-project.eu).

Developing of the database of meteorological and radiation fields for Moscow region (urban reanalysis) for 1981-2014 period with high spatial and temporal resolution. Strategy and first results.

NASA Astrophysics Data System (ADS)

Konstantinov, Pavel; Varentsov, Mikhail; Platonov, Vladimir; Samsonov, Timofey; Zhdanova, Ekaterina; Chubarova, Natalia

2017-04-01

The main goal of this investigation is to develop a kind of "urban reanalysis" - the database of meteorological and radiation fields under Moscow megalopolis for period 1981-2014 with high spatial resolution. Main meteorological fields for Moscow region are reproduced with COSMO_CLM regional model (including urban parameters) with horizontal resolution 1x1 km. Time resolution of output fields is 1 hour. For radiation fields is quite useful to calculate SVF (Sky View Factor) for obtaining losses of UV radiation in complex urban conditions. Usually, the raster-based SVF analysis the shadow-casting algorithm proposed by Richens (1997) is popular (see Ratti and Richens 2004, Gal et al. 2008, for example). SVF image is obtained by combining shadow images obtained from different directions. An alternative is to use raster-based SVF calculation similar to vector approach using digital elevation model of urban relief. Output radiation field includes UV-radiation with horizontal resolution 1x1 km This study was financially supported by the Russian Foundation for Basic Research within the framework of the scientific project no. 15-35-21129 _mol_a_ved and project no 15-35-70006 mol_a_mos References: 1. Gal, T., Lindberg, F., and Unger, J., 2008. Computing continuous sky view factors using 3D urban raster and vector databases: comparison and application to urban climate. Theoretical and applied climatology, 95 (1-2), 111-123. 2. Richens, P., 1997. Image processing for urban scale environmental modelling. In: J.D. Spitler and J.L.M. Hensen, eds. th Intemational IBPSA Conference Building Simulation, Prague. 3. Ratti, C. and Richens, P., 2004. Raster analysis of urban form. Environment and Planning B: Planning and Design, 31 (2), 297-309.

Perspectives of primary health care staff on the implementation of a sexual health quality improvement program: a qualitative study in remote aboriginal communities in Australia.

PubMed

Hengel, Belinda; Bell, Stephen; Garton, Linda; Ward, James; Rumbold, Alice; Taylor-Thomson, Debbie; Silver, Bronwyn; McGregor, Skye; Dyda, Amalie; Knox, Janet; Guy, Rebecca; Maher, Lisa; Kaldor, John Martin

2018-04-02

Young people living in remote Australian Aboriginal communities experience high rates of sexually transmissible infections (STIs). STRIVE (STIs in Remote communities, ImproVed and Enhanced primary care) was a cluster randomised control trial of a sexual health continuous quality improvement (CQI) program. As part of the trial, qualitative research was conducted to explore staff perceptions of the CQI components, their normalisation and integration into routine practice, and the factors which influenced these processes. In-depth semi-structured interviews were conducted with 41 clinical staff at 22 remote community clinics during 2011-2013. Normalisation process theory was used to frame the analysis of interview data and to provide insights into enablers and barriers to the integration and normalisation of the CQI program and its six specific components. Of the CQI components, participants reported that the clinical data reports had the highest degree of integration and normalisation. Action plan setting, the Systems Assessment Tool, and the STRIVE coordinator role, were perceived as adding value to the program, but were less readily integrated or normalised. The remaining two components (dedicated funding for health promotion and service incentive payments) were seen as least relevant. Our analysis also highlighted factors which enabled greater integration of the CQI components. These included familiarity with CQI tools, increased accountability of health centre staff and the translation of the CQI program into guideline-driven care. The analysis also identified barriers, including high staff turnover, limited time involved in the program and competing clinical demands and programs. Across all of the CQI components, the clinical data reports had the highest degree of integration and normalisation. The action plans, systems assessment tool and the STRIVE coordinator role all complemented the data reports and allowed these components to be translated directly into

PREFACE: Physics and biology of neurodegenerative diseases Physics and biology of neurodegenerative diseases

NASA Astrophysics Data System (ADS)

Pastore, Annalisa

2012-06-01

In 1939, William T Astbury, who was at the time a professor at the University of Leeds, wrote a letter to Dorothy Hodgkins, a crystallographer colleague who would eventually be awarded a Nobel Prize (1964) [1]. Astbury was working on determining the structure of silk and had found that these fibres had a so-called cross-beta arrangement, with the hydrogen bonds holding a beta-sheet structure perpendicular to the fibre axis. This structure was very robust and thus would account well for the properties of the silk fibre. Being very impressed by this structural solution at a time when protein structure was just being discovered, he wrote to Dorothy Hodgkins formulating the hypothesis that all proteins could adopt a cross-beta structure similar to that found for silk as a sort of ultimate solution. Approximately 70 years later, this prediction was reconsidered and is now generally accepted to be correct: most if not all proteins seem to be able to form fibrils, commonly named amyloids, that adopt the same structural features found in silk. The field of amyloid fibres bloomed in the mid-90s when several researchers—among them Chris Dobson, a professor first at Oxford and then at Cambridge—observed that proteins could aggregate by concomitant formation of fibrillar structures (reviewed in [2]). It was certainly not news that proteins could aggregate with an irreversible mechanism. However, what nearly came as a surprise was the realization that aggregation is often accompanied by a major structural rearrangement, which almost invariably associates with protein misfolding (i.e. loss of the native structure and adoption of a beta-rich structure) and amyloid fibre formation. Even more interesting was the growing evidence that amyloid fibres have very special mechanical properties, being extremely resilient and not easily degraded. At the same time it was noticed that different diseases, generically named amyloidoses, are associated with fibrillar aggregates. Today

Anhydrobiosis vs. aging: comparative genomics of protein repair L-isoaspartyl methyltransferases in the sleeping chironomid. .

NASA Astrophysics Data System (ADS)

Gusev, Oleg; Kikawada, Takahiro; Shagimardanova, Elena; Suetsugu, Yoshitaka; Ayupov, Rustam

and larval stages. Finally, the expression of Pimt1 gene in both chironomids was not changed in response to desiccation, while the clustered PvPimt2-12 showed strong up-regulation in response to water loss and other abiotic stresses. The abundance of PvPimt2-12 mRNAs was maximal in anhydrobiotic larvae, and it resembles the case of plant seeds where accumulation of PIMT provides additional protection for proteins during long dry storage. Predicted proteins of PvPimT2-12 contain conservative L-isoaspartyl methyltransferase functional domain. At the same time the length and structure of N- and C- terminals of the predicted proteins show significant variation, suggesting different substrate preferences or other specific properties of different Pv-PIMT Furthermore, the multi-member family in Pv is the first observation of drastic expansion and evolution of Pimt genes in general, and particularly in a single insect species. This work was supported by Russian Foundation for Basic Research (No. 12-08-33157 mol_a_ved and No. 14-04-01657_A).

A theoretical model of the influence of spray on the exchange of momentum, with storm and hurricane winds

NASA Astrophysics Data System (ADS)

Troitskaya, Yuliya; Ezhova, Ekaterina; Soustova, Irina

2013-04-01

flow during the life cycle from taking them off the water to fall into the water. Contribution of droplets to the momentum balance of air flow is determined by the total momentum balance of sea sprays. The calculations in the model showed that the momentum exchange with the spray can lead to either a weak (less than 10%) increase of the aerodynamic surface drag or to a weak reduction (within Koga's model [2]). Recommendations for the experiment on investigation of the "life cycle" of spray in the air flow are suggested. This work was supported by RFBR (project 11-05-12047-ofi-m, 13-05-00865-a, 12-05-33070 mol-a-ved, 12-05-31435 mol-a, 12-05-01064_A). References 1. Troitskaya, Y. I., D. A. Sergeev, A. A. Kandaurov, G. A. Baidakov, M. A. Vdovin, and V. I. Kazakov Laboratory and theoretical modeling of air-sea momentum transfer under severe wind conditions J.Geophys. Res., 117, C00J21, doi:10.1029/2011JC007778. 2. Koga M. Direct production of droplets from breaking wind-waves - its observation by a multi-colored overlapping exposure photographing technique // Tellus. 1981. V.33. Issue 6. P. 552-563. 3. Spiel D.E. On the birth of jet drops from bubbles bursting on water surfaces // J. Geophys. Res. 1995. V.100. P. 4995-5006. 4. Andreas E. L., 1998: A new sea spray generation function for wind speeds up to 32 m s21. J. Phys. Oceanogr., 28, 2175-2184.