Upper extremity fractures among hospitalized road traffic accident adults.

PubMed

Rubin, Guy; Peleg, Kobi; Givon, Adi; Rozen, Nimrod

2015-02-01

Upper extremity fractures (UEFs) associated with road traffic accidents (RTAs) may result in long-term disability. Previous studies have examined UEF profiles with small patient populations. The objective of this study was to examine the injury profiles of UEFs in all mechanisms of injury related to RTAs. Data on 71,231 RTA adult patients between 1997 and 2012 whose records were entered in a centralized country trauma database were reviewed. Data on UEFs related to mechanism of injury (car, motorcycle, bicycle, and pedestrian) including associated injuries, multiple UEFs, and frequency of UEF were analyzed. Of 71,231 adult RTA cases recorded in 1997-2012, 12,754 (17.9%) included UEFs. Motorcycle (27%) and bicycle riders (25%) had the greater risk for UEF (P<.0001). Of 12,754 patients with UEFs, 9701 (76%) had other injuries. Pedestrians (86%) and car occupants (81%) had the greater risk for associated injuries (P<.0001). Most of the injuries were head/face/neck (52%), lower extremities (49%), and chest (46%) injuries (P<.0001). Twenty-two percent of all cases had multiple UEFs. The motorcycle riders (27%) had the greater risk for multiple UEFs (P<.0001). Of 12,754 patients with UEFs we found 16,371 UEFs. Most of the fractures were in the radius (22%), humerus (19%), and clavicle (17%) (P<.0001). This study contributes the largest database on reported adult UEFs related to all mechanisms of injury in RTAs and finds the comparative epidemiology of associated injuries, multiple UEFs, and frequency of UEFs. It is important that the treating surgeon is aware of the complexity of the UEF patient, the strong possibility for associated injury, the possibility for multiple fractures in the upper limbs, and the most common fractures associated with each mechanism of accident. Copyright © 2014 Elsevier Inc. All rights reserved.

A supramolecular biomimetic skin combining a wide spectrum of mechanical properties and multiple sensory capabilities.

PubMed

Lei, Zhouyue; Wu, Peiyi

2018-03-19

Biomimetic skin-like materials, capable of adapting shapes to variable environments and sensing external stimuli, are of great significance in a wide range of applications, including artificial intelligence, soft robotics, and smart wearable devices. However, such highly sophisticated intelligence has been mainly found in natural creatures while rarely realized in artificial materials. Herein, we fabricate a type of biomimetic iontronics to imitate natural skins using supramolecular polyelectrolyte hydrogels. The dynamic viscoelastic networks provide the biomimetic skin with a wide spectrum of mechanical properties, including flexible reconfiguration ability, robust elasticity, extremely large stretchability, autonomous self-healability, and recyclability. Meanwhile, polyelectrolytes' ionic conductivity allows multiple sensory capabilities toward temperature, strain, and stress. This work provides not only insights into dynamic interactions and sensing mechanism of supramolecular iontronics, but may also promote the development of biomimetic skins with sophisticated intelligence similar to natural skins.

Nanotechnology as a therapeutic tool to combat microbial resistance.

PubMed

Pelgrift, Robert Y; Friedman, Adam J

2013-11-01

Use of nanoparticles is among the most promising strategies to overcome microbial drug resistance. This review article consists of three parts. The first part discusses the epidemiology of microbial drug resistance. The second part describes mechanisms of drug resistance used by microbes. The third part explains how nanoparticles can overcome this resistance, including the following: Nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles all use multiple mechanisms simultaneously to combat microbes, thereby making development of resistance to these nanoparticles unlikely. Packaging multiple antimicrobial agents within the same nanoparticle also makes development of resistance unlikely. Nanoparticles can overcome existing drug resistance mechanisms, including decreased uptake and increased efflux of drug from the microbial cell, biofilm formation, and intracellular bacteria. Finally, nanoparticles can target antimicrobial agents to the site of infection, so that higher doses of drug are given at the infected site, thereby overcoming resistance. © 2013.

Satellite Remote Sensing of Harmful Algal Blooms (HABs) and a Potential Synthesized Framework

PubMed Central

Shen, Li; Xu, Huiping; Guo, Xulin

2012-01-01

Harmful algal blooms (HABs) are severe ecological disasters threatening aquatic systems throughout the World, which necessitate scientific efforts in detecting and monitoring them. Compared with traditional in situ point observations, satellite remote sensing is considered as a promising technique for studying HABs due to its advantages of large-scale, real-time, and long-term monitoring. The present review summarizes the suitability of current satellite data sources and different algorithms for detecting HABs. It also discusses the spatial scale issue of HABs. Based on the major problems identified from previous literature, including the unsystematic understanding of HABs, the insufficient incorporation of satellite remote sensing, and a lack of multiple oceanographic explanations of the mechanisms causing HABs, this review also attempts to provide a comprehensive understanding of the complicated mechanism of HABs impacted by multiple oceanographic factors. A potential synthesized framework can be established by combining multiple accessible satellite remote sensing approaches including visual interpretation, spectra analysis, parameters retrieval and spatial-temporal pattern analysis. This framework aims to lead to a systematic and comprehensive monitoring of HABs based on satellite remote sensing from multiple oceanographic perspectives. PMID:22969372

Free Energy Landscape and Multiple Folding Pathways of an H-Type RNA Pseudoknot

PubMed Central

Bian, Yunqiang; Zhang, Jian; Wang, Jun; Wang, Jihua; Wang, Wei

2015-01-01

How RNA sequences fold to specific tertiary structures is one of the key problems for understanding their dynamics and functions. Here, we study the folding process of an H-type RNA pseudoknot by performing a large-scale all-atom MD simulation and bias-exchange metadynamics. The folding free energy landscapes are obtained and several folding intermediates are identified. It is suggested that the folding occurs via multiple mechanisms, including a step-wise mechanism starting either from the first helix or the second, and a cooperative mechanism with both helices forming simultaneously. Despite of the multiple mechanism nature, the ensemble folding kinetics estimated from a Markov state model is single-exponential. It is also found that the correlation between folding and binding of metal ions is significant, and the bound ions mediate long-range interactions in the intermediate structures. Non-native interactions are found to be dominant in the unfolded state and also present in some intermediates, possibly hinder the folding process of the RNA. PMID:26030098

The Social Life of a Data Base

NASA Technical Reports Server (NTRS)

Linde, Charlotte; Wales, Roxana; Clancy, Dan (Technical Monitor)

2002-01-01

This paper presents the complex social life of a large data base. The topics include: 1) Social Construction of Mechanisms of Memory; 2) Data Bases: The Invisible Memory Mechanism; 3) The Human in the Machine; 4) Data of the Study: A Large-Scale Problem Reporting Data Base; 5) The PRACA Study; 6) Description of PRACA; 7) PRACA and Paper; 8) Multiple Uses of PRACA; 9) The Work of PRACA; 10) Multiple Forms of Invisibility; 11) Such Systems are Everywhere; and 12) Two Morals to the Story. This paper is in viewgraph form.

Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation: Transition State Stabilization via Multiple Non-Covalent Interactions

PubMed Central

Zuend, Stephan J.

2009-01-01

An experimental and computational investigation of amido-thiourea promoted imine hydrocyanation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple non-covalent interactions; these ion pairs collapse to form the enantiomeric α-aminonitrile products. This mechanistic proposal is supported by the observation of a statistically significant correlation between experimental and calculated enantioselectivities induced by eight different catalysts (P ≪ 0.01). The computed models reveal a basis for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and catalyst, including thiourea-cyanide and amide-iminium interactions. PMID:19778044

16 CFR 1507.12 - Multiple-tube fireworks devices.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Section 1507.12 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FEDERAL HAZARDOUS SUBSTANCES ACT... the inclined plane (not including the portion of the plane below the mechanical stop) shall be at... equivalent instrument. The mechanical stop on the inclined plane shall be 1/16 inches (1.6 mm) in height and...

Project Physics Tests 3, The Triumph of Mechanics.

ERIC Educational Resources Information Center

Harvard Univ., Cambridge, MA. Harvard Project Physics.

Test items relating to Project Physics Unit 3 are presented in this booklet. Included are 70 multiple-choice and 20 problem-and-essay questions. Concepts of mechanics are examined on energy, momentum, kinetic theory of gases, pulse analyses, "heat death," water waves, power, conservation laws, normal distribution, thermodynamic laws, and…

Cable and Line Inspection Mechanism

NASA Technical Reports Server (NTRS)

Ross, Terence J. (Inventor)

2003-01-01

An automated cable and line inspection mechanism visually scans the entire surface of a cable as the mechanism travels along the cable=s length. The mechanism includes a drive system, a video camera, a mirror assembly for providing the camera with a 360 degree view of the cable, and a laser micrometer for measuring the cable=s diameter. The drive system includes an electric motor and a plurality of drive wheels and tension wheels for engaging the cable or line to be inspected, and driving the mechanism along the cable. The mirror assembly includes mirrors that are positioned to project multiple images of the cable on the camera lens, each of which is of a different portion of the cable. A data transceiver and a video transmitter are preferably employed for transmission of video images, data and commands between the mechanism and a remote control station.

Cable and line inspection mechanism

NASA Technical Reports Server (NTRS)

Ross, Terence J. (Inventor)

2003-01-01

An automated cable and line inspection mechanism visually scans the entire surface of a cable as the mechanism travels along the cable=s length. The mechanism includes a drive system, a video camera, a mirror assembly for providing the camera with a 360 degree view of the cable, and a laser micrometer for measuring the cable=s diameter. The drive system includes an electric motor and a plurality of drive wheels and tension wheels for engaging the cable or line to be inspected, and driving the mechanism along the cable. The mirror assembly includes mirrors that are positioned to project multiple images of the cable on the camera lens, each of which is of a different portion of the cable. A data transceiver and a video transmitter are preferably employed for transmission of video images, data and commands between the mechanism and a remote control station.

Implementing Applied Behavior Analysis for Effective Orientation and Mobility Instruction of Students with Multiple Disabilities

ERIC Educational Resources Information Center

O'Mea, Melanie L.

2013-01-01

Working with children who have multiple disabilities that include visual impairments can be especially challenging. Many disabling conditions manifest into behavioral difficulties that may take away from learning. Acting out may be a student's way of expressing a lack of healthy coping mechanisms in relation to his or her environment. Implementing…

Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.

PubMed

Tsui, Dana Wai Yi; Murtaza, Muhammed; Wong, Alvin Seng Cheong; Rueda, Oscar M; Smith, Christopher G; Chandrananda, Dineika; Soo, Ross A; Lim, Hong Liang; Goh, Boon Cher; Caldas, Carlos; Forshew, Tim; Gale, Davina; Liu, Wei; Morris, James; Marass, Francesco; Eisen, Tim; Chin, Tan Min; Rosenfeld, Nitzan

2018-06-01

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR -mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Cells, Biomarkers, and Posttraumatic Stress Disorder: Evidence for Peripheral Involvement in a Central Disease

DTIC Science & Technology

2012-01-01

including; Alzheimer’s disease (Mac- cioni et al. 2009), Parkinson’s disease (Hirsch and Hunot 2009), spinal cord injury (Chan 2008), multiple sclerosis ...states such as multiple sclerosis (Kraus et al. 2000), human immunodeficiency virus dementia (Fischer- Smith et al. 2001), and meningitis (Cauwels et al...Immunologic mechanisms of multiple sclerosis . Neuroi- maging Clin. N. Am. 18, 577–588. Gaylord K. M. (2006) The psychosocial effects of combat: the frequently

Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience

PubMed Central

Holstein, Sarah A.; McCarthy, Philip L.

2017-01-01

Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. The IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory, however, the more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided greater insight into their mechanism of action. Here the clinical efficacy of these agents in myeloma is reviewed as well as discussion of structure-function relationship, the molecular mechanisms of action, and the association of IMiDs with second primary malignancies and thrombosis. PMID:28205024

Regulation of vesicular trafficking and leukocyte function by Rab27 GTPases and their effectors

PubMed Central

Catz, Sergio Daniel

2013-01-01

The Rab27 family of GTPases regulates the efficiency and specificity of exocytosis in hematopoietic cells, including neutrophils, CTLs, NK cells, and mast cells. However, the mechanisms regulated by Rab27 GTPases are cell-specific, as they depend on the differential expression and function of particular effector molecules that are recruited by the GTPases. In addition, Rab27 GTPases participate in multiple steps of the regulation of the secretory process, including priming, tethering, docking, and fusion through sequential interaction with multiple effector molecules. Finally, recent reports suggest that Rab27 GTPases and their effectors regulate vesicular trafficking mechanisms other than exocytosis, including endocytosis and phagocytosis. This review focuses on the latest discoveries on the function of Rab27 GTPases and their effectors Munc13-4 and Slp1 in neutrophil function comparatively to their functions in other leukocytes. PMID:23378593

The application of multiple biophysical cues to engineer functional neocartilage for treatment of osteoarthritis. Part II: signal transduction.

PubMed

Brady, Mariea A; Waldman, Stephen D; Ethier, C Ross

2015-02-01

The unique mechanoelectrochemical environment of cartilage has motivated researchers to investigate the effect of multiple biophysical cues, including mechanical, magnetic, and electrical stimulation, on chondrocyte biology. It is well established that biophysical stimuli promote chondrocyte proliferation, differentiation, and maturation within "biological windows" of defined dose parameters, including mode, frequency, magnitude, and duration of stimuli (see companion review Part I: Cellular Response). However, the underlying molecular mechanisms and signal transduction pathways activated in response to multiple biophysical stimuli remain to be elucidated. Understanding the mechanisms of biophysical signal transduction will deepen knowledge of tissue organogenesis, remodeling, and regeneration and aiding in the treatment of pathologies such as osteoarthritis. Further, this knowledge will provide the tissue engineer with a potent toolset to manipulate and control cell fate and subsequently develop functional replacement cartilage. The aim of this article is to review chondrocyte signal transduction pathways in response to mechanical, magnetic, and electrical cues. Signal transduction does not occur along a single pathway; rather a number of parallel pathways appear to be activated, with calcium signaling apparently common to all three types of stimuli, though there are different modes of activation. Current tissue engineering strategies, such as the development of "smart" functionalized biomaterials that enable the delivery of growth factors or integration of conjugated nanoparticles, may further benefit from targeting known signal transduction pathways in combination with external biophysical cues.

Mechanical design of NASA Ames Research Center vertical motion simulator

NASA Technical Reports Server (NTRS)

Engelbert, D. F.; Bakke, A. P.; Chargin, M. K.; Vallotton, W. C.

1976-01-01

NASA has designed and is constructing a new flight simulator with large vertical travel. Several aspects of the mechanical design of this Vertical Motion Simulator (VMS) are discussed, including the multiple rack and pinion vertical drive, a pneumatic equilibration system, and the friction-damped rigid link catenaries used as cable supports.

A rare condition of anorectal dysfunction in a patient with multiple sclerosis: Coexistence of faecal incontinence and mechanical constipation: Report of case

PubMed Central

Dandin, Özgür; Akpak, Yaşam Kemal; Karakaş, Dursun Özgür; Hazer, Batuhan; Ergin, Tuncer; Dandinoğlu, Taner; Teomete, Uygar

2014-01-01

INTRODUCTION Multiple sclerosis is a chronic demyelinating neurological disease and causing a variety of neurological symptoms, including discomfort of anorectal function. Constipation and faecal incontinence present as anorectal dysfunction in MS and anal manometry, colonic transit time, electromyography, and defecography can be used for assessment. PRESENTATION OF CASE We presented a thirty-three years old woman with rare condition of anorectal dysfunction in multiple sclerosis. Anal manometry, defecography were done, and synchronously anal incontinence and mechanical constipation due to rectocele and anismus were detected in this patient. DISCUSSION Although anal incontinence and constipation are seen often in patients with multiple sclerosis, in the literature, coexistence of animus, rectocele and anal incontinence are quite rare. CONCLUSION Defecography and anal manometry are useful diagnostic methods for demonstration of anorectal dysfuntions in patients with MS. PMID:25460483

A rare condition of anorectal dysfunction in a patient with multiple sclerosis: Coexistence of faecal incontinence and mechanical constipation: Report of case.

PubMed

Dandin, Özgür; Akpak, Yaşam Kemal; Karakaş, Dursun Özgür; Hazer, Batuhan; Ergin, Tuncer; Dandinoğlu, Taner; Teomete, Uygar

2014-01-01

Multiple sclerosis is a chronic demyelinating neurological disease and causing a variety of neurological symptoms, including discomfort of anorectal function. Constipation and faecal incontinence present as anorectal dysfunction in MS and anal manometry, colonic transit time, electromyography, and defecography can be used for assessment. We presented a thirty-three years old woman with rare condition of anorectal dysfunction in multiple sclerosis. Anal manometry, defecography were done, and synchronously anal incontinence and mechanical constipation due to rectocele and anismus were detected in this patient. Although anal incontinence and constipation are seen often in patients with multiple sclerosis, in the literature, coexistence of animus, rectocele and anal incontinence are quite rare. Defecography and anal manometry are useful diagnostic methods for demonstration of anorectal dysfuntions in patients with MS. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses

PubMed Central

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-01-01

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage. PMID:27021285

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses.

PubMed

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-03-29

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage.

Mission Concepts and Operations for Asteroid Mitigation Involving Multiple Gravity Tractors

NASA Technical Reports Server (NTRS)

Foster, Cyrus; Bellerose, Julie; Jaroux, Belgacem; Mauro, David

2012-01-01

The gravity tractor concept is a proposed method to deflect an imminent asteroid impact through gravitational tugging over a time scale of years. In this study, we present mission scenarios and operational considerations for asteroid mitigation efforts involving multiple gravity tractors. We quantify the deflection performance improvement provided by a multiple gravity tractor campaign and assess its sensitivity to staggered launches. We next explore several proximity operation strategies to accommodate multiple gravity tractors at a single asteroid including formation-flying and mechanically-docked configurations. Finally, we utilize 99942 Apophis as an illustrative example to assess the performance of a multiple gravity tractor campaign.

Concept of multiple-cell cavity for axion dark matter search

NASA Astrophysics Data System (ADS)

Jeong, Junu; Youn, SungWoo; Ahn, Saebyeok; Kim, Jihn E.; Semertzidis, Yannis K.

2018-02-01

In cavity-based axion dark matter search experiments exploring high mass regions, multiple-cavity design is under consideration as a method to increase the detection volume within a given magnet bore. We introduce a new idea, referred to as a multiple-cell cavity, which provides various benefits including a larger detection volume, simpler experimental setup, and easier phase-matching mechanism. We present the characteristics of this concept and demonstrate the experimental feasibility with an example of a double-cell cavity.

(abstract) Experimental Results From Internetworking Data Applications Over Various Wireless Networks Using a Single Flexible Error Control Protocol

NASA Technical Reports Server (NTRS)

Kanai, T.; Kramer, M.; McAuley, A. J.; Nowack, S.; Pinck, D. S.; Ramirez, G.; Stewart, I.; Tohme, H.; Tong, L.

1995-01-01

This paper describes results from several wireless field trials in New Jersey, California, and Colorado, conducted jointly by researchers at Bellcore, JPL, and US West over the course of 1993 and 1994. During these trials, applications communicated over multiple wireless networks including satellite, low power PCS, high power cellular, packet data, and the wireline Public Switched Telecommunications Network (PSTN). Key goals included 1) designing data applications and an API suited to mobile users, 2) investigating internetworking issues, 3) characterizing wireless networks under various field conditions, and 4) comparing the performance of different protocol mechanisms over the diverse networks and applications. We describe experimental results for different protocol mechanisms and parameters, such as acknowledgment schemes and packet sizes. We show the need for powerful error control mechanisms such as selective acknowledgements and combining data from multiple transmissions. We highlight the possibility of a common protocol for all wireless networks, from micro-cellular PCS to satellite networks.

Integration and Testing Challenges of Small, Multiple Satellite Missions: Experiences From The Space Technology 5 Project

NASA Technical Reports Server (NTRS)

Sauerwein, Timothy A.; Gostomski, Thomas

2007-01-01

This brief presentation describes the mechanical and electrical integration activities and environmental testing challenges of the Space Technology 5 (ST5) Project. Lessons learned during this process are highlighted, including performing mechanical activities serially to gain efficiency through repetition and performing electrical activities based on the level of subsystem expertise available.

Student Assessment System. Domain Referenced Tests. Transportation/Automotive Mechanics. Volume II: Theory. Georgia Vocational Education Program Articulation.

ERIC Educational Resources Information Center

Watkins, James F., Comp.

These written domain referenced tests (DRTs) for the area of transportation/automotive mechanics test cognitive abilities or knowledge of theory. Introductory materials describe domain referenced testing and test development. Each multiple choice test includes a domain statement, describing the behavior and content of the domain, and a test item…

Mechanic/maintenance training and certification program.

DOT National Transportation Integrated Search

2017-04-01

The Indiana Department of Transportation (INDOT) is divided into six districts, with district offices located in La Porte, Fort Wayne, : Crawfordsville, Greenfield, Vincennes, and Seymour. Each district includes multiple vehicle maintenance shops (to...

Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis.

PubMed

Ravits, John; Appel, Stanley; Baloh, Robert H; Barohn, Richard; Brooks, Benjamin Rix; Elman, Lauren; Floeter, Mary Kay; Henderson, Christopher; Lomen-Hoerth, Catherine; Macklis, Jeffrey D; McCluskey, Leo; Mitsumoto, Hiroshi; Przedborski, Serge; Rothstein, Jeffrey; Trojanowski, John Q; van den Berg, Leonard H; Ringel, Steven

2013-05-01

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.

Computational Models and Emergent Properties of Respiratory Neural Networks

PubMed Central

Lindsey, Bruce G.; Rybak, Ilya A.; Smith, Jeffrey C.

2012-01-01

Computational models of the neural control system for breathing in mammals provide a theoretical and computational framework bringing together experimental data obtained from different animal preparations under various experimental conditions. Many of these models were developed in parallel and iteratively with experimental studies and provided predictions guiding new experiments. This data-driven modeling approach has advanced our understanding of respiratory network architecture and neural mechanisms underlying generation of the respiratory rhythm and pattern, including their functional reorganization under different physiological conditions. Models reviewed here vary in neurobiological details and computational complexity and span multiple spatiotemporal scales of respiratory control mechanisms. Recent models describe interacting populations of respiratory neurons spatially distributed within the Bötzinger and pre-Bötzinger complexes and rostral ventrolateral medulla that contain core circuits of the respiratory central pattern generator (CPG). Network interactions within these circuits along with intrinsic rhythmogenic properties of neurons form a hierarchy of multiple rhythm generation mechanisms. The functional expression of these mechanisms is controlled by input drives from other brainstem components, including the retrotrapezoid nucleus and pons, which regulate the dynamic behavior of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple levels of circuit organization. This allows flexible, state-dependent expression of different neural pattern-generation mechanisms under various physiological conditions, enabling a wide repertoire of respiratory behaviors. Some models consider control of the respiratory CPG by pulmonary feedback and network reconfiguration during defensive behaviors such as cough. Future directions in modeling of the respiratory CPG are considered. PMID:23687564

Distinct representations of subtraction and multiplication in the neural systems for numerosity and language

PubMed Central

Prado, Jérôme; Mutreja, Rachna; Zhang, Hongchuan; Mehta, Rucha; Desroches, Amy S.; Minas, Jennifer E.; Booth, James R.

2010-01-01

It has been proposed that recent cultural inventions such as symbolic arithmetic recycle evolutionary older neural mechanisms. A central assumption of this hypothesis is that the degree to which a pre-existing mechanism is recycled depends upon the degree of similarity between its initial function and the novel task. To test this assumption, we investigated whether the brain region involved in magnitude comparison in the intraparietal sulcus (IPS), localized by a numerosity comparison task, is recruited to a greater degree by arithmetic problems that involve number comparison (single-digit subtractions) than by problems that involve retrieving facts from memory (single-digit multiplications). Our results confirmed that subtractions are associated with greater activity in the IPS than multiplications, whereas multiplications elicit greater activity than subtractions in regions involved in verbal processing including the middle temporal gyrus and inferior frontal gyrus that were localized by a phonological processing task. Pattern analyses further indicated that the neural mechanisms more active for subtraction than multiplication in the IPS overlap with those involved in numerosity comparison, and that the strength of this overlap predicts inter-individual performance in the subtraction task. These findings provide novel evidence that elementary arithmetic relies on the co-option of evolutionary older neural circuits. PMID:21246667

Intraspecific density dependence and a guild of consumers coexisting on one resource.

PubMed

McPeek, Mark A

2012-12-01

The importance of negative intraspecific density dependence to promoting species coexistence in a community is well accepted. However, such mechanisms are typically omitted from more explicit models of community dynamics. Here I analyze a variation of the Rosenzweig-MacArthur consumer-resource model that includes negative intraspecific density dependence for consumers to explore its effect on the coexistence of multiple consumers feeding on a single resource. This analysis demonstrates that a guild of multiple consumers can easily coexist on a single resource if each limits its own abundance to some degree, and stronger intraspecific density dependence permits a wider variety of consumers to coexist. The mechanism permitting multiple consumers to coexist works in a fashion similar to apparent competition or to each consumer having its own specialized predator. These results argue for a more explicit emphasis on how negative intraspecific density dependence is generated and how these mechanisms combine with species interactions to shape overall community structure.

Antiviral Defense Mechanisms in Honey Bees

PubMed Central

Brutscher, Laura M.; Daughenbaugh, Katie F.; Flenniken, Michelle L.

2015-01-01

Honey bees are significant pollinators of agricultural crops and other important plant species. High annual losses of honey bee colonies in North America and in some parts of Europe have profound ecological and economic implications. Colony losses have been attributed to multiple factors including RNA viruses, thus understanding bee antiviral defense mechanisms may result in the development of strategies that mitigate colony losses. Honey bee antiviral defense mechanisms include RNA-interference, pathogen-associated molecular pattern (PAMP) triggered signal transduction cascades, and reactive oxygen species generation. However, the relative importance of these and other pathways is largely uncharacterized. Herein we review the current understanding of honey bee antiviral defense mechanisms and suggest important avenues for future investigation. PMID:26273564

NON-MENDELIAN ETIOLOGIC FACTORS IN NEUROPSYCHIATRIC ILLNESS: PLEIOTROPY, EPIGENETICS, AND CONVERGENCE

PubMed Central

Deutsch, Curtis K; McIlvane, William J

2013-01-01

The target article by Charney on behavior genetics/genomics discusses how numerous molecular factors can inform heritability estimations and genetic association studies. These factors find application in the search for genes for behavioral phenotypes, including neuropsychiatric disorders. We elaborate upon how single causal factors can generate multiple phenotypes, and discuss how multiple causal factors may converge on common neurodevelopmental mechanisms. PMID:23095384

Multiple-time scales analysis of physiological time series under neural control

NASA Technical Reports Server (NTRS)

Peng, C. K.; Hausdorff, J. M.; Havlin, S.; Mietus, J. E.; Stanley, H. E.; Goldberger, A. L.

1998-01-01

We discuss multiple-time scale properties of neurophysiological control mechanisms, using heart rate and gait regulation as model systems. We find that scaling exponents can be used as prognostic indicators. Furthermore, detection of more subtle degradation of scaling properties may provide a novel early warning system in subjects with a variety of pathologies including those at high risk of sudden death.

Insecticide resistance is mediated by multiple mechanisms in recently introduced Aedes aegypti from Madeira Island (Portugal).

PubMed

Seixas, Gonçalo; Grigoraki, Linda; Weetman, David; Vicente, José Luís; Silva, Ana Clara; Pinto, João; Vontas, John; Sousa, Carla Alexandra

2017-07-01

Aedes aegypti is a major mosquito vector of arboviruses, including dengue, chikungunya and Zika. In 2005, Ae. aegypti was identified for the first time in Madeira Island. Despite an initial insecticide-based vector control program, the species expanded throughout the Southern coast of the island, suggesting the presence of insecticide resistance. Here, we characterized the insecticide resistance status and the underlying mechanisms of two populations of Ae. aegypti from Madeira Island, Funchal and Paúl do Mar. WHO susceptibility bioassays indicated resistance to cyfluthrin, permethrin, fenitrothion and bendiocarb. Use of synergists significantly increased mortality rates, and biochemical assays indicated elevated activities of detoxification enzymes, suggesting the importance of metabolic resistance. Microarray-based transcriptome analysis detected significant upregulation in both populations of nine cytochrome P450 oxidase genes (including four known pyrethroid metabolizing enzymes), the organophosphate metabolizer CCEae3a, Glutathione-S-transferases, and multiple putative cuticle proteins. Genotyping of knockdown resistance loci linked to pyrethroid resistance revealed fixation of the 1534C mutation, and presence with moderate frequencies of the V1016I mutation in each population. Significant resistance to three major insecticide classes (pyrethroid, carbamate and organophosphate) is present in Ae. aegypti from Madeira Island, and appears to be mediated by multiple mechanisms. Implementation of appropriate resistance management strategies including rotation of insecticides with alternative modes of action, and methods other than chemical-based vector control are strongly advised to delay or reverse the spread of resistance and achieve efficient control.

Biosynthesis of Jasmine Lactone in Tea ( Camellia sinensis) Leaves and Its Formation in Response to Multiple Stresses.

PubMed

Zeng, Lanting; Zhou, Ying; Fu, Xiumin; Liao, Yinyin; Yuan, Yunfei; Jia, Yongxia; Dong, Fang; Yang, Ziyin

2018-04-18

Jasmine lactone has a potent odor that contributes to the fruity, sweet floral aroma of tea ( Camellia sinensis). Our previous study demonstrated that jasmine lactone was mostly accumulated at the turnover stage of the oolong tea manufacturing process. This study investigates the previously unknown mechanism of formation of jasmine lactone in tea leaves exposed to multiple stresses occurring during the growth and manufacturing processes. Both continuous mechanical damage and the dual stress of low temperature and mechanical damage enhanced jasmine lactone accumulation in tea leaves. In addition, only one pathway, via hydroperoxy fatty acids from unsaturated fatty acid, including linoleic acid and α-linolenic acid, under the action of lipoxygenases (LOXs), especially CsLOX1, was significantly affected by these stresses. This is the first evidence of the mechanism of jasmine lactone formation in tea leaves and is a characteristic example of plant volatile formation in response to dual stress.

Mechanically scanned deployable antenna study

NASA Technical Reports Server (NTRS)

1983-01-01

The conceptual design of a Mechanically Scanned Deployable Antenna which is launched by the STS (Space Shuttle) to provide radiometric brightness temperature maps of the Earth and oceans at selected frequency bands in the frequency range of 1.4 GHz to 11 GHz is presented. Unlike previous scanning radiometric systems, multiple radiometers for each frequency are required in order to fill in the resolution cells across the swath created by the 15 meter diameter spin stabilized system. This multiple beam radiometric system is sometimes designated as a ""whiskbroom'' system in that it combines the techniques of the scanning and ""pushbroom'' type systems. The definition of the feed system including possible feed elements and location, determination of the fundamental reflector feed offset geometry including offset angles and f/D ratio, preliminary estimates of the beam efficiency of the feed reflector system, a summary of reflector mesh losses at the proposed radiometric frequency bands, an overall conceptual configuration design and preliminary structural and thermal analyses are included.

Mesoscopic Modeling of Blood Clotting: Coagulation Cascade and Platelets Adhesion

NASA Astrophysics Data System (ADS)

Yazdani, Alireza; Li, Zhen; Karniadakis, George

2015-11-01

The process of clot formation and growth at a site on a blood vessel wall involve a number of multi-scale simultaneous processes including: multiple chemical reactions in the coagulation cascade, species transport and flow. To model these processes we have incorporated advection-diffusion-reaction (ADR) of multiple species into an extended version of Dissipative Particle Dynamics (DPD) method which is considered as a coarse-grained Molecular Dynamics method. At the continuum level this is equivalent to the Navier-Stokes equation plus one advection-diffusion equation for each specie. The chemistry of clot formation is now understood to be determined by mechanisms involving reactions among many species in dilute solution, where reaction rate constants and species diffusion coefficients in plasma are known. The role of blood particulates, i.e. red cells and platelets, in the clotting process is studied by including them separately and together in the simulations. An agonist-induced platelet activation mechanism is presented, while platelets adhesive dynamics based on a stochastic bond formation/dissociation process is included in the model.

Flexibility, Diversity, and Cooperativity: Pillars of Enzyme Catalysis

PubMed Central

Hammes, Gordon G.; Benkovic, Stephen J.; Hammes-Schiffer, Sharon

2011-01-01

This brief review discusses our current understanding of the molecular basis of enzyme catalysis. A historical development is presented, beginning with steady state kinetics and progressing through modern fast reaction methods, NMR, and single molecule fluorescence techniques. Experimental results are summarized for ribonuclease, aspartate aminotransferase, and especially dihydrofolate reductase (DHFR). Multiple intermediates, multiple conformations, and cooperative conformational changes are shown to be an essential part of virtually all enzyme mechanisms. In the case of DHFR, theoretical investigations have provided detailed information about the movement of atoms within the enzyme-substrate complex as the reaction proceeds along the collective reaction coordinate for hydride transfer. A general mechanism is presented for enzyme catalysis that includes multiple intermediates and a complex, multidimensional standard free energy surface. Protein flexibility, diverse protein conformations, and cooperative conformational changes are important features of this model. PMID:22029278

Distributed Circuit Plasticity: New Clues for the Cerebellar Mechanisms of Learning.

PubMed

D'Angelo, Egidio; Mapelli, Lisa; Casellato, Claudia; Garrido, Jesus A; Luque, Niceto; Monaco, Jessica; Prestori, Francesca; Pedrocchi, Alessandra; Ros, Eduardo

2016-04-01

The cerebellum is involved in learning and memory of sensory motor skills. However, the way this process takes place in local microcircuits is still unclear. The initial proposal, casted into the Motor Learning Theory, suggested that learning had to occur at the parallel fiber-Purkinje cell synapse under supervision of climbing fibers. However, the uniqueness of this mechanism has been questioned, and multiple forms of long-term plasticity have been revealed at various locations in the cerebellar circuit, including synapses and neurons in the granular layer, molecular layer and deep-cerebellar nuclei. At present, more than 15 forms of plasticity have been reported. There has been a long debate on which plasticity is more relevant to specific aspects of learning, but this question turned out to be hard to answer using physiological analysis alone. Recent experiments and models making use of closed-loop robotic simulations are revealing a radically new view: one single form of plasticity is insufficient, while altogether, the different forms of plasticity can explain the multiplicity of properties characterizing cerebellar learning. These include multi-rate acquisition and extinction, reversibility, self-scalability, and generalization. Moreover, when the circuit embeds multiple forms of plasticity, it can easily cope with multiple behaviors endowing therefore the cerebellum with the properties needed to operate as an effective generalized forward controller.

Unique Bond Breaking in Crystalline Phase Change Materials and the Quest for Metavalent Bonding.

PubMed

Zhu, Min; Cojocaru-Mirédin, Oana; Mio, Antonio M; Keutgen, Jens; Küpers, Michael; Yu, Yuan; Cho, Ju-Young; Dronskowski, Richard; Wuttig, Matthias

2018-05-01

Laser-assisted field evaporation is studied in a large number of compounds, including amorphous and crystalline phase change materials employing atom probe tomography. This study reveals significant differences in field evaporation between amorphous and crystalline phase change materials. High probabilities for multiple events with more than a single ion detected per laser pulse are only found for crystalline phase change materials. The specifics of this unusual field evaporation are unlike any other mechanism shown previously to lead to high probabilities of multiple events. On the contrary, amorphous phase change materials as well as other covalently bonded compounds and metals possess much lower probabilities for multiple events. Hence, laser-assisted field evaporation in amorphous and crystalline phase change materials reveals striking differences in bond rupture. This is indicative for pronounced differences in bonding. These findings imply that the bonding mechanism in crystalline phase change materials differs substantially from conventional bonding mechanisms such as metallic, ionic, and covalent bonding. Instead, the data reported here confirm a recently developed conjecture, namely that metavalent bonding is a novel bonding mechanism besides those mentioned previously. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands.

PubMed

Allison, Simon J; Sadiq, Maria; Baronou, Efstathia; Cooper, Patricia A; Dunnill, Chris; Georgopoulos, Nikolaos T; Latif, Ayşe; Shepherd, Samantha; Shnyder, Steve D; Stratford, Ian J; Wheelhouse, Richard T; Willans, Charlotte E; Phillips, Roger M

2017-09-10

Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Lightweight Radiator System for a Spacecraft

NASA Technical Reports Server (NTRS)

Copeland, Robert J.; Mason, Georgia; Weislogel, Mark M.

2005-01-01

Three documents describe various aspects of a proposed lightweight, deployable radiator system for dissipating excess heat from the life-support system of a habitable spacecraft. The first document focuses on a radiator tube that would include a thin metal liner surrounded and supported by a thicker carbon-fiber-reinforced composite tubular structure that, in turn, would be formed as part of a unitary composite radiator-fin structure consisting mostly of a sheet of reticulated vitreous carbon laminated between carbon-fiber-reinforced face sheets. The thermal and mechanical properties, including the anisotropies, of the component materials are taken into account in the design. The second document describes thermo-structural bumpers, in the form of exterior multiple-ply carbon-fiber sheets enclosing hollows on opposite sides of a radiator fin, which would protect the radiator tube against impinging micrometeors and orbital debris. The third document describes a radiator system that would include multiple panels containing the aforementioned components, among others. The system would also include mechanisms for deploying the panels from compact stowage. Deployment would not involve breaking and remaking of fluid connections to the radiator panels.

Association of Central Adiposity With Adverse Cardiac Mechanics: Findings From the Hypertension Genetic Epidemiology Network Study.

PubMed

Selvaraj, Senthil; Martinez, Eva E; Aguilar, Frank G; Kim, Kwang-Youn A; Peng, Jie; Sha, Jin; Irvin, Marguerite R; Lewis, Cora E; Hunt, Steven C; Arnett, Donna K; Shah, Sanjiv J

2016-06-01

Central obesity, defined by increased waist circumference or waist:hip ratio (WHR), is associated with increased cardiovascular events, including heart failure. However, the pathophysiological link between central obesity and adverse cardiovascular outcomes remains poorly understood. We hypothesized that central obesity and larger WHR are independently associated with worse cardiac mechanics (reduced left ventricular strain and systolic [s'] and early diastolic [e'] tissue velocities). We performed speckle-tracking analysis of echocardiograms from participants in the Hypertension Genetic Epidemiology Network (HyperGEN) study, a population- and family-based epidemiological study (n=2181). Multiple indices of systolic and diastolic cardiac mechanics were measured. We evaluated the association between central obesity and cardiac mechanics using multivariable-adjusted linear mixed-effects models to account for relatedness among participants. The mean age of the cohort was 51±14 years, 58% were women, and 47% were black. Mean body mass index was 30.8±7.1 kg/m(2), waist circumference was 102±17 cm, WHR was 0.91±0.08, and 80% had central obesity based on waist circumference and WHR criteria. After adjusting for multiple potential confounders (including age, sex, race, physical activity, body mass index, heart rate, smoking status, systolic blood pressure, fasting glucose, total cholesterol, antihypertensive medication use, glomerular filtration rate, left ventricular mass index, wall motion abnormalities, and ejection fraction), central obesity and WHR remained associated with worse global longitudinal strain, early diastolic strain rate, s' velocity, and e' velocity (P<0.05 for all comparisons). There were no significant statistical interactions between WHR and obesity status. In this cross-sectional study of participants with multiple comorbidities, central obesity was found to be associated with adverse cardiac mechanics. © 2016 American Heart Association, Inc.

Multiple Approaches to Design Education

ERIC Educational Resources Information Center

Fox, Richard L.; And Others

1974-01-01

Discusses implementation of Sloan Foundation projects at the Case Western School of Engineering, including the development of a computer assisted mechanical structural design course, the establishment of a complex systems laboratory, and personnel views of industry-university design projects. (CC)

Mechanisms for Differential Protein Production in Toxin–Antitoxin Systems

PubMed Central

Deter, Heather S.; Jensen, Roderick V.; Mather, William H.; Butzin, Nicholas C.

2017-01-01

Toxin–antitoxin (TA) systems are key regulators of bacterial persistence, a multidrug-tolerant state found in bacterial species that is a major contributing factor to the growing human health crisis of antibiotic resistance. Type II TA systems consist of two proteins, a toxin and an antitoxin; the toxin is neutralized when they form a complex. The ratio of antitoxin to toxin is significantly greater than 1.0 in the susceptible population (non-persister state), but this ratio is expected to become smaller during persistence. Analysis of multiple datasets (RNA-seq, ribosome profiling) and results from translation initiation rate calculators reveal multiple mechanisms that ensure a high antitoxin-to-toxin ratio in the non-persister state. The regulation mechanisms include both translational and transcriptional regulation. We classified E. coli type II TA systems into four distinct classes based on the mechanism of differential protein production between toxin and antitoxin. We find that the most common regulation mechanism is translational regulation. This classification scheme further refines our understanding of one of the fundamental mechanisms underlying bacterial persistence, especially regarding maintenance of the antitoxin-to-toxin ratio. PMID:28677629

Numerical implementation of multiple peeling theory and its application to spider web anchorages.

PubMed

Brely, Lucas; Bosia, Federico; Pugno, Nicola M

2015-02-06

Adhesion of spider web anchorages has been studied in recent years, including the specific functionalities achieved through different architectures. To better understand the delamination mechanisms of these and other biological or artificial fibrillar adhesives, and how their adhesion can be optimized, we develop a novel numerical model to simulate the multiple peeling of structures with arbitrary branching and adhesion angles, including complex architectures. The numerical model is based on a recently developed multiple peeling theory, which extends the energy-based single peeling theory of Kendall, and can be applied to arbitrarily complex structures. In particular, we numerically show that a multiple peeling problem can be treated as the superposition of single peeling configurations even for complex structures. Finally, we apply the developed numerical approach to study spider web anchorages, showing how their function is achieved through optimal geometrical configurations.

Numerical implementation of multiple peeling theory and its application to spider web anchorages

PubMed Central

Brely, Lucas; Bosia, Federico; Pugno, Nicola M.

2015-01-01

Adhesion of spider web anchorages has been studied in recent years, including the specific functionalities achieved through different architectures. To better understand the delamination mechanisms of these and other biological or artificial fibrillar adhesives, and how their adhesion can be optimized, we develop a novel numerical model to simulate the multiple peeling of structures with arbitrary branching and adhesion angles, including complex architectures. The numerical model is based on a recently developed multiple peeling theory, which extends the energy-based single peeling theory of Kendall, and can be applied to arbitrarily complex structures. In particular, we numerically show that a multiple peeling problem can be treated as the superposition of single peeling configurations even for complex structures. Finally, we apply the developed numerical approach to study spider web anchorages, showing how their function is achieved through optimal geometrical configurations. PMID:25657835

Fostering the Development of Critical Thinking Skills, and Reading Comprehension of Undergraduates Using a Web 2.0 Tool Coupled with a Learning System

ERIC Educational Resources Information Center

Mendenhall, Anne; Johnson, Tristan E.

2010-01-01

A social annotation model learning system (SAM-LS) was created using multiple instructional strategies thereby supporting the student in improving in critical thinking, critical writing and related literacy. There are four mechanisms in which the SAM-LS methodology is believed to improve learning and performance. These mechanisms include providing…

Insecticide resistance is mediated by multiple mechanisms in recently introduced Aedes aegypti from Madeira Island (Portugal)

PubMed Central

Seixas, Gonçalo; Grigoraki, Linda; Weetman, David; Vicente, José Luís; Silva, Ana Clara; Pinto, João; Vontas, John

2017-01-01

Background Aedes aegypti is a major mosquito vector of arboviruses, including dengue, chikungunya and Zika. In 2005, Ae. aegypti was identified for the first time in Madeira Island. Despite an initial insecticide-based vector control program, the species expanded throughout the Southern coast of the island, suggesting the presence of insecticide resistance. Here, we characterized the insecticide resistance status and the underlying mechanisms of two populations of Ae. aegypti from Madeira Island, Funchal and Paúl do Mar. Methodology/Principal findings WHO susceptibility bioassays indicated resistance to cyfluthrin, permethrin, fenitrothion and bendiocarb. Use of synergists significantly increased mortality rates, and biochemical assays indicated elevated activities of detoxification enzymes, suggesting the importance of metabolic resistance. Microarray-based transcriptome analysis detected significant upregulation in both populations of nine cytochrome P450 oxidase genes (including four known pyrethroid metabolizing enzymes), the organophosphate metabolizer CCEae3a, Glutathione-S-transferases, and multiple putative cuticle proteins. Genotyping of knockdown resistance loci linked to pyrethroid resistance revealed fixation of the 1534C mutation, and presence with moderate frequencies of the V1016I mutation in each population. Conclusions/Significance Significant resistance to three major insecticide classes (pyrethroid, carbamate and organophosphate) is present in Ae. aegypti from Madeira Island, and appears to be mediated by multiple mechanisms. Implementation of appropriate resistance management strategies including rotation of insecticides with alternative modes of action, and methods other than chemical-based vector control are strongly advised to delay or reverse the spread of resistance and achieve efficient control. PMID:28742096

Genome-wide analysis of the interaction between the endosymbiotic bacterium Wolbachia and its Drosophila host.

PubMed

Xi, Zhiyong; Gavotte, Laurent; Xie, Yan; Dobson, Stephen L

2008-01-02

Intracellular Wolbachia bacteria are obligate, maternally-inherited, endosymbionts found frequently in insects and other invertebrates. The success of Wolbachia can be attributed in part to an ability to alter host reproduction via mechanisms including cytoplasmic incompatibility (CI), parthenogenesis, feminization and male killing. Despite substantial scientific effort, the molecular mechanisms underlying the Wolbachia/host interaction are unknown. Here, an in vitro Wolbachia infection was generated in the Drosophila S2 cell line, and transcription profiles of infected and uninfected cells were compared by microarray. Differentially-expressed patterns related to reproduction, immune response and heat stress response are observed, including multiple genes that have been previously reported to be involved in the Wolbachia/host interaction. Subsequent in vivo characterization of differentially-expressed products in gonads demonstrates that Angiotensin Converting Enzyme (Ance) varies between Wolbachia infected and uninfected flies and that the variation occurs in a sex-specific manner. Consistent with expectations for the conserved CI mechanism, the observed Ance expression pattern is repeatable in different Drosophila species and with different Wolbachia types. To examine Ance involvement in the CI phenotype, compatible and incompatible crosses of Ance mutant flies were conducted. Significant differences are observed in the egg hatch rate resulting from incompatible crosses, providing support for additional experiments examining for an interaction of Ance with the CI mechanism. Wolbachia infection is shown to affect the expression of multiple host genes, including Ance. Evidence for potential Ance involvement in the CI mechanism is described, including the prior report of Ance in spermatid differentiation, Wolbachia-induced sex-specific effects on Ance expression and an Ance mutation effect on CI levels. The results support the use of Wolbachia infected cell cultures as an appropriate model for predicting in vivo host/Wolbachia interactions.

Genome-wide analysis of the interaction between the endosymbiotic bacterium Wolbachia and its Drosophila host

PubMed Central

Xi, Zhiyong; Gavotte, Laurent; Xie, Yan; Dobson, Stephen L

2008-01-01

Background Intracellular Wolbachia bacteria are obligate, maternally-inherited, endosymbionts found frequently in insects and other invertebrates. The success of Wolbachia can be attributed in part to an ability to alter host reproduction via mechanisms including cytoplasmic incompatibility (CI), parthenogenesis, feminization and male killing. Despite substantial scientific effort, the molecular mechanisms underlying the Wolbachia/host interaction are unknown. Results Here, an in vitro Wolbachia infection was generated in the Drosophila S2 cell line, and transcription profiles of infected and uninfected cells were compared by microarray. Differentially-expressed patterns related to reproduction, immune response and heat stress response are observed, including multiple genes that have been previously reported to be involved in the Wolbachia/host interaction. Subsequent in vivo characterization of differentially-expressed products in gonads demonstrates that Angiotensin Converting Enzyme (Ance) varies between Wolbachia infected and uninfected flies and that the variation occurs in a sex-specific manner. Consistent with expectations for the conserved CI mechanism, the observed Ance expression pattern is repeatable in different Drosophila species and with different Wolbachia types. To examine Ance involvement in the CI phenotype, compatible and incompatible crosses of Ance mutant flies were conducted. Significant differences are observed in the egg hatch rate resulting from incompatible crosses, providing support for additional experiments examining for an interaction of Ance with the CI mechanism. Conclusion Wolbachia infection is shown to affect the expression of multiple host genes, including Ance. Evidence for potential Ance involvement in the CI mechanism is described, including the prior report of Ance in spermatid differentiation, Wolbachia-induced sex-specific effects on Ance expression and an Ance mutation effect on CI levels. The results support the use of Wolbachia infected cell cultures as an appropriate model for predicting in vivo host/Wolbachia interactions. PMID:18171476

Resveratrol and Alzheimer's Disease: Mechanistic Insights.

PubMed

Ahmed, Touqeer; Javed, Sehrish; Javed, Sana; Tariq, Ameema; Šamec, Dunja; Tejada, Silvia; Nabavi, Seyed Fazel; Braidy, Nady; Nabavi, Seyed Mohammad

2017-05-01

Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by progressive cognitive and memory deficits. The pathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles. Although several mechanisms have been used to explain the underlying pathogenesis of AD, current treatment regimens remain inadequate. The neuroprotective effects of the polyphenolic stilbene resveratrol (3,5,4'-trihydroxy-trans-stilbene) have been investigated in several in vitro and in vivo models of AD. The current review discusses the multiple potential mechanisms of action of resveratrol on the pathobiology of AD. Moreover, due to the limited pharmacokinetic parameters of resveratrol, multiple strategies aimed at increasing the bioavailability of resveratrol have also been addressed.

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation

PubMed Central

Chen, Chen; Zhou, Yifan; Wang, Jingqi; Yan, Yaping; Peng, Lisheng; Qiu, Wei

2018-01-01

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuroinflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. miRNAs regulate CD4+ T cells to differentiate toward various T cell subtypes including Th17 cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17 cells, and potential miRNA targets for current disease-modifying treatments.

Simplified computational methods for elastic and elastic-plastic fracture problems

NASA Technical Reports Server (NTRS)

Atluri, Satya N.

1992-01-01

An overview is given of some of the recent (1984-1991) developments in computational/analytical methods in the mechanics of fractures. Topics covered include analytical solutions for elliptical or circular cracks embedded in isotropic or transversely isotropic solids, with crack faces being subjected to arbitrary tractions; finite element or boundary element alternating methods for two or three dimensional crack problems; a 'direct stiffness' method for stiffened panels with flexible fasteners and with multiple cracks; multiple site damage near a row of fastener holes; an analysis of cracks with bonded repair patches; methods for the generation of weight functions for two and three dimensional crack problems; and domain-integral methods for elastic-plastic or inelastic crack mechanics.

Radio frequency identification (RFID) tagging for material tracking and future asset management : research project capsule.

DOT National Transportation Integrated Search

2016-07-01

Current Louisiana Department of Transportation and Development (DOTD) : practice allows multiple mixtures or materials to be submitted and subsequently : used during a highway construction project. Such materials include mechanically : stabilized ear...

Multiple IMU system hardware interface design, volume 2

NASA Technical Reports Server (NTRS)

Landey, M.; Brown, D.

1975-01-01

The design of each system component is described. Emphasis is placed on functional requirements unique in this system, including data bus communication, data bus transmitters and receivers, and ternary-to-binary torquing decision logic. Mechanization drawings are presented.

The Mediated MIMIC Model for Understanding the Underlying Mechanism of DIF.

PubMed

Cheng, Ying; Shao, Can; Lathrop, Quinn N

2016-02-01

Due to its flexibility, the multiple-indicator, multiple-causes (MIMIC) model has become an increasingly popular method for the detection of differential item functioning (DIF). In this article, we propose the mediated MIMIC model method to uncover the underlying mechanism of DIF. This method extends the usual MIMIC model by including one variable or multiple variables that may completely or partially mediate the DIF effect. If complete mediation effect is found, the DIF effect is fully accounted for. Through our simulation study, we find that the mediated MIMIC model is very successful in detecting the mediation effect that completely or partially accounts for DIF, while keeping the Type I error rate well controlled for both balanced and unbalanced sample sizes between focal and reference groups. Because it is successful in detecting such mediation effects, the mediated MIMIC model may help explain DIF and give guidance in the revision of a DIF item.

The Mediated MIMIC Model for Understanding the Underlying Mechanism of DIF

PubMed Central

Cheng, Ying; Shao, Can; Lathrop, Quinn N.

2015-01-01

Due to its flexibility, the multiple-indicator, multiple-causes (MIMIC) model has become an increasingly popular method for the detection of differential item functioning (DIF). In this article, we propose the mediated MIMIC model method to uncover the underlying mechanism of DIF. This method extends the usual MIMIC model by including one variable or multiple variables that may completely or partially mediate the DIF effect. If complete mediation effect is found, the DIF effect is fully accounted for. Through our simulation study, we find that the mediated MIMIC model is very successful in detecting the mediation effect that completely or partially accounts for DIF, while keeping the Type I error rate well controlled for both balanced and unbalanced sample sizes between focal and reference groups. Because it is successful in detecting such mediation effects, the mediated MIMIC model may help explain DIF and give guidance in the revision of a DIF item.

Actuatable capacitive transducer for quantitative nanoindentation combined with transmission electron microscopy

DOEpatents

Warren, Oden L.; Asif, S. A. Syed; Cyrankowski, Edward; Kounev, Kalin

2010-09-21

An actuatable capacitive transducer including a transducer body, a first capacitor including a displaceable electrode and electrically configured as an electrostatic actuator, and a second capacitor including a displaceable electrode and electrically configured as a capacitive displacement sensor, wherein the second capacitor comprises a multi-plate capacitor. The actuatable capacitive transducer further includes a coupling shaft configured to mechanically couple the displaceable electrode of the first capacitor to the displaceable electrode of the second capacitor to form a displaceable electrode unit which is displaceable relative to the transducer body, and an electrically-conductive indenter mechanically coupled to the coupling shaft so as to be displaceable in unison with the displaceable electrode unit.-

Actuatable capacitive transducer for quantitative nanoindentation combined with transmission electron microscopy

DOEpatents

Warren, Oden L; Asif, Syed Amanula Syed; Cyrankowski, Edward; Kounev, Kalin

2013-06-04

An actuatable capacitive transducer including a transducer body, a first capacitor including a displaceable electrode and electrically configured as an electrostatic actuator, and a second capacitor including a displaceable electrode and electrically configured as a capacitive displacement sensor, wherein the second capacitor comprises a multi-plate capacitor. The actuatable capacitive transducer further includes a coupling shaft configured to mechanically couple the displaceable electrode of the first capacitor to the displaceable electrode of the second capacitor to form a displaceable electrode unit which is displaceable relative to the transducer body, and an electrically-conductive indenter mechanically coupled to the coupling shaft so as to be displaceable in unison with the displaceable electrode unit.

Myosin II Activity Softens Cells in Suspension.

PubMed

Chan, Chii J; Ekpenyong, Andrew E; Golfier, Stefan; Li, Wenhong; Chalut, Kevin J; Otto, Oliver; Elgeti, Jens; Guck, Jochen; Lautenschläger, Franziska

2015-04-21

The cellular cytoskeleton is crucial for many cellular functions such as cell motility and wound healing, as well as other processes that require shape change or force generation. Actin is one cytoskeleton component that regulates cell mechanics. Important properties driving this regulation include the amount of actin, its level of cross-linking, and its coordination with the activity of specific molecular motors like myosin. While studies investigating the contribution of myosin activity to cell mechanics have been performed on cells attached to a substrate, we investigated mechanical properties of cells in suspension. To do this, we used multiple probes for cell mechanics including a microfluidic optical stretcher, a microfluidic microcirculation mimetic, and real-time deformability cytometry. We found that nonadherent blood cells, cells arrested in mitosis, and naturally adherent cells brought into suspension, stiffen and become more solidlike upon myosin inhibition across multiple timescales (milliseconds to minutes). Our results hold across several pharmacological and genetic perturbations targeting myosin. Our findings suggest that myosin II activity contributes to increased whole-cell compliance and fluidity. This finding is contrary to what has been reported for cells attached to a substrate, which stiffen via active myosin driven prestress. Our results establish the importance of myosin II as an active component in modulating suspended cell mechanics, with a functional role distinctly different from that for substrate-adhered cells. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

From membrane tension to channel gating: A principal energy transfer mechanism for mechanosensitive channels.

PubMed

Zhang, Xuejun C; Liu, Zhenfeng; Li, Jie

2016-11-01

Mechanosensitive (MS) channels are evolutionarily conserved membrane proteins that play essential roles in multiple cellular processes, including sensing mechanical forces and regulating osmotic pressure. Bacterial MscL and MscS are two prototypes of MS channels. Numerous structural studies, in combination with biochemical and cellular data, provide valuable insights into the mechanism of energy transfer from membrane tension to gating of the channel. We discuss these data in a unified two-state model of thermodynamics. In addition, we propose a lipid diffusion-mediated mechanism to explain the adaptation phenomenon of MscS. © 2016 The Protein Society.

Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?

PubMed Central

van Meurs, Matijs; Kümpers, Philipp; Ligtenberg, Jack JM; Meertens, John HJM; Molema, Grietje; Zijlstra, Jan G

2009-01-01

Multiple organ dysfunction syndrome (MODS) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. The mortality rate is high despite intensive supportive care. The pathophysiological mechanism underlying MODS are not entirely clear, although several have been proposed. Overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and – despite many unanswered questions – therapies targeting these mechanisms have been developed. Unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. We clearly need to understand better the mechanisms that underlie MODS. The endothelium certainly plays an active role in MODS. It functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. An important regulator of these systems is the angiopoietin/Tie2 signalling system. In this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy. PMID:19435476

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

PubMed

Bardo, M T

1998-01-01

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

Coordinated learning of grid cell and place cell spatial and temporal properties: multiple scales, attention and oscillations.

PubMed

Grossberg, Stephen; Pilly, Praveen K

2014-02-05

A neural model proposes how entorhinal grid cells and hippocampal place cells may develop as spatial categories in a hierarchy of self-organizing maps (SOMs). The model responds to realistic rat navigational trajectories by learning both grid cells with hexagonal grid firing fields of multiple spatial scales, and place cells with one or more firing fields, that match neurophysiological data about their development in juvenile rats. Both grid and place cells can develop by detecting, learning and remembering the most frequent and energetic co-occurrences of their inputs. The model's parsimonious properties include: similar ring attractor mechanisms process linear and angular path integration inputs that drive map learning; the same SOM mechanisms can learn grid cell and place cell receptive fields; and the learning of the dorsoventral organization of multiple spatial scale modules through medial entorhinal cortex to hippocampus (HC) may use mechanisms homologous to those for temporal learning through lateral entorhinal cortex to HC ('neural relativity'). The model clarifies how top-down HC-to-entorhinal attentional mechanisms may stabilize map learning, simulates how hippocampal inactivation may disrupt grid cells, and explains data about theta, beta and gamma oscillations. The article also compares the three main types of grid cell models in the light of recent data.

Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine

PubMed Central

Zhang, Zhong-Rong; Leung, Wing Nang; Cheung, Ho Yee; Chan, Chun Wai

2015-01-01

This paper reviews the latest understanding of biological and pharmacological properties of osthole (7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one), a natural product found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. In vitro and in vivo experimental results have revealed that osthole demonstrates multiple pharmacological actions including neuroprotective, osteogenic, immunomodulatory, anticancer, hepatoprotective, cardiovascular protective, and antimicrobial activities. In addition, pharmacokinetic studies showed osthole uptake and utilization are fast and efficient in body. Moreover, the mechanisms of multiple pharmacological activities of osthole are very likely related to the modulatory effect on cyclic adenosine monophosphate (cAMP) and cyclic adenosine monophosphate (cGMP) level, though some mechanisms remain unclear. This review aims to summarize the pharmacological properties of osthole and give an overview of the underlying mechanisms, which showcase its potential as a multitarget alternative medicine. PMID:26246843

Mechanical interface having multiple grounded actuators

DOEpatents

Martin, Kenneth M.; Levin, Mike D.; Rosenberg, Louis B.

1998-01-01

An apparatus and method for interfacing the motion of a user-manipulable object with a computer system includes a user object physically contacted or grasped by a user. A 3-D spatial mechanism is coupled to the user object, such as a stylus or a medical instrument, and provides three degrees of freedom to the user object. Three grounded actuators provide forces in the three degrees of freedom. Two of the degrees of freedom are a planar workspace provided by a closed-loop linkage of members, and the third degree of freedom is rotation of the planar workspace provided by a rotatable carriage. Capstan drive mechanisms transmit forces between actuators and the user object and include drums coupled to the carriage, pulleys coupled to grounded actuators, and flexible cables transmitting force between the pulleys and the drums. The flexibility of the cable allows the drums to rotate with the carriage while the pulleys and actuators remain fixed to ground. The interface also may include a floating gimbal mechanism coupling the linkage to the user object. The floating gimbal mechanism includes rotatably coupled gimbal members that provide three degrees of freedom to the user object and capstan mechanisms coupled between sensors and the gimbal members for providing enhanced sensor resolution.

Obesity, Inflammation, and Cancer.

PubMed

Deng, Tuo; Lyon, Christopher J; Bergin, Stephen; Caligiuri, Michael A; Hsueh, Willa A

2016-05-23

Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism that stems from obesity, including insulin resistance, hyperglycemia, and dyslipidemia, can further impact tumor growth and development. This review describes how adipose tissue becomes inflamed in obesity, summarizes ways these mechanisms impact cancer development, and discusses their role in four adipose-associated cancers that demonstrate elevated incidence or mortality in obesity.

DESIGN AND PROTOTYPE OF A SUSTAINABLE EGG-WASHER

EPA Science Inventory

This project is part of the senior design course for Engineering Science and Mechanics at Virginia Tech. Anticipated results will be a working prototype chosen from multiple designs. We will include test results supporting our selection. We will characterize the stresses ex...

Root-synthesised cytokinins induce salinity tolerance in tomato (Solanum lycopersicum L.)

USDA-ARS?s Scientific Manuscript database

Soil salinity decreases crop yield via multiple mechanisms, including decreasing concentrations of the growth-promoting, senescence-delaying and insect resistance-enhancing plant hormones cytokinins. Two approaches evaluated whether root-localised ipt (a key enzyme for cytokinin biosynthesis) gene e...

Multiscale Mechanics of Articular Cartilage: Potentials and Challenges of Coupling Musculoskeletal, Joint, and Microscale Computational Models

PubMed Central

Halloran, J. P.; Sibole, S.; van Donkelaar, C. C.; van Turnhout, M. C.; Oomens, C. W. J.; Weiss, J. A.; Guilak, F.; Erdemir, A.

2012-01-01

Articular cartilage experiences significant mechanical loads during daily activities. Healthy cartilage provides the capacity for load bearing and regulates the mechanobiological processes for tissue development, maintenance, and repair. Experimental studies at multiple scales have provided a fundamental understanding of macroscopic mechanical function, evaluation of the micromechanical environment of chondrocytes, and the foundations for mechanobiological response. In addition, computational models of cartilage have offered a concise description of experimental data at many spatial levels under healthy and diseased conditions, and have served to generate hypotheses for the mechanical and biological function. Further, modeling and simulation provides a platform for predictive risk assessment, management of dysfunction, as well as a means to relate multiple spatial scales. Simulation-based investigation of cartilage comes with many challenges including both the computational burden and often insufficient availability of data for model development and validation. This review outlines recent modeling and simulation approaches to understand cartilage function from a mechanical systems perspective, and illustrates pathways to associate mechanics with biological function. Computational representations at single scales are provided from the body down to the microstructure, along with attempts to explore multiscale mechanisms of load sharing that dictate the mechanical environment of the cartilage and chondrocytes. PMID:22648577

Nanomechanical testing system

DOEpatents

Vodnick, David James; Dwivedi, Arpit; Keranen, Lucas Paul; Okerlund, Michael David; Schmitz, Roger William; Warren, Oden Lee; Young, Christopher David

2014-07-08

An automated testing system includes systems and methods to facilitate inline production testing of samples at a micro (multiple microns) or less scale with a mechanical testing instrument. In an example, the system includes a probe changing assembly for coupling and decoupling a probe of the instrument. The probe changing assembly includes a probe change unit configured to grasp one of a plurality of probes in a probe magazine and couple one of the probes with an instrument probe receptacle. An actuator is coupled with the probe change unit, and the actuator is configured to move and align the probe change unit with the probe magazine and the instrument probe receptacle. In another example, the automated testing system includes a multiple degree of freedom stage for aligning a sample testing location with the instrument. The stage includes a sample stage and a stage actuator assembly including translational and rotational actuators.

Nanomechanical testing system

DOEpatents

Vodnick, David James; Dwivedi, Arpit; Keranen, Lucas Paul; Okerlund, Michael David; Schmitz, Roger William; Warren, Oden Lee; Young, Christopher David

2015-01-27

An automated testing system includes systems and methods to facilitate inline production testing of samples at a micro (multiple microns) or less scale with a mechanical testing instrument. In an example, the system includes a probe changing assembly for coupling and decoupling a probe of the instrument. The probe changing assembly includes a probe change unit configured to grasp one of a plurality of probes in a probe magazine and couple one of the probes with an instrument probe receptacle. An actuator is coupled with the probe change unit, and the actuator is configured to move and align the probe change unit with the probe magazine and the instrument probe receptacle. In another example, the automated testing system includes a multiple degree of freedom stage for aligning a sample testing location with the instrument. The stage includes a sample stage and a stage actuator assembly including translational and rotational actuators.

Nanomechanical testing system

DOEpatents

Vodnick, David James; Dwivedi, Arpit; Keranen, Lucas Paul; Okerlund, Michael David; Schmitz, Roger William; Warren, Oden Lee; Young, Christopher David

2015-02-24

An automated testing system includes systems and methods to facilitate inline production testing of samples at a micro (multiple microns) or less scale with a mechanical testing instrument. In an example, the system includes a probe changing assembly for coupling and decoupling a probe of the instrument. The probe changing assembly includes a probe change unit configured to grasp one of a plurality of probes in a probe magazine and couple one of the probes with an instrument probe receptacle. An actuator is coupled with the probe change unit, and the actuator is configured to move and align the probe change unit with the probe magazine and the instrument probe receptacle. In another example, the automated testing system includes a multiple degree of freedom stage for aligning a sample testing location with the instrument. The stage includes a sample stage and a stage actuator assembly including translational and rotational actuators.

Mechanism Design for Multi-slot Ads Auction in Sponsored Search Markets

NASA Astrophysics Data System (ADS)

Deng, Xiaotie; Sun, Yang; Yin, Ming; Zhou, Yunhong

In this paper, we study pricing models for multi-slot advertisements, where advertisers can bid to place links to their sales webpages at one or multiple slots on a webpage, called the multi-slot AD auction problem. We develop and analyze several important mechanisms, including the VCG mechanism for multi-slot ads auction, the optimal social welfare solution, as well as two weighted GSP-like protocols (mixed and hybrid). Furthermore, we consider that forward-looking Nash equilibrium and prove its existence in the weighted GSP-like pricing protocols.

Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates.

PubMed

Xu, Shi

2015-11-01

This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy. this review goes over major progress in preclinical and clinical studies of ADCs, in the past 5 years. The pharmacokinetics and pharmacodynamics of ADCs involve multiple mechanisms, including internalization of ADCs by target cells, intracellular trafficking, release of conjugated drugs, and payload. These mechanisms actually jointly determine the efficacy of ADCs. Therefore, the optimization of ADCs should take them as necessary rationales.

Shielded multi-stage EMI noise filter

DOEpatents

Kisner, Roger Allen; Fugate, David Lee

2016-11-08

Electromagnetic interference (EMI) noise filter embodiments and methods for filtering are provided herein. EMI noise filters include multiple signal exclusion enclosures. The multiple signal exclusion enclosures contain filter circuit stages. The signal exclusion enclosures can attenuate noise generated external to the enclosures and/or isolate noise currents generated by the corresponding filter circuits within the enclosures. In certain embodiments, an output of one filter circuit stage is connected to an input of the next filter circuit stage. The multiple signal exclusion enclosures can be chambers formed using conductive partitions to divide an outer signal exclusion enclosure. EMI noise filters can also include mechanisms to maintain the components of the filter circuit stages at a consistent temperature. For example, a metal base plate can distribute heat among filter components, and an insulating material can be positioned inside signal exclusion enclosures.

Agent oriented programming

NASA Technical Reports Server (NTRS)

Shoham, Yoav

1994-01-01

The goal of our research is a methodology for creating robust software in distributed and dynamic environments. The approach taken is to endow software objects with explicit information about one another, to have them interact through a commitment mechanism, and to equip them with a speech-acty communication language. System-level applications include software interoperation and compositionality. A government application of specific interest is an infrastructure for coordination among multiple planners. Daily activity applications include personal software assistants, such as programmable email, scheduling, and new group agents. Research topics include definition of mental state of agents, design of agent languages as well as interpreters for those languages, and mechanisms for coordination within agent societies such as artificial social laws and conventions.

The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility.

PubMed

de Angelis, Cristina; Galdiero, Mariano; Pivonello, Claudia; Salzano, Ciro; Gianfrilli, Daniele; Piscitelli, Prisco; Lenzi, Andrea; Colao, Annamaria; Pivonello, Rosario

2017-10-01

Cadmium is an environmental pollutant known as endocrine disruptor. Testis is particularly susceptible to cadmium, and testis injury occurs at high but even low levels of exposure. Cadmium reproductive toxicity is mediated by multiple mechanisms, including structural damage to testis vasculature and blood-testis barrier, inflammation, cytotoxicity on Sertoli and Leydig cells, oxidative stress mainly by means of mimicry and interference with essential ions, apoptosis, interference with selected signaling pathways and epigenetic regulation of genes involved in the regulation of reproductive function, and disturbance of the hypothalamus-pituitary-gonadal axis. The current review outlines epidemiological observational findings from environmental and occupational exposure in humans, and reports experimental studies in humans and animals. Lastly, a focus on the pathogenetic mechanisms of cadmium toxicity and on the specific mechanisms of cadmium sensitivity and resistance, particularly assessed in animal models, is included. Despite convincing experimental findings in animals and supporting evidences in humans identifying cadmium as reproductive toxicant, observational findings are controversial, suffering from heterogeneity of study design and pattern of exposure, and from co-exposure to multiple pollutants. Copyright © 2017 Elsevier Inc. All rights reserved.

Robotics technology discipline

NASA Technical Reports Server (NTRS)

Montemerlo, Melvin D.

1990-01-01

Viewgraphs on robotics technology discipline for Space Station Freedom are presented. Topics covered include: mechanisms; sensors; systems engineering processes for integrated robotics; man/machine cooperative control; 3D-real-time machine perception; multiple arm redundancy control; manipulator control from a movable base; multi-agent reasoning; and surfacing evolution technologies.

Atraumatic Spinal Cord Injury in the Novice Surfer: A Comprehensive Review and Update

PubMed Central

Flick, David; Cheng, Moses

2017-01-01

Novice surfers are at risk for a rare but potentially devastating form of atraumatic myelopathy. There are 16 published studies on this condition, including 66 cases. The most common suggested mechanism of injury is static hyperextension. However, active mechanisms, in contrast to static, have also been proposed and may be contributory. First time surfers, defined as those who have never been on a surfboard prior to the day of injury, are at particular risk. These individuals make up 89.5%–100% of the reported novice surfers found in the various reports. Multiple neurologic deficits occur and often include paraparesis, paraplegia, urinary retention, and hyperesthesia. While these deficits resolve in some cases, there are reports of multiple instances of permanent injury. Increased awareness of this condition is arguably the most effective preventative measure, as it may lead to avoidance of the predisposing postures. It may also lead to earlier diagnosis in the acute setting, which will become relevant as treatment modalities continue to be refined. PMID:28210528

Multiple nosocomial infections: a risk of modern intensive care.

PubMed

Leviten, D L; Shulman, S T

1980-03-01

Many components of modern medical care greatly predispose subjects to nosocomial infection. These include cancer chemotherapy, organ transplantation, immunosuppression, and intensive supportive care, particularly in conjunction with mechanical ventilatory support, invasive monitoring devices and prolonged central or peripheral intravenous therapy. The hazard of nosocomial infection associated with residence in a modern intensive care unit is dramatized by the case history of a near-drowning victim whose hospital course was complicated by an unusually large number and variety of nosocomial bacterial infections. Sixteen different bacterial organisms were isolated from cultures of blood, purulent thoracostomy tube drainage, or purulent tracheal secretions during the patient's prolonged hospital course. Factors which predisposed this patient to nosocomial infections included prolonged positive pressure mechanical ventilation, long-term broad spectrum antibiotics, indwelling arterial and central venous lines, violation of anatomic barriers by foreign bodies such as multiple thoracostomy tubes, and residence in an intensive care unit. This patient's case demonstrates that effective means to prevent nosocomial colonization and infection are urgently needed.

Meditation as an Adjunct to the Management of Multiple Sclerosis

PubMed Central

Levin, Adam B.; Hadgkiss, Emily J.; Weiland, Tracey J.; Jelinek, George A.

2014-01-01

Background. Multiple sclerosis (MS) disease course is known to be adversely affected by several factors including stress. A proposed mechanism for decreasing stress and therefore decreasing MS morbidity and improving quality of life is meditation. This review aims to critically analyse the current literature regarding meditation and MS. Methods. Four major databases were used to search for English language papers published before March 2014 with the terms MS, multiple sclerosis, meditation, and mindfulness. Results. 12 pieces of primary literature fitting the selection criteria were selected: two were randomised controlled studies, four were cohort studies, and six were surveys. The current literature varies in quality; however common positive effects of meditation include improved quality of life (QOL) and improved coping skills. Conclusion. All studies suggest possible benefit to the use of meditation as an adjunct to the management of multiple sclerosis. Additional rigorous clinical trials are required to validate the existing findings and determine if meditation has an impact on disease course over time. PMID:25105026

Reducing the net torque and flow ripple effects of multiple hydraulic piston motor drives

NASA Technical Reports Server (NTRS)

Bartos, R. D.

1992-01-01

The torque and flow ripple effects which result when multiple hydraulic motors are used to drive a single motion of a mechanical device can significantly affect the way in which the device performs. This article presents a mathematical model describing the torque and flow ripple effects of a bent-axis hydraulic piston motor. The model is used to show how the ripple magnitude can be reduced when multiple motors are used to drive a motion. A discussion of the hydraulic servo system of the 70-m antennas located with the Deep Space Network is included to demonstrate the application of the concepts presented.

Sample Acquisition and Handling System from a Remote Platform

NASA Technical Reports Server (NTRS)

Badescu, Mircea; Sherrit, Stewart; Jones, Jack A.

2011-01-01

A system has been developed to acquire and handle samples from a suspended remote platform. The system includes a penetrator, a penetrator deployment mechanism, and a sample handler. A gravity-driven harpoon sampler was used for the system, but other solutions can be used to supply the penetration energy, such as pyrotechnic, pressurized gas, or springs. The deployment mechanism includes a line that is attached to the penetrator, a spool for reeling in the line, and a line engagement control mechanism. The penetrator has removable tips that can collect liquid, ice, or solid samples. The handling mechanism consists of a carousel that can store a series of identical or different tips, assist in penetrator reconfiguration for multiple sample acquisition, and deliver the sample to a series of instruments for analysis. The carousel sample handling system was combined with a brassboard reeling mechanism and a penetrator with removable tips. It can attach the removable tip to the penetrator, release and retrieve the penetrator, remove the tip, and present it to multiple instrument stations. The penetrator can be remotely deployed from an aerobot, penetrate and collect the sample, and be retrieved with the sample to the aerobot. The penetrator with removable tips includes sample interrogation windows and a sample retainment spring for unconsolidated samples. The line engagement motor can be used to control the penetrator release and reeling engagement, and to evenly distribute the line on the spool by rocking between left and right ends of the spool. When the arm with the guiding ring is aligned with the spool axis, the line is free to unwind from the spool without rotating the spool. When the arm is perpendicular to the spool axis, the line can move only if the spool rotates.

Recent Advances in Composite Damage Mechanics

NASA Technical Reports Server (NTRS)

Reifsnider, Ken; Case, Scott; Iyengar, Nirmal

1996-01-01

The state of the art and recent developments in the field of composite material damage mechanics are reviewed, with emphasis on damage accumulation. The kinetics of damage accumulation are considered with emphasis on the general accumulation of discrete local damage events such as single or multiple fiber fractures or microcrack formation. The issues addressed include: how to define strength in the presence of widely distributed damage, and how to combine mechanical representations in order to predict the damage tolerance and life of engineering components. It is shown that a damage mechanics approach can be related to the thermodynamics of the damage accumulation processes in composite laminates subjected to mechanical loading and environmental conditions over long periods of time.

Beyond the therapeutic shackles of the monoamines: New mechanisms in bipolar disorder biology.

PubMed

Data-Franco, João; Singh, Ajeet; Popovic, Dina; Ashton, Melanie; Berk, Michael; Vieta, Eduard; Figueira, M L; Dean, Olivia M

2017-01-04

Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics - much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti-apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N-acetylcysteine, the anti-inflammatory celecoxib, and ketamine - with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space. Copyright © 2016 Elsevier Inc. All rights reserved.

Methods for multi-material stereolithography

DOEpatents

Wicker, Ryan [El Paso, TX; Medina, Francisco [El Paso, TX; Elkins, Christopher [Redwood City, CA

2011-06-14

Methods and systems of stereolithography for building cost-efficient and time-saving multi-material, multi-functional and multi-colored prototypes, models and devices configured for intermediate washing and curing/drying is disclosed including: laser(s), liquid and/or platform level sensing system(s), controllable optical system(s), moveable platform(s), elevator platform(s), recoating system(s) and at least one polymer retaining receptacle. Multiple polymer retaining receptacles may be arranged in a moveable apparatus, wherein each receptacle is adapted to actively/passively maintain a uniform, desired level of polymer by including a recoating device and a material fill/remove system. The platform is movably accessible to the polymer retaining receptacle(s), elevator mechanism(s) and washing and curing/drying area(s) which may be housed in a shielded enclosure(s). The elevator mechanism is configured to vertically traverse and rotate the platform, thus providing angled building, washing and curing/drying capabilities. A horizontal traversing mechanism may be included to facilitate manufacturing between components of SL cabinet(s) and/or alternative manufacturing technologies.

Systems-level mechanisms of action of Panax ginseng: a network pharmacological approach.

PubMed

Park, Sa-Yoon; Park, Ji-Hun; Kim, Hyo-Su; Lee, Choong-Yeol; Lee, Hae-Jeung; Kang, Ki Sung; Kim, Chang-Eop

2018-01-01

Panax ginseng has been used since ancient times based on the traditional Asian medicine theory and clinical experiences, and currently, is one of the most popular herbs in the world. To date, most of the studies concerning P. ginseng have focused on specific mechanisms of action of individual constituents. However, in spite of many studies on the molecular mechanisms of P. ginseng , it still remains unclear how multiple active ingredients of P. ginseng interact with multiple targets simultaneously, giving the multidimensional effects on various conditions and diseases. In order to decipher the systems-level mechanism of multiple ingredients of P. ginseng , a novel approach is needed beyond conventional reductive analysis. We aim to review the systems-level mechanism of P. ginseng by adopting novel analytical framework-network pharmacology. Here, we constructed a compound-target network of P. ginseng using experimentally validated and machine learning-based prediction results. The targets of the network were analyzed in terms of related biological process, pathways, and diseases. The majority of targets were found to be related with primary metabolic process, signal transduction, nitrogen compound metabolic process, blood circulation, immune system process, cell-cell signaling, biosynthetic process, and neurological system process. In pathway enrichment analysis of targets, mainly the terms related with neural activity showed significant enrichment and formed a cluster. Finally, relative degrees analysis for the target-disease association of P. ginseng revealed several categories of related diseases, including respiratory, psychiatric, and cardiovascular diseases.

Human Spermatozoa Contain Multiple Targets for Protein S-Nitrosylation: An Alternative Mechanism of the Modulation of Sperm Function by Nitric Oxide?

PubMed Central

Lefièvre, Linda; Chen, Yongjian; Conner, Sarah J; Scott, Joanna L; Publicover, Steve J; Ford, W Christopher L; Barratt, Christopher LR

2009-01-01

Nitric oxide (NO) enhances human sperm motility and capacitation associated with increased protein phosphorylation. NO activates soluble guanylyl cyclase, but can also modify protein function covalently via S-nitrosylation of cysteine. Remarkably, this mechanism remains unexplored in sperm although they depend on post-translational protein modification to achieve changes in function required for fertilisation. Our objective was to identify targets for S-nitrosylation in human sperm. Spermatozoa were incubated with NO donors and S-nitrosylated proteins were identified using the biotin switch assay and a proteomic approach using tandem mass spectrometry. 240 S-nitrosylated proteins were detected in sperm incubated with S-nitrosoglutathione. Minimal levels were observed in glutathione or untreated samples. Proteins identified consistently based on multiple peptides included established targets for S-nitrosylation in other cells e.g. tubulin,, glutathione-S-transferase and heat shock proteins but also novel targets including A-kinase anchoring protein (AKAP) types 3 and 4, voltage-dependent anion-selective channel protein 3 and semenogelin 1 and 2. In situ localisation revealed S-nitrosylated targets on the post-acrosomal region of the head and throughout the flagellum. Potential targets for S-nitrosylation in human sperm include physiologically significant proteins not previously reported in other cells. Their identification will provide novel insight into the mechanism of action of NO in spermatozoa. PMID:17683036

Small RNA biology is systems biology.

PubMed

Jost, Daniel; Nowojewski, Andrzej; Levine, Erel

2011-01-01

During the last decade small regulatory RNA (srRNA) emerged as central players in the regulation of gene expression in all kingdoms of life. Multiple pathways for srRNA biogenesis and diverse mechanisms of gene regulation may indicate that srRNA regulation evolved independently multiple times. However, small RNA pathways share numerous properties, including the ability of a single srRNA to regulate multiple targets. Some of the mechanisms of gene regulation by srRNAs have significant effect on the abundance of free srRNAs that are ready to interact with new targets. This results in indirect interactions among seemingly unrelated genes, as well as in a crosstalk between different srRNA pathways. Here we briefly review and compare the major srRNA pathways, and argue that the impact of srRNA is always at the system level. We demonstrate how a simple mathematical model can ease the discussion of governing principles. To demonstrate these points we review a few examples from bacteria and animals.

Upper-Division Student Difficulties with Separation of Variables

ERIC Educational Resources Information Center

Wilcox, Bethany R.; Pollock, Steven J.

2015-01-01

Separation of variables can be a powerful technique for solving many of the partial differential equations that arise in physics contexts. Upper-division physics students encounter this technique in multiple topical areas including electrostatics and quantum mechanics. To better understand the difficulties students encounter when utilizing the…

Working Memory and Language Learning: A Review

ERIC Educational Resources Information Center

Archibald, Lisa M. D.

2017-01-01

Children with speech, language, and communication needs (SLCN) form a highly heterogeneous group, including those with an unexplained delay in language development known as specific language impairment (SLI). There is growing recognition that multiple mechanisms underlie the range of profiles observed in these children. Broadly speaking, both the…

Prolonged Mechanical Ventilation as a Predictor of Mortality After Cardiac Surgery.

PubMed

Fernandez-Zamora, Maria Dolores; Gordillo-Brenes, Antonio; Banderas-Bravo, Esther; Arboleda-Sánchez, José Andrés; Hinojosa-Pérez, Rafael; Aguilar-Alonso, Eduardo; Herruzo-Aviles, Ángel; Curiel-Balsera, Emilio; Sánchez-Rodríguez, Ángel; Rivera-Fernández, Ricardo

2018-05-01

Mortality among the small percentage of cardiac surgery patients receiving prolonged mechanical ventilation is high, but this issue appears to be inadequately addressed in guidelines. This study is a retrospective analysis of prospective, multi-center, and observational study in Spain including all adults undergoing cardiac surgery in 3 Andalusian hospitals between June 2008 and December 2012. The study included 3,588 adults with mean ± SD age of 63.5 ± 12.8 y and with median (interquartile range) EuroSCORE of 5 (3-7) points. Prolonged mechanical ventilation (> 24 h) was required by 415 subjects (11.6%), with ICU mortality of 44.3% (184 subjects), and was not required by 3,173 subjects (88.4%), with ICU mortality of 3.1% (99 subjects, P < .001). Prolonged mechanical ventilation was associated with more complications and was required by 4.5% of subjects with a EuroSCORE <5, 11.2% with a score of 5-7, 27.2% with a score of 8-10, and 32.2% with a score > 10. In the multivariable analysis, ICU mortality was associated with illness severity, duration of bypass surgery, surgery type, and prolonged mechanical ventilation (odds ratio 15.19, 95% CI 11.56-22.09). The main cause of death was multiple organ failure and sepsis in subjects who required prolonged mechanical ventilation (50.3%) and cardiogenic shock in those who did not (59.2%). Prolonged postoperative mechanical ventilation was required by 10-20% of cardiac surgery subjects, who constitute a specific group that represents most of the postoperative mortality, which is associated with multiple organ failure and sepsis. Copyright © 2018 by Daedalus Enterprises.

From bench to patient: model systems in drug discovery

PubMed Central

Breyer, Matthew D.; Look, A. Thomas; Cifra, Alessandra

2015-01-01

ABSTRACT Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides. PMID:26438689

Parallel updating and weighting of multiple spatial maps for visual stability during whole body motion

PubMed Central

Medendorp, W. P.

2015-01-01

It is known that the brain uses multiple reference frames to code spatial information, including eye-centered and body-centered frames. When we move our body in space, these internal representations are no longer in register with external space, unless they are actively updated. Whether the brain updates multiple spatial representations in parallel, or whether it restricts its updating mechanisms to a single reference frame from which other representations are constructed, remains an open question. We developed an optimal integration model to simulate the updating of visual space across body motion in multiple or single reference frames. To test this model, we designed an experiment in which participants had to remember the location of a briefly presented target while being translated sideways. The behavioral responses were in agreement with a model that uses a combination of eye- and body-centered representations, weighted according to the reliability in which the target location is stored and updated in each reference frame. Our findings suggest that the brain simultaneously updates multiple spatial representations across body motion. Because both representations are kept in sync, they can be optimally combined to provide a more precise estimate of visual locations in space than based on single-frame updating mechanisms. PMID:26490289

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system

PubMed Central

Sowa, Steven W.; Gelderman, Grant; Leistra, Abigail N.; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A.; Romeo, Tony; Baldea, Michael

2017-01-01

Abstract Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. PMID:28126921

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.

PubMed

Gong, Lauren; Parikh, Sunil; Rosenthal, Philip J; Greenhouse, Bryan

2013-09-11

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria

PubMed Central

2013-01-01

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria. PMID:24025776

Multiple deformation mechanisms of Ti-22.4Nb-0.73Ta-2.0Zr-1.34O alloy

NASA Astrophysics Data System (ADS)

Yang, Y.; Li, G. P.; Cheng, G. M.; Li, Y. L.; Yang, K.

2009-02-01

Ti-22.4Nb-0.73Ta-2.0Zr-1.34O (at. %) alloy after cold compression to ˜5.2% strain was investigated. The alloy exhibited multiple plastic deformation mechanisms, including the stress-induced α″ martensitic (SIM α″) and ω phase transformations, 1/2⟨111⟩ dislocations slipping on the {112}β planes as well as {332}⟨113⟩β and {112}⟨111⟩β twinning, which have not previously been reported to coexist in a titanium alloy. It was also found that β phase with the {200} planes vertical to the compression direction was almost completely consumed away by a β →SIM α″ transformation, and a (100) texture of SIM α″ formed.

Hyperbaric oxygen therapy for traumatic brain injury

PubMed Central

2011-01-01

Traumatic brain injury (TBI) is a major public health issue. The complexity of TBI has precluded the use of effective therapies. Hyperbaric oxygen therapy (HBOT) has been shown to be neuroprotective in multiple neurological disorders, but its efficacy in the management of TBI remains controversial. This review focuses on HBOT applications within the context of experimental and clinical TBI. We also discuss its potential neuroprotective mechanisms. Early or delayed multiple sessions of low atmospheric pressure HBOT can reduce intracranial pressure, improve mortality, as well as promote neurobehavioral recovery. The complimentary, synergistic actions of HBOT include improved tissue oxygenation and cellular metabolism, anti-apoptotic, and anti-inflammatory mechanisms. Thus HBOT may serve as a promising neuroprotective strategy that when combined with other therapeutic targets for TBI patients which could improve long-term outcomes. PMID:22146562

Numerical analysis of laser ablation and damage in glass with multiple picosecond laser pulses.

PubMed

Sun, Mingying; Eppelt, Urs; Russ, Simone; Hartmann, Claudia; Siebert, Christof; Zhu, Jianqiang; Schulz, Wolfgang

2013-04-08

This study presents a novel numerical model for laser ablation and laser damage in glass including beam propagation and nonlinear absorption of multiple incident ultrashort laser pulses. The laser ablation and damage in the glass cutting process with a picosecond pulsed laser was studied. The numerical results were in good agreement with our experimental observations, thereby revealing the damage mechanism induced by laser ablation. Beam propagation effects such as interference, diffraction and refraction, play a major role in the evolution of the crater structure and the damage region. There are three different damage regions, a thin layer and two different kinds of spikes. Moreover, the electronic damage mechanism was verified and distinguished from heat modification using the experimental results with different pulse spatial overlaps.

Brain nuclear receptors and body weight regulation

PubMed Central

O’Malley, Bert W.; Elmquist, Joel K.

2017-01-01

Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essential roles in the regulation of energy homeostasis. Understanding the role and the underlying mechanisms of NRs in the context of energy balance control may facilitate the identification of novel targets to treat obesity. Notably, NRs are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of energy balance, including feeding, energy expenditure and physical activity. In this Review we summarize some of the recent literature regarding effects of brain NRs on body weight regulation and discuss mechanisms underlying these effects. PMID:28218618

Dendritic Spine Pathology in Schizophrenia

PubMed Central

Glausier, Jill R.; Lewis, David A.

2012-01-01

Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia. PMID:22546337

Effect of simulated Earth reentry exposure on mechanical properties of several oxide dispersion strengthened and superalloy sheet materials

NASA Technical Reports Server (NTRS)

Whittenberger, J. D.

1977-01-01

The effects of simulated multiple reentry into the earth's atmosphere on the mechanical properties of several high temperature metallic sheet materials were evaluated. The materials included five tin-gage (nominally 0.025- or 0.037-cm) oxide dispersion strengthened (ODS) alloys and two thin-gage (nominally 0.037-cm) superalloys. Multiple reentry conditions were simulated through cyclic Plasma Arc Tunnel (PAT) exposure. PAT exposure generally consisted of 100 cycles of 600 second duration at 1255, 1366, or 1477 K in a Mach 4.6 airstream with an impact pressure of nominally 800 N/m2. PAT exposure generally produced a uniform oxide scale, oxide pits or intergranular oxidation, Kirkendall porosity, and alloy depletion zones except for the aluminum-containing ODS alloys. Only a uniform oxide scale was formed on the aluminum-containing ODS alloys. PAT exposure did not significantly affect the mechanical properties of the thin-gage (nominally 0.025- or 0.037-cm) alloys evaluated. Thus it appears that the microstructural changes produced by Plasma Arc Tunnel exposure has little influence on mechanical properties.

Development of a Finite Element Model of the Human Shoulder to Investigate the Mechanical Responses and Injuries in Side Impact

NASA Astrophysics Data System (ADS)

Iwamoto, Masami; Miki, Kazuo; Yang, King H.

Previous studies in both fields of automotive safety and orthopedic surgery have hypothesized that immobilization of the shoulder caused by the shoulder injury could be related to multiple rib fractures, which are frequently life threatening. Therefore, for more effective occupant protection, it is important to understand the relationship between shoulder injury and multiple rib fractures in side impact. The purpose of this study is to develop a finite element model of the human shoulder in order to understand this relationship. The shoulder model included three bones (the humerus, scapula and clavicle) and major ligaments and muscles around the shoulder. The model also included approaches to represent bone fractures and joint dislocations. The relationships between shoulder injury and immobilization of the shoulder are discussed using model responses for lateral shoulder impact. It is also discussed how the injury can be related to multiple rib fractures.

Multiple Sclerosis and Catastrophic Health Expenditure in Iran.

PubMed

Juyani, Yaser; Hamedi, Dorsa; Hosseini Jebeli, Seyede Sedighe; Qasham, Maryam

2016-09-01

There are many disabling medical conditions which can result in catastrophic health expenditure. Multiple Sclerosis is one of the most costly medical conditions through the world which encounter families to the catastrophic health expenditures. This study aims to investigate on what extent Multiple sclerosis patients face catastrophic costs. This study was carried out in Ahvaz, Iran (2014). The study population included households that at least one of their members suffers from MS. To analyze data, Logit regression model was employed by using the default software STATA12. 3.37% of families were encountered with catastrophic costs. Important variables including brand of drug, housing, income and health insurance were significantly correlated with catastrophic expenditure. This study suggests that although a small proportion of MS patients met the catastrophic health expenditure, mechanisms that pool risk and cost (e.g. health insurance) are required to protect them and improve financial and access equity in health care.

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment: A Scientific Statement From the American Heart Association.

PubMed

Ferguson, Jane F; Allayee, Hooman; Gerszten, Robert E; Ideraabdullah, Folami; Kris-Etherton, Penny M; Ordovás, José M; Rimm, Eric B; Wang, Thomas J; Bennett, Brian J

2016-06-01

Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention. © 2016 American Heart Association, Inc.

Muscle-related side-effects of statins: from mechanisms to evidence-based solutions.

PubMed

Taylor, Beth A; Thompson, Paul D

2015-06-01

This article highlights the recent findings regarding statin-associated muscle side effects, including mechanisms and treatment as well as the need for more comprehensive clinical trials in statin myalgia. Statin myalgia is difficult to diagnose and treat, as major clinical trials have not routinely assessed muscle side-effects, there are few clinically relevant biomarkers and assessment tools for the symptoms, many apparent statin-related muscle symptoms may be nonspecific and related to other drugs or health conditions, and prevalence estimates vary widely. Data thus suggest that only 30-50% of patients with self-reported statin myalgia actually experience muscle pain on statins during blinded, placebo-controlled trials. In addition, evidence to date involving mechanisms underlying statin myalgia and its range of symptoms and presentations supports the hypothesis that there are multiple, interactive and potentially additive mechanisms underlying statin-associated muscle side-effects. There are likely multiple and interactive mechanisms underlying statin myalgia, and recent studies have produced equivocal data regarding prevalence of statin-associated muscle side-effects, contributing factors and effectiveness of common interventions. Therefore, more clinical trials on statin myalgia are critical to the field, as are systematic resources for quantifying, predicting and reporting statin-associated muscle side-effects.

Procedure for implementation of temperature-dependent mechanical property capability in the Engineering Analysis Language (EAL) system

NASA Technical Reports Server (NTRS)

Glass, David E.; Robinson, James C.

1990-01-01

A procedure is presented to allow the use of temperature dependent mechanical properties in the Engineering Analysis Language (EAL) System for solid structural elements. This is accomplished by including a modular runstream in the main EAL runstream. The procedure is applicable for models with multiple materials and with anisotropic properties, and can easily be incorporated into an existing EAL runstream. The procedure (which is applicable for EAL elastic solid elements) is described in detail, followed by a description of the validation of the routine. A listing of the EAL runstream used to validate the procedure is included in the Appendix.

AtomicJ: An open source software for analysis of force curves

NASA Astrophysics Data System (ADS)

Hermanowicz, Paweł; Sarna, Michał; Burda, Kvetoslava; Gabryś, Halina

2014-06-01

We present an open source Java application for analysis of force curves and images recorded with the Atomic Force Microscope. AtomicJ supports a wide range of contact mechanics models and implements procedures that reduce the influence of deviations from the contact model. It generates maps of mechanical properties, including maps of Young's modulus, adhesion force, and sample height. It can also calculate stacks, which reveal how sample's response to deformation changes with indentation depth. AtomicJ analyzes force curves concurrently on multiple threads, which allows for high speed of analysis. It runs on all popular operating systems, including Windows, Linux, and Macintosh.

Anaplasma marginale superinfection attributable to pathogen strains with distinct genomic backgrounds.

USDA-ARS?s Scientific Manuscript database

Microbial strain structure is dynamic over space and time; shifts in pathogen strain structure result in changing patterns of disease. The scale of change in space and time differs markedly among pathogens depending on multiple factors including pathogen-specific mechanisms of genetic change and the...

Upper-Division Student Difficulties with the Dirac Delta Function

ERIC Educational Resources Information Center

Wilcox, Bethany R.; Pollock, Steven J.

2015-01-01

The Dirac delta function is a standard mathematical tool that appears repeatedly in the undergraduate physics curriculum in multiple topical areas including electrostatics, and quantum mechanics. While Dirac delta functions are often introduced in order to simplify a problem mathematically, students still struggle to manipulate and interpret them.…

Structural and Multilingual Approaches to Subject Access on the Web.

ERIC Educational Resources Information Center

Chan, Lois Mai; Lin, Xia; Zeng, Marcia

This paper presents some of the efforts currently being made to develop mechanisms that can organize World Wide Web resources for efficient and effective retrieval, as well as programs that can accommodate multiple languages. Part 1 discusses structural approaches to organizing Web resources, including the use of hierarchical or…

Fibroblast growth factors, old kids on the new block

PubMed Central

Li, Xiaokun; Wang, Cong; Xiao, Jian; McKeehan, Wallace L.; Wang, Fen

2016-01-01

The fibroblast growth factors (FGFs) are a family of cell intrinsic regulatory peptides that control a broad spectrum of cellular activities. The family includes canonic FGFs that elicit their activities by activating the FGF receptor (FGFR) tyrosine kinase and non-canonic members that elicit their activities intracellularly and via FGFR-independent mechanisms. The FGF signaling axis is highly complex due to the existence of multiple isoforms of both ligands and receptors, as well as cofactors that include the chemically heterogeneous heparan sulfate (HS) cofactors, and in the case of endocrine FGFs, the Klotho coreceptors. Resident FGF signaling controls embryonic development, maintains tissue homeostasis, promotes wound healing and tissue regeneration, and regulates functions of multiple organs. However, ectopic or aberrant FGF signaling is a culprit for various diseases, including congenital birth defects, metabolic disorder, and cancer. The molecular mechanisms by which the specificity of FGF signaling is achieved remain incompletely understood. Since its application as a druggable target has been gradually recognized by pharmaceutical companies and translational researchers, understanding the determinants of FGF signaling specificity has become even more important in order to get into the position to selectively suppress a particular pathway without affecting others to minimize side effects. PMID:26768548

Guide to Using Sierra

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

Shaw, Ryan Phillip; Agelastos, Anthony Michael; Miller, Joel D.

2015-03-01

Sierra is an engineering mechanics simulation code suite supporting the Nation's Nuclear Weapons mission as well as other customers. It has explicit ties to Sandia National Labs' workfow, including geometry and meshing, design and optimization, and visualization. Dis- tinguishing strengths include "application aware" development, scalability, SQA and V&V, multiple scales, and multi-physics coupling. This document is intended to help new and existing users of Sierra as a user manual and troubleshooting guide.

Guide to Using Sierra

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

Shaw, Ryan Phillip; Agelastos, Anthony Michael; Miller, Joel D.

2017-04-01

Sierra is an engineering mechanics simulation code suite supporting the Nation's Nuclear Weapons mission as well as other customers. It has explicit ties to Sandia National Labs' workfow, including geometry and meshing, design and optimization, and visualization. Dis- tinguishing strengths include "application aware" development, scalability, SQA and V&V, multiple scales, and multi-physics coupling. This document is intended to help new and existing users of Sierra as a user manual and troubleshooting guide.

Investigation of Basic Mechanisms of Radiation Effects in Carbon-Based Electronic Materials

DTIC Science & Technology

2017-06-01

materials characterization, and carbon nanotube diodes, FET, and PZT-memory test device structures for electrical measurements. Pre - and post -irradiation...definition (Radiation exposure) Task 2) The grantee shall perform testing to include: - Radiation testing . May be multiple types. - Pre and post -rad...technologies for electronic devices. Experiential radiation testing has included exposure to 10 keV X-rays, 4 MeV protons, heavy ions, and Ultra

Defense Mechanisms: Discussions and Bibliographies; General or Multiple, and Specific.

ERIC Educational Resources Information Center

Pedrini, D. T.; Pedrini, Bonnie C.

This publication considers some Freudian ego mechanisms. The first discussion and bibliography concerns defense mechanisms, in general or in multiple; after which, the discussions and bibliographies concern specific defense mechanisms: denial; displacement, substitution, sublimation; fixation; identification, introjection, incorporation,…

Influence of polysaccharides on the rheology and stabilization of α-pinene emulsions.

PubMed

García, Ma Carmen; Alfaro, Ma Carmen; Calero, Nuria; Muñoz, José

2014-05-25

This work focuses on the need to include polysaccharides in a slightly concentrated O(α-pinene)/W emulsion, formulated with amphiphilic copolymers as emulsifiers. Rheology, laser diffraction and multiple light scattering were the main techniques used to assess the performance of gellan gum, xanthan gum and a mixture of both hydrocolloids as stabilizers. Small amplitude oscillatory shear results were consistent with the existence of three distinct microstructures and relaxation mechanisms, which depended on the hydrocolloid system used. The mechanical spectrum of the emulsion containing both polysaccharides signalled the occurrence of thermodynamic incompatibility between the two. Flow curves fitted to the Carreau-Yasuda model demonstrated a negative synergistic effect between gellan and xanthan gums. The droplet size distribution was similar for these systems, which highlighted the importance of the continuous phase for emulsion stability. Multiple light scattering illustrated that creaming was practically eliminated by the incorporation of polysaccharides, coalescence being the main destabilization mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved.

Renal thrombotic microangiopathy caused by interferon beta-1a treatment for multiple sclerosis

PubMed Central

Mahe, Julien; Meurette, Aurélie; Moreau, Anne; Vercel, Caroline; Jolliet, Pascale

2013-01-01

Interferon beta-1a is available as an immunomodulating agent for relapsing forms of multiple sclerosis. Common side effects include flu-like symptoms, asthenia, anorexia, and administration site reaction. Kidney disorders are rarely reported. In this study we describe the case of a woman who has been undergoing treatment with interferon beta-1a for multiple sclerosis for 5 years. She developed a hemolytic-uremic syndrome with intravascular hemolysis in a context of severe hypertension. A kidney biopsy showed a thrombotic microangiopathy. This observation highlights an uncommon side effect of long-term interferon beta-1a therapy. Pathophysiological mechanisms leading to this complication might be explained by the antiangiogenic activity of interferon. PMID:23950639

Investigating and Improving Student Understanding of Key Ideas in Quantum Mechanics throughout Instruction

NASA Astrophysics Data System (ADS)

Emigh, Paul Jeffrey

This dissertation describes research on student understanding of quantum mechanics across multiple levels of instruction. The primary focus has been to identify patterns in student reasoning related to key concepts in quantum mechanics. The specific topics include quantum measurements, time dependence, vector spaces, and angular momentum. The research has spanned a variety of different quantum courses intended for introductory physics students, upper-division physics majors, and graduate students in physics. The results of this research have been used to develop a set of curriculum, Tutorials in Physics: Quantum Mechanics, for addressing the most persistent student difficulties. We document both the development of this curriculum and how it has impacted and improved student understanding of quantum mechanics.

Incorporation of coupled nonequilibrium chemistry into a two-dimensional nozzle code (SEAGULL)

NASA Technical Reports Server (NTRS)

Ratliff, A. W.

1979-01-01

A two-dimensional multiple shock nozzle code (SEAGULL) was extended to include the effects of finite rate chemistry. The basic code that treats multiple shocks and contact surfaces was fully coupled with a generalized finite rate chemistry and vibrational energy exchange package. The modified code retains all of the original SEAGULL features plus the capability to treat chemical and vibrational nonequilibrium reactions. Any chemical and/or vibrational energy exchange mechanism can be handled as long as thermodynamic data and rate constants are available for all participating species.

Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response

PubMed Central

Shahin, Mohamed H; Johnson, Julie A

2016-01-01

Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response. PMID:26874237

Embryo mechanics: balancing force production with elastic resistance during morphogenesis.

PubMed

Davidson, Lance A

2011-01-01

Morphogenesis requires the spatial and temporal control of embryo mechanics, including force production and mechanical resistance to those forces, to coordinate tissue deformation and large-scale movements. Thus, biomechanical processes play a key role in directly shaping the embryo. Additional roles for embryo mechanics during development may include the patterning of positional information and to provide feedback to ensure the success of morphogenetic movements in shaping the larval body and organs. To understand the multiple roles of mechanics during development requires familiarity with engineering principles of the mechanics of structures, the viscoelastic properties of biomaterials, and the integration of force and stress within embryonic structures as morphogenesis progresses. In this chapter, we review the basic engineering principles of biomechanics as they relate to morphogenesis, introduce methods for quantifying embryo mechanics and the limitations of these methods, and outline a formalism for investigating the role of embryo mechanics in birth defects. We encourage the nascent field of embryo mechanics to adopt standard engineering terms and test methods so that studies of diverse organisms can be compared and universal biomechanical principles can be revealed. Copyright © 2011 Elsevier Inc. All rights reserved.

Laser Doppler vibrometry measurement of the mechanical myogram

NASA Astrophysics Data System (ADS)

Rohrbaugh, John W.; Sirevaag, Erik J.; Richter, Edward J.

2013-12-01

Contracting muscles show complex dimensional changes that include lateral expansion. Because this expansion process is intrinsically vibrational, driven by repetitive actions of multiple motor units, it can be sensed and quantified using the method of Laser Doppler Vibrometry (LDV). LDV has a number of advantages over more traditional mechanical methods based on microphones and accelerometers. The LDV mechanical myogram from a small hand muscle (the first dorsal interosseous) was studied under conditions of elastic loading applied to the tip of the abducted index finger. The LDV signal was shown to be related systematically to the level of force production, and to compare favorably with conventional methods for sensing the mechanical and electrical aspects of muscle contraction.

Prevalence of carpal fracture in Singapore.

PubMed

Hey, Hwee Weng Dennis; Dennis, Hey Hwee Weng; Chong, Alphonsus Khin Sze; Sze, Alphonsus Chong Khin; Murphy, Diarmuid

2011-02-01

To determine the prevalence of carpal fracture in Singapore, to compare demographic differences between isolated scaphoid and other carpal fractures, and to identify parameters associated with multiple carpal fractures. A total of 149 patients with 162 carpal fractures seen at the National University Hospital in 2009 were enrolled into the study. We retrospectively reviewed their case records and radiographic studies. Pertinent demographic data including patient age, gender, occupation, injured wrist, dominant hand, mechanism of injury, and type of carpal fracture were then recorded and statistically analyzed. We also performed a separate analysis of isolated scaphoid versus other carpal fractures and single versus multiple carpal fractures. Patients with carpal fracture were predominantly male (132), below 40 years of age (116), and usually right hand dominant (136). The more common occupations were students (30), full-time military national servicemen (24), and construction workers (14). Most presented after a fall on an outstretched hand from standing height (81). The scaphoid was the most common single carpal fracture (99). This was followed by triquetrum (27), hamate (5), pisiform (4), lunate (2), capitate (1), and trapezium (1). No fracture of the trapezoid was encountered. Ten patients had multiple carpal fractures, of which 4 were perilunate fracture dislocations. The mean age and male/female ratio for isolated scaphoid and other carpal fractures was 26 years versus 41 years (p<.001) and 13:1 versus 4:1 (p=.036), respectively. A high-energy mechanism of injury was the only parameter associated with multiple carpal fractures (p=.009). The prevalence of carpal fracture in our population was consistent with studies performed in other countries. Military conscription was identified as an at-risk activity predisposing to carpal fracture. Isolated scaphoid and other carpal fractures exhibit different demographics in terms of age and gender, which may be related to differences in the mechanism of injury. A high-energy mechanism of injury was associated with multiple carpal fractures. Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

integIRTy: a method to identify genes altered in cancer by accounting for multiple mechanisms of regulation using item response theory.

PubMed

Tong, Pan; Coombes, Kevin R

2012-11-15

Identifying genes altered in cancer plays a crucial role in both understanding the mechanism of carcinogenesis and developing novel therapeutics. It is known that there are various mechanisms of regulation that can lead to gene dysfunction, including copy number change, methylation, abnormal expression, mutation and so on. Nowadays, all these types of alterations can be simultaneously interrogated by different types of assays. Although many methods have been proposed to identify altered genes from a single assay, there is no method that can deal with multiple assays accounting for different alteration types systematically. In this article, we propose a novel method, integration using item response theory (integIRTy), to identify altered genes by using item response theory that allows integrated analysis of multiple high-throughput assays. When applied to a single assay, the proposed method is more robust and reliable than conventional methods such as Student's t-test or the Wilcoxon rank-sum test. When used to integrate multiple assays, integIRTy can identify novel-altered genes that cannot be found by looking at individual assay separately. We applied integIRTy to three public cancer datasets (ovarian carcinoma, breast cancer, glioblastoma) for cross-assay type integration which all show encouraging results. The R package integIRTy is available at the web site http://bioinformatics.mdanderson.org/main/OOMPA:Overview. kcoombes@mdanderson.org. Supplementary data are available at Bioinformatics online.

Update on Multiple Ovulations in Dairy Cattle

PubMed Central

Macmillan, Kira; Kastelic, John P.

2018-01-01

Simple Summary Multiple ovulations (MOV) in cattle can lead to twin pregnancies, which negatively affects the health, production, and reproduction of cows. Despite many studies, the causal mechanisms behind MOV are still not well understood. There is a general agreement that MOV are more likely during periods of low progesterone (P4), which may increase the luteinizing hormone (LH) release at the time of selection, resulting in more than one follicle becoming dominant. The MOV rate also increases in older cows and when the selection of a dominant follicle occurs concurrently with a high milk yield. Additional risk factors for MOV are ovarian cysts, diet, season, and genetics. A better understanding of the mechanisms underlying MOV may help to mitigate twinning, perhaps through the appropriate reproductive management protocols or genetic selection. Abstract This review updates the causal mechanisms and risk factors for multiple ovulations (MOV) in cattle. Clearly, MOV can lead to twin pregnancies, which negatively affects the health, production, and reproduction of cows. Therefore, a better understanding of the factors causing MOV may help to reduce twinning. Multiple ovulations occur after two or more follicles deviate and achieve codominance. The MOV rate is influenced by a complex network of hormones. For example, MOV is more common during periods of low progesterone (P4), that is, in anovulatory cattle or when luteolysis coincides with the selection of the future ovulatory follicle. There is also strong evidence for the luteinizing hormone (LH) being the primary factor leading to codominance, as high P4 concentrations suppress the transient LH surges and can reduce the ovulation rate in cattle or even inhibit deviation. Rates of MOV are increased in older and higher-producing dairy cows. Increased milk production and dry matter intake (DMI) increases hormone clearance, including P4; however, the association between milk yield and MOV has not been consistent. Additional risk factors for MOV include ovarian cysts, diet, season, and genetics. PMID:29695075

Fission time scale from pre-scission neutron and α multiplicities in the 16O + 194Pt reaction

NASA Astrophysics Data System (ADS)

Kapoor, K.; Verma, S.; Sharma, P.; Mahajan, R.; Kaur, N.; Kaur, G.; Behera, B. R.; Singh, K. P.; Kumar, A.; Singh, H.; Dubey, R.; Saneesh, N.; Jhingan, A.; Sugathan, P.; Mohanto, G.; Nayak, B. K.; Saxena, A.; Sharma, H. P.; Chamoli, S. K.; Mukul, I.; Singh, V.

2017-11-01

Pre- and post-scission α -particle multiplicities have been measured for the reaction 16O+P194t at 98.4 MeV forming R210n compound nucleus. α particles were measured at various angles in coincidence with the fission fragments. Moving source technique was used to extract the pre- and post-scission contributions to the particle multiplicity. Study of the fission mechanism using the different probes are helpful in understanding the detailed reaction dynamics. The neutron multiplicities for this reaction have been reported earlier. The multiplicities of neutrons and α particles were reproduced using standard statistical model code joanne2 by varying the transient (τt r) and saddle to scission (τs s c) times. This code includes deformation dependent-particle transmission coefficients, binding energies and level densities. Fission time scales of the order of 50-65 ×10-21 s are required to reproduce the neutron and α -particle multiplicities.

From bench to patient: model systems in drug discovery.

PubMed

Breyer, Matthew D; Look, A Thomas; Cifra, Alessandra

2015-10-01

Model systems, including laboratory animals, microorganisms, and cell- and tissue-based systems, are central to the discovery and development of new and better drugs for the treatment of human disease. In this issue, Disease Models & Mechanisms launches a Special Collection that illustrates the contribution of model systems to drug discovery and optimisation across multiple disease areas. This collection includes reviews, Editorials, interviews with leading scientists with a foot in both academia and industry, and original research articles reporting new and important insights into disease therapeutics. This Editorial provides a summary of the collection's current contents, highlighting the impact of multiple model systems in moving new discoveries from the laboratory bench to the patients' bedsides. © 2015. Published by The Company of Biologists Ltd.

Sarmentine, a natural herbicide from Piper species with multiple herbicide mechanisms of action

USDA-ARS?s Scientific Manuscript database

Sarmentine, 1-(1-pyrrolidinyl)-(2E,4E)-2,4-decadien-1-one, is a natural amide isolated from the fruits of Piper species. The compound has a number of interesting biological properties, including its broad-spectrum activity on weeds as a contact herbicide. Initial studies highlighted a similarity in ...

Energy budget closure observed in paired Eddy Covariance towers with increased and continuous daily turbulence

USDA-ARS?s Scientific Manuscript database

The lack of energy closure has been a longstanding issue with Eddy Covariance (EC). Multiple mechanisms have been proposed to explain the discrepancies in energy balance including diurnal energy storage changes, advection of energy, and larger scale turbulent processes that cannot be resolved by fi...

Level of Processing Modulates the Neural Correlates of Emotional Memory Formation

ERIC Educational Resources Information Center

Ritchey, Maureen; LaBar, Kevin S.; Cabeza, Roberto

2011-01-01

Emotion is known to influence multiple aspects of memory formation, including the initial encoding of the memory trace and its consolidation over time. However, the neural mechanisms whereby emotion impacts memory encoding remain largely unexplored. The present study used a levels-of-processing manipulation to characterize the impact of emotion on…

Reduced-Order Modeling of Unsteady Aerodynamics Across Multiple Mach Regimes

DTIC Science & Technology

2013-01-01

including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing ...Literature Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.3 Thesis Overview... Review Aeroelasticity, which is the study of the interaction between fluids and structures when a feedback mechanism exists between the fluid and the

Film as Identity Exploration: A Multimodal Analysis of Youth-Produced Films

ERIC Educational Resources Information Center

Halverson, Erica Rosenfeld

2010-01-01

Background/Context: Researchers have begun to document and understand the work youth do as they compose in multiple media including video games, online virtual worlds, participatory fan cultural practices, and in the digital media arts. However, we lack mechanisms for analyzing the products, especially when it comes to understanding the…

Environmental quality modifies the relationship between county-level leisure-time physical inactivity and obesity in the U.S.

EPA Science Inventory

Background/Aim More than one-third of U.S. adults are obese, making them vulnerable to multiple poor outcomes including diabetes, heart disease, cancer, and death. Physical inactivity is a well-established mechanism contributing to obesity that can be promoted or hindered by nume...

Impact of vegetation control and annual fertilization on properties of loblolly pine wood at age 12

Treesearch

Alexander Clark; Bruce E. Borders; Richard F. Daniels

2004-01-01

Loblolly pine (Pinus taeda L.) stands in the Coastal Plain and Piedmont of Georgia were subjected to four intensive silvicultural regimes to monitor and record relative tree growth. Treatments included: intensive mechanical site preparation, complete vegetation control with multiple applications of herbicides, annual high rates of nitrogen...

Ghrelin stimulates growth hormone release from the pituitary via hypothalamic growth hormone-releasing hormone neurons in the cichlid, Oreochromis niloticus

USDA-ARS?s Scientific Manuscript database

Ghrelin, a gastric peptide, is implicated in a multiplicity of biological functions, including energy homeostasis and reproduction. Neuronal systems that are involved in energy homeostasis as well as reproduction traverse the hypothalamus, however, the mechanism by which they control energy homeosta...

A pharmacodynamic comparison of piperidine and pyridine alkaloid actions at fetal muscle-type nicotinic acetylcholine receptors (nAChR)

USDA-ARS?s Scientific Manuscript database

Piperidine and pyridine alkaloids are found in many species of plants including Lobelia spp., Conium spp., Nicotiana spp., and Lupinus spp. Some of these alkaloids cause multiple congenital contracture deformities (MCC) and cleft palates in cattle, pigs, sheep, and goats. The mechanism behind MCC ...

Compression and neutron and ion beams emission mechanisms within a plasma focus device

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

Yousefi, H. R.; Mohanty, S. R.; Nakada, Y.

This paper reports some results of investigations of the neutron emission from middle energy Mather-type plasma focus. Multiple compressions were observed, and it seems that multiple compression regimes can occur at low pressure, while single compression appeared at higher pressure, which is favorable for neutron production. The multiple compression mechanism can be attributed to the (m=0 type) instability. The m=0 type instability is a necessary condition for fusion activity and x-ray production, but is not sufficient by itself. Accompanying the multiple compressions, multiple deuteron and neutron pulses were detected, which implies that there are different kinds of acceleration mechanisms.

Characteristics of psychiatric hospitalizations with multiple mechanical restraint episodes versus hospitalization with a single mechanical restraint episode.

PubMed

Guzman-Parra, Jose; Guzik, Justyna; Garcia-Sanchez, Juan A; Pino-Benitez, Isabel; Aguilera-Serrano, Carlos; Mayoral-Cleries, Fermin

2016-10-30

We investigated the characteristics of multiple episodes of mechanical restraint versus a single episode in a psychiatric ward of a public general hospital. The following characteristics were associated with multiple restraints: young age, length of hospital stay, not being readmitted within 30 days from previous discharge, and admission in the previous year before the implementation of an intervention program to reduce mechanical restraint. The study suggests that both organizational factors and patients' disturbed behaviour are associated with the risk of being mechanically restrained several times. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Regulatory RNAs and control of epigenetic mechanisms: expectations for cognition and cognitive dysfunction.

PubMed

Butler, Anderson A; Webb, William M; Lubin, Farah D

2016-01-01

The diverse functions of noncoding RNAs (ncRNAs) can influence virtually every aspect of the transcriptional process including epigenetic regulation of genes. In the CNS, regulatory RNA networks and epigenetic mechanisms have broad relevance to gene transcription changes involved in long-term memory formation and cognition. Thus, it is becoming increasingly clear that multiple classes of ncRNAs impact neuronal development, neuroplasticity, and cognition. Currently, a large gap exists in our knowledge of how ncRNAs facilitate epigenetic processes, and how this phenomenon affects cognitive function. In this review, we discuss recent findings highlighting a provocative role for ncRNAs including lncRNAs and piRNAs in the control of epigenetic mechanisms involved in cognitive function. Furthermore, we discuss the putative roles for these ncRNAs in cognitive disorders such as schizophrenia and Alzheimer's disease.

Responds of Bone Cells to Microgravity: Ground-Based Research

NASA Astrophysics Data System (ADS)

Zhang, Jian; Li, Jingbao; Xu, Huiyun; Yang, Pengfei; Xie, Li; Qian, Airong; Zhao, Yong; Shang, Peng

2015-11-01

Severe loss of bone occurs due to long-duration spaceflight. Mechanical loading stimulates bone formation, while bone degradation happens under mechanical unloading. Bone remodeling is a dynamic process in which bone formation and bone resorption are tightly coupled. Increased bone resorption and decreased bone formation caused by reduced mechanical loading, generally result in disrupted bone remodeling. Bone remodeling is orchestrated by multiple bone cells including osteoblast, osteocyte, osteoclast and mesenchymal stem cell. It is yet not clear that how these bone cells sense altered gravity, translate physical stimulus into biochemical signals, and then regulate themselves structurally and functionally. In this paper, studies elucidating the bioeffects of microgravity on bone cells (osteoblast, osteocyte, osteoclast, mesenchymal stem cell) using various platforms including spaceflight and ground-based simulated microgravity were summarized. Promising gravity-sensitive signaling pathways and protein molecules were proposed.

Polar Expansion Dynamics in the Plant Kingdom: A Diverse and Multifunctional Journey on the Path to Pollen Tubes

PubMed Central

Domozych, David S.; Fujimoto, Chelsea; LaRue, Therese

2013-01-01

Polar expansion is a widespread phenomenon in plants spanning all taxonomic groups from the Charophycean Green Algae to pollen tubes in Angiosperms and Gymnosperms. Current data strongly suggests that many common features are shared amongst cells displaying polar growth mechanics including changes to the structural features of localized regions of the cell wall, mobilization of targeted secretion mechanisms, employment of the actin cytoskeleton for directing secretion and in many cases, endocytosis and coordinated interaction of multiple signal transduction mechanisms prompted by external biotic and abiotic cues. The products of polar expansion perform diverse functions including delivery of male gametes to the egg, absorption, anchorage, adhesion and photo-absorption efficacy. A comparative analysis of polar expansion dynamics is provided with special emphasis on those found in early divergent plants. PMID:27137370

Modeling the Interactions Between Multiple Crack Closure Mechanisms at Threshold

NASA Technical Reports Server (NTRS)

Newman, John A.; Riddell, William T.; Piascik, Robert S.

2003-01-01

A fatigue crack closure model is developed that includes interactions between the three closure mechanisms most likely to occur at threshold; plasticity, roughness, and oxide. This model, herein referred to as the CROP model (for Closure, Roughness, Oxide, and Plasticity), also includes the effects of out-of plane cracking and multi-axial loading. These features make the CROP closure model uniquely suited for, but not limited to, threshold applications. Rough cracks are idealized here as two-dimensional sawtooths, whose geometry induces mixed-mode crack- tip stresses. Continuum mechanics and crack-tip dislocation concepts are combined to relate crack face displacements to crack-tip loads. Geometric criteria are used to determine closure loads from crack-face displacements. Finite element results, used to verify model predictions, provide critical information about the locations where crack closure occurs.

Integrative FourD omics approach profiles the target network of the carbon storage regulatory system.

PubMed

Sowa, Steven W; Gelderman, Grant; Leistra, Abigail N; Buvanendiran, Aishwarya; Lipp, Sarah; Pitaktong, Areen; Vakulskas, Christopher A; Romeo, Tony; Baldea, Michael; Contreras, Lydia M

2017-02-28

Multi-target regulators represent a largely untapped area for metabolic engineering and anti-bacterial development. These regulators are complex to characterize because they often act at multiple levels, affecting proteins, transcripts and metabolites. Therefore, single omics experiments cannot profile their underlying targets and mechanisms. In this work, we used an Integrative FourD omics approach (INFO) that consists of collecting and analyzing systems data throughout multiple time points, using multiple genetic backgrounds, and multiple omics approaches (transcriptomics, proteomics and high throughput sequencing crosslinking immunoprecipitation) to evaluate simultaneous changes in gene expression after imposing an environmental stress that accentuates the regulatory features of a network. Using this approach, we profiled the targets and potential regulatory mechanisms of a global regulatory system, the well-studied carbon storage regulatory (Csr) system of Escherichia coli, which is widespread among bacteria. Using 126 sets of proteomics and transcriptomics data, we identified 136 potential direct CsrA targets, including 50 novel ones, categorized their behaviors into distinct regulatory patterns, and performed in vivo fluorescence-based follow up experiments. The results of this work validate 17 novel mRNAs as authentic direct CsrA targets and demonstrate a generalizable strategy to integrate multiple lines of omics data to identify a core pool of regulator targets. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Mechanical coupling for a rotor shaft assembly of dissimilar materials

DOEpatents

Shi, Jun [Glastonbury, CT; Bombara, David [New Hartford, CT; Green, Kevin E [Broad Brook, CT; Bird, Connic [Rocky Hill, CT; Holowczak, John [South Windsor, CT

2009-05-05

A mechanical coupling for coupling a ceramic disc member to a metallic shaft includes a first wedge clamp and a second wedge clamp. A fastener engages a threaded end of a tie-bolt to sandwich the ceramic disc between the wedge clamps. An axial spring is positioned between the fastener and the second wedge clamp to apply an axial preload along the longitudinal axis. Another coupling utilizes a rotor shaft end of a metallic rotor shaft as one wedge clamp. Still another coupling includes a solid ceramic rotor disc with a multiple of tie-bolts radially displaced from the longitudinal axis to exert the preload on the solid ceramic rotor disc.

Progressive Damage Analysis of Bonded Composite Joints

NASA Technical Reports Server (NTRS)

Leone, Frank A., Jr.; Girolamo, Donato; Davila, Carlos G.

2012-01-01

The present work is related to the development and application of progressive damage modeling techniques to bonded joint technology. The joint designs studied in this work include a conventional composite splice joint and a NASA-patented durable redundant joint. Both designs involve honeycomb sandwich structures with carbon/epoxy facesheets joined using adhesively bonded doublers.Progressive damage modeling allows for the prediction of the initiation and evolution of damage within a structure. For structures that include multiple material systems, such as the joint designs under consideration, the number of potential failure mechanisms that must be accounted for drastically increases the complexity of the analyses. Potential failure mechanisms include fiber fracture, intraply matrix cracking, delamination, core crushing, adhesive failure, and their interactions. The bonded joints were modeled using highly parametric, explicitly solved finite element models, with damage modeling implemented via custom user-written subroutines. Each ply was discretely meshed using three-dimensional solid elements. Layers of cohesive elements were included between each ply to account for the possibility of delaminations and were used to model the adhesive layers forming the joint. Good correlation with experimental results was achieved both in terms of load-displacement history and the predicted failure mechanism(s).

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

PubMed Central

Shen, Ding-Wu; Pouliot, Lynn M.; Hall, Matthew D.

2012-01-01

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis. PMID:22659329

Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes.

PubMed

Shen, Ding-Wu; Pouliot, Lynn M; Hall, Matthew D; Gottesman, Michael M

2012-07-01

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function

PubMed Central

German, Peter; Bai, Shanshan; Liu, Xian-De; Sun, Mianen; Zhou, Lijun; Kalra, Sarathi; Zhang, Xuesong; Minelli, Rosalba; Scott, Kenneth L.; Mills, Gordon B.; Jonasch, Eric; Ding, Zhiyong

2016-01-01

Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation, and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long form variant of VHL was often detected as multiple bands by Western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetic and pharmacologic approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein, thereby promoting HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases. PMID:26973240

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

PubMed

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response.

PubMed

Shahin, Mohamed H; Johnson, Julie A

2016-04-01

Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response. Copyright © 2016. Published by Elsevier Ltd.

Modeling a Single SEP Event from Multiple Vantage Points Using the iPATH Model

NASA Astrophysics Data System (ADS)

Hu, Junxiang; Li, Gang; Fu, Shuai; Zank, Gary; Ao, Xianzhi

2018-02-01

Using the recently extended 2D improved Particle Acceleration and Transport in the Heliosphere (iPATH) model, we model an example gradual solar energetic particle event as observed at multiple locations. Protons and ions that are energized via the diffusive shock acceleration mechanism are followed at a 2D coronal mass ejection-driven shock where the shock geometry varies across the shock front. The subsequent transport of energetic particles, including cross-field diffusion, is modeled by a Monte Carlo code that is based on a stochastic differential equation method. Time intensity profiles and particle spectra at multiple locations and different radial distances, separated in longitudes, are presented. The results shown here are relevant to the upcoming Parker Solar Probe mission.

[Axonopathy in the pathogenesis of multiple sclerosis, peripheral diffuse and local motor neuropathies and motor neuron disease].

PubMed

Merkulov, Iu A; Merkulova, D M; Iosifova, O A; Zavalishin, I A

2010-01-01

Two hundreds and seventy-six patients including 43 patients with multiple sclerosis, 24 - with acute inflammatory demyelinating polyneuropathy (AIDP), 144 - with chronic inflammatory demyelinating polyneuropathy (CIDP), 27 - with motor multifocal neuropathy (MMN), 38 - with lateral amyotrophic sclerosis (LAS) have been examined. Symptoms of axonal degeneration, manifested in denervation phenomena in both clinical and instrumental studies (electromyography, transcranial magnetic stimulation, MRT), were revealed in all groups of patients. The formation of excitation conduction blocks is an universal pathophysiological mechanism of the axonopathy development in AIDP, CIDP, MMN and LAS. Symptoms of axonopathy and peripheral demyelinization in patients with multiple sclerosis and LAS suggest the possibility of transformation of immunopathological process from the central nervous system to the peripheral one.

Advancements in Nanomedicine for Multiple Myeloma.

PubMed

Detappe, Alexandre; Bustoros, Mark; Mouhieddine, Tarek H; Ghoroghchian, P Peter

2018-06-01

In the past decades, considerable progress has been made in our understanding and treatment of multiple myeloma. Several challenges remain including our abilities to longitudinally image tumor responses to treatment, to combine various therapeutic agents with different mechanisms of action but with overlapping toxicities, and to efficiently harness the power of the immune system to augment remission and/or to induce permanent cures. Nanomedicine may help to address many of these outstanding issues, affording novel diagnostic capabilities and offering disruptive technologies that promise to revolutionize treatment. Here, we review recent developments and the future of nanomedicine for multiple myeloma, highlighting new considerations in nanoparticle designs that may help to augment active targeting, to facilitate longitudinal imaging, and to improve drug delivery. Copyright © 2018 Elsevier Ltd. All rights reserved.

Insecticide resistance and resistance mechanisms in bed bugs, Cimex spp. (Hemiptera: Cimicidae).

PubMed

Dang, Kai; Doggett, Stephen L; Veera Singham, G; Lee, Chow-Yang

2017-06-29

The worldwide resurgence of bed bugs [both Cimex lectularius L. and Cimex hemipterus (F.)] over the past two decades is believed in large part to be due to the development of insecticide resistance. The transcriptomic and genomic studies since 2010, as well as morphological, biochemical and behavioral studies, have helped insecticide resistance research on bed bugs. Multiple resistance mechanisms, including penetration resistance through thickening or remodelling of the cuticle, metabolic resistance by increased activities of detoxification enzymes (e.g. cytochrome P450 monooxygenases and esterases), and knockdown resistance by kdr mutations, have been experimentally identified as conferring insecticide resistance in bed bugs. Other candidate resistance mechanisms, including behavioral resistance, some types of physiological resistance (e.g. increasing activities of esterases by point mutations, glutathione S-transferase, target site insensitivity including altered AChEs, GABA receptor insensitivity and altered nAChRs), symbiont-mediated resistance and other potential, yet undiscovered mechanisms may exist. This article reviews recent studies of resistance mechanisms and the genes governing insecticide resistance, potential candidate resistance mechanisms, and methods of monitoring insecticide resistance in bed bugs. This article provides an insight into the knowledge essential for the development of both insecticide resistance management (IRM) and integrated pest management (IPM) strategies for successful bed bug management.

MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

PubMed Central

Sakai, Atsushi; Saitow, Fumihito; Maruyama, Motoyo; Miyake, Noriko; Miyake, Koichi; Shimada, Takashi; Okada, Takashi; Suzuki, Hidenori

2017-01-01

miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia. PMID:28677679

Assessment of mechanism, type and severity of injury in multiple trauma patients: A cross sectional study of a trauma center in Iran.

PubMed

Reihani, Hamidreza; Pirazghandi, Hossein; Bolvardi, Ehsan; Ebrahimi, Mohsen; Pishbin, Elham; Ahmadi, Koorosh; Safdarian, Mahdi; Saadat, Soheil; Rahimi-Movaghar, Vafa

2017-04-01

To accurately assess the mechanism, type and severity of injury in Iranian multiple trauma patients of a trauma center. Patients with multiple traumas referring to the emergency department of Hasheminejad University Hospital in Mashhad, Iran, entered this cross sectional study from March 2013 to December 2013. All the patients with injury severity score (ISS) > 9 were included in this study. Data analysis was performed by SPSS software (Version 11.5) and P values less than 0.05 were considered as significant differences. Among the 6306 hospitalized trauma patients during this period, 148 had ISS>9. The male female ratio was 80%. The mean age of the patients was (33.5 ± 19.3) years. And 71% of the patients were younger than 44 years old. There were 19 (13%) deaths from which 68.5% were older than 44 years old. The mean transfer time from the injury scene to hospital was (55 ± 26) minutes. The most frequent mechanisms of injury were motorcycle crashes and falling from height, which together included 66.2% of all the injuries. A total of 84% of hospital deaths occurred after the first 24 h of hospitalization. Head and neck were the most common body injured areas with a prevalence of 111 cases (75%). Motorcycle crashes have high frequency in Iran. Since most victims are young males, injury prevention strategies should be considered to reduce the burden of injuries. Copyright © 2017 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Mechanical Properties and Failure of Biopolymers: Atomistic Reactions to Macroscale Response

PubMed Central

Jung, GangSeob; Qin, Zhao

2017-01-01

The behavior of chemical bonding under various mechanical loadings is an intriguing mechanochemical property of biological materials, and the property plays a critical role in determining their deformation and failure mechanisms. Because of their astonishing mechanical properties and roles in constituting the basis of a variety of physiologically relevant materials, biological protein materials have been intensively studied. Understanding the relation between chemical bond networks (structures) and their mechanical properties offers great possibilities to enable new materials design in nanotechnology and new medical treatments for human diseases. Here we focus on how the chemical bonds in biological systems affect mechanical properties and how they change during mechanical deformation and failure. Three representative cases of biomaterials related to the human diseases are discussed in case studies, including: amyloids, intermediate filaments, and collagen, each describing mechanochemical features and how they relate to the pathological conditions at multiple scales. PMID:26108895

Binary variable multiple-model multiple imputation to address missing data mechanism uncertainty: Application to a smoking cessation trial

PubMed Central

Siddique, Juned; Harel, Ofer; Crespi, Catherine M.; Hedeker, Donald

2014-01-01

The true missing data mechanism is never known in practice. We present a method for generating multiple imputations for binary variables that formally incorporates missing data mechanism uncertainty. Imputations are generated from a distribution of imputation models rather than a single model, with the distribution reflecting subjective notions of missing data mechanism uncertainty. Parameter estimates and standard errors are obtained using rules for nested multiple imputation. Using simulation, we investigate the impact of missing data mechanism uncertainty on post-imputation inferences and show that incorporating this uncertainty can increase the coverage of parameter estimates. We apply our method to a longitudinal smoking cessation trial where nonignorably missing data were a concern. Our method provides a simple approach for formalizing subjective notions regarding nonresponse and can be implemented using existing imputation software. PMID:24634315

Epileptogenesis: can the science of epigenetics give us answers?

PubMed

Lubin, Farah D

2012-05-01

Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.

A realistic evaluation: the case of protocol-based care

PubMed Central

2010-01-01

Background 'Protocol based care' was envisioned by policy makers as a mechanism for delivering on the service improvement agenda in England. Realistic evaluation is an increasingly popular approach, but few published examples exist, particularly in implementation research. To fill this gap, within this paper we describe the application of a realistic evaluation approach to the study of protocol-based care, whilst sharing findings of relevance about standardising care through the use of protocols, guidelines, and pathways. Methods Situated between positivism and relativism, realistic evaluation is concerned with the identification of underlying causal mechanisms, how they work, and under what conditions. Fundamentally it focuses attention on finding out what works, for whom, how, and in what circumstances. Results In this research, we were interested in understanding the relationships between the type and nature of particular approaches to protocol-based care (mechanisms), within different clinical settings (context), and what impacts this resulted in (outcomes). An evidence review using the principles of realist synthesis resulted in a number of propositions, i.e., context, mechanism, and outcome threads (CMOs). These propositions were then 'tested' through multiple case studies, using multiple methods including non-participant observation, interviews, and document analysis through an iterative analysis process. The initial propositions (conjectured CMOs) only partially corresponded to the findings that emerged during analysis. From the iterative analysis process of scrutinising mechanisms, context, and outcomes we were able to draw out some theoretically generalisable features about what works, for whom, how, and what circumstances in relation to the use of standardised care approaches (refined CMOs). Conclusions As one of the first studies to apply realistic evaluation in implementation research, it was a good fit, particularly given the growing emphasis on understanding how context influences evidence-based practice. The strengths and limitations of the approach are considered, including how to operationalise it and some of the challenges. This approach provided a useful interpretive framework with which to make sense of the multiple factors that were simultaneously at play and being observed through various data sources, and for developing explanatory theory about using standardised care approaches in practice. PMID:20504293

Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments

PubMed Central

Chu, Chenyu; Deng, Jia

2017-01-01

Epigallocatechin-3-gallate (EGCG), a component extracted from green tea, has been proved to have multiple effects on human pathological and physiological processes, and its mechanisms are discrepant in cancer, vascularity, bone regeneration, and nervous system. Although there are multiple benefits associated with EGCG, more and more challenges are still needed to get through. For example, EGCG shows low bioactivity via oral administration. This review focuses on effects of EGCG, including anti-cancer, antioxidant, anti-inflammatory, anticollagenase, and antifibrosis effects, to express the potential of EGCG and necessity of further studies in this field. PMID:28884125

Re-engineering the Pancreas Tumor Microenvironment: A “Regenerative Program” Hacked

PubMed Central

Evan, Gerard I.; Hah, Nasun; Littlewood, Trevor D.; Sodir, Nicole M.; Vidal, Tania Campos; Downes, Michael; Evans, Ronald M.

2017-01-01

The “hallmarks” of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix and immune cells. The oncogenically-activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immune-suppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity and maintenance. Hence, interfering with such super enhancer driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extra-terminal motif proteins (BETs) have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanism suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease. PMID:28373363

Janus Kinase Antagonists and Other Novel Small Molecules for the Treatment of Crohn's Disease.

PubMed

Boland, Brigid S; Vermeire, Séverine

2017-09-01

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Using Community Insight to Understand Physical Activity Adoption in Overweight and Obese African American and Hispanic Women: A Qualitative Study

ERIC Educational Resources Information Center

Mama, Scherezade K.; McCurdy, Sheryl A.; Evans, Alexandra E.; Thompson, Deborah I.; Diamond, Pamela M.; Lee, Rebecca E.

2015-01-01

Ecologic models suggest that multiple levels of influencing factors are important for determining physical activity participation and include individual, social, and environmental factors. The purpose of this qualitative study was to use an ecologic framework to gain a deeper understanding of the underlying behavioral mechanisms that influence…

Omnivorous Representation Might Lead to Indigestion: Commentary on Amaral and Roeper

ERIC Educational Resources Information Center

Slabakova, Roumyana

2014-01-01

This article offers commentary that the Multiple Grammar (MG) language acquisition theory proposed by Luiz Amaral and Tom Roeper (A&R) in the present issue lacks elaboration of the psychological mechanisms at work in second language acquisition. Topics discussed include optionality in a speaker's grammar and the rules of verb position in…

The Positive and Negative Effects of Science Concept Tests on Student Conceptual Understanding

ERIC Educational Resources Information Center

Chang, Chun-Yen; Yeh, Ting-Kuang; Barufaldi, James P.

2010-01-01

This study explored the phenomenon of testing effect during science concept assessments, including the mechanism behind it and its impact upon a learner's conceptual understanding. The participants consisted of 208 high school students, in either the 11th or 12th grade. Three types of tests (traditional multiple-choice test, correct concept test,…

Deleting HDAC3 Rescues Long-Term Memory Impairments Induced by Disruption of the Neuron-Specific Chromatin Remodeling Subunit BAF53b

ERIC Educational Resources Information Center

Shu, Guanhua; Kramár, Enikö A.; López, Alberto J.; Huynh, Grace; Wood, Marcelo A.; Kwapis, Janine L.

2018-01-01

Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific…

Effects of acquisition, loss, and neofunctionalization of trichothecene biosynthetic genes on variation in trichothecene structure, pathway regulation, and self-protection mechanisms in the Hypocreales

USDA-ARS?s Scientific Manuscript database

Trichothecenes are secondary metabolites produced by multiple genera in the order Hypocreales, including Fusarium, Myrothecium, Stachybotrys, and Trichoderma. These metabolites are of concern because they are toxic to humans and animals, can contribute to pathogenicity in Fusarium, and are required ...

Endophytic Trichoderma isolates from tropical environments delay disease onset and induce resistance against Phytophthora capsici in hot pepper using multiple mechanisms

USDA-ARS?s Scientific Manuscript database

Isolates of several Trichoderma spp., were collected from tropical environments as potential biocontrol agents for cacao (Theobroma cacao) diseases. The diversity of isolates collected, including new species, and there endophytic nature on their host plants, led us to consider if these isolates have...

Comparison study of thickness swell performance of commercial oriented strandboard flooring products

Treesearch

Hongmei Gu; Siqun Wang; Trairat Neimsuwan; Sunguo Wang

2005-01-01

The multiple layer structure of oriented strandboard (OSB) has a significant influence on its performance, including thickness swell (TS). TS is recognized as an important performance property for OSB products. Optimization of TS through layer property ma- nipulation to achieve the lowest total TS while maintaining acceptable mechanical properties is attainable if the...

Bellows flow-induced vibrations

NASA Technical Reports Server (NTRS)

Tygielski, P. J.; Smyly, H. M.; Gerlach, C. R.

1983-01-01

The bellows flow excitation mechanism and results of comprehensive test program are summarized. The analytical model for predicting bellows flow induced stress is refined. The model includes the effects of an upstream elbow, arbitrary geometry, and multiple piles. A refined computer code for predicting flow induced stress is described which allows life prediction if a material S-N diagram is available.

A Comprehensive Examination of Preschool Teachers' Implementation Fidelity When Using a Supplemental Language and Literacy Curriculum

ERIC Educational Resources Information Center

Piasta, Shayne B.; Justice, Laura M.; McGinty, Anita; Mashburn, Andrew; Slocum, Laura

2015-01-01

Background: Recent curriculum studies raise a number of questions concerning teachers' implementation fidelity, including the extent to which fidelity to multiple curriculum components is achieved and measured and the extent to which fidelity serves as a mechanism for impacting children's learning. Objective: Within the context of a language and…

Multiple-stripe lithiation mechanism of individual SnO2 nanowires in a flooding geometry

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

Zhong, Li; Liu, Xiao H.; Wang, G. F.

2011-06-17

The atomic scale lithiation mechanism of individual SnO2 nanowires in a flooding geometry with the entire wires being immersed in the electrolyte was revealed by in-situ transmission electron microscopy. The lithiation initiated multiple stripes with width of a few nanometer parallel to {020} planes transversing the entire wires, serving as multiple reaction fronts for late stage of lithiation. Inside the stripes, we identified high density of dislocations and enlarged inter-planar spacing, which provide effective path for lithium ion transport. The density of the stripes increased with further lithiation, and eventually they merged with one another, causing a large enlongation andmore » volume expansion and the crystalline to amorphous phase transformation. This multiple stripes and multiple reaction fronts lithiation mechanism is unexpected and differs completely from the expected core-shell lithiation mechanism.« less

Rapid increase in pertactin-deficient Bordetella pertussis isolates, Australia.

PubMed

Lam, Connie; Octavia, Sophie; Ricafort, Lawrence; Sintchenko, Vitali; Gilbert, Gwendolyn L; Wood, Nicholas; McIntyre, Peter; Marshall, Helen; Guiso, Nicole; Keil, Anthony D; Lawrence, Andrew; Robson, Jenny; Hogg, Geoff; Lan, Ruiting

2014-04-01

Acellular vaccines against Bordetella pertussis were introduced in Australia in 1997. By 2000, these vaccines had replaced whole-cell vaccines. During 2008-2012, a large outbreak of pertussis occurred. During this period, 30% (96/320) of B. pertussis isolates did not express the vaccine antigen pertactin (Prn). Multiple mechanisms of Prn inactivation were documented, including IS481 and IS1002 disruptions, a variation within a homopolymeric tract, and deletion of the prn gene. The mechanism of lack of expression of Prn in 16 (17%) isolates could not be determined at the sequence level. These findings suggest that B. pertussis not expressing Prn arose independently multiple times since 2008, rather than by expansion of a single Prn-negative clone. All but 1 isolate had ptxA1, prn2, and ptxP3, the alleles representative of currently circulating strains in Australia. This pattern is consistent with continuing evolution of B. pertussis in response to vaccine selection pressure.

Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat.

PubMed

Smith, S J; Cases, S; Jensen, D R; Chen, H C; Sande, E; Tow, B; Sanan, D A; Raber, J; Eckel, R H; Farese, R V

2000-05-01

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.

Modulation of C. elegans Touch Sensitivity Is Integrated at Multiple Levels

PubMed Central

Chen, Xiaoyin

2014-01-01

Sensory systems can adapt to different environmental signals. Here we identify four conditions that modulate anterior touch sensitivity in Caenorhabditis elegans after several hours and demonstrate that such sensory modulation is integrated at multiple levels to produce a single output. Prolonged vibration involving integrin signaling directly sensitizes the touch receptor neurons (TRNs). In contrast, hypoxia, the dauer state, and high salt reduce touch sensitivity by preventing the release of long-range neuroregulators, including two insulin-like proteins. Integration of these latter inputs occurs at upstream neurohormonal cells and at the insulin signaling cascade within the TRNs. These signals and those from integrin signaling converge to modulate touch sensitivity by regulating AKT kinases and DAF-16/FOXO. Thus, activation of either the integrin or insulin pathways can compensate for defects in the other pathway. This modulatory system integrates conflicting signals from different modalities, and adapts touch sensitivity to both mechanical and non-mechanical conditions. PMID:24806678

Dynamical correlation effects on photoisomerization: Ab initio multiple spawning dynamics with MS-CASPT2 for a model trans-protonated Schiff base

DOE PAGES

Liu, Lihong; Liu, Jian; Martinez, Todd J.

2015-12-17

Here, we investigate the photoisomerization of a model retinal protonated Schiff base (trans-PSB3) using ab initio multiple spawning (AIMS) based on multi-state second order perturbation theory (MSPT2). Discrepancies between the photodynamical mechanism computed with three-root state-averaged complete active space self-consistent field (SA-3-CASSCF, which does not include dynamic electron correlation effects) and MSPT2 show that dynamic correlation is critical in this photoisomerization reaction. Furthermore, we show that the photodynamics of trans-PSB3 is not well described by predictions based on minimum energy conical intersections (MECIs) or minimum energy conical intersection (CI) seam paths. Instead, most of the CIs involved in the photoisomerizationmore » are far from MECIs and minimum energy CI seam paths. Thus, both dynamical nuclear effects and dynamic electron correlation are critical to understanding the photochemical mechanism.« less

Cascading Effects of BPT for Child Internalizing Problems and Caregiver Depression

PubMed Central

Gonzalez, Michelle A.; Jones, Deborah J.

2016-01-01

Behavioral Parent Training (BPT) is the standard of care for early onset (3 to 8 years old) disruptive behavior disorders (DBDs). Preliminary evidence suggests that BPT may also produce cascading treatment effects for comorbid and interrelated symptomatology in children, primarily internalizing problems, as well as symptomatology in multiple systems of the family, including caregiver depressive symptomatology. What is less well understood, however, is why and how BPT functions to impact these multiple symptom clusters within and between family members. Accordingly, this manuscript aims to serve as a conceptual and theoretical consideration of the mechanisms through which BPT may produce generalized treatment effects among children with early onset DBDs and internalizing problems, as well as the psychosocial difficulties among their caregivers. It is our intention that the hypothesized mechanisms highlighted in this review may guide advances in clinical research, as well as assessment and practice. PMID:27676702

Universal core model for multiple-gate field-effect transistors with short channel and quantum mechanical effects

NASA Astrophysics Data System (ADS)

Shin, Yong Hyeon; Bae, Min Soo; Park, Chuntaek; Park, Joung Won; Park, Hyunwoo; Lee, Yong Ju; Yun, Ilgu

2018-06-01

A universal core model for multiple-gate (MG) field-effect transistors (FETs) with short channel effects (SCEs) and quantum mechanical effects (QMEs) is proposed. By using a Young’s approximation based solution for one-dimensional Poisson’s equations the total inversion charge density (Q inv ) in the channel is modeled for double-gate (DG) and surrounding-gate SG (SG) FETs, following which a universal charge model is derived based on the similarity of the solutions, including for quadruple-gate (QG) FETs. For triple-gate (TG) FETs, the average of DG and QG FETs are used. A SCEs model is also proposed considering the potential difference between the channel’s surface and center. Finally, a QMEs model for MG FETs is developed using the quantum correction compact model. The proposed universal core model is validated on commercially available three-dimensional ATLAS numerical simulations.

Ultrafast collinear scattering and carrier multiplication in graphene.

PubMed

Brida, D; Tomadin, A; Manzoni, C; Kim, Y J; Lombardo, A; Milana, S; Nair, R R; Novoselov, K S; Ferrari, A C; Cerullo, G; Polini, M

2013-01-01

Graphene is emerging as a viable alternative to conventional optoelectronic, plasmonic and nanophotonic materials. The interaction of light with charge carriers creates an out-of-equilibrium distribution, which relaxes on an ultrafast timescale to a hot Fermi-Dirac distribution, that subsequently cools emitting phonons. Although the slower relaxation mechanisms have been extensively investigated, the initial stages still pose a challenge. Experimentally, they defy the resolution of most pump-probe setups, due to the extremely fast sub-100 fs carrier dynamics. Theoretically, massless Dirac fermions represent a novel many-body problem, fundamentally different from Schrödinger fermions. Here we combine pump-probe spectroscopy with a microscopic theory to investigate electron-electron interactions during the early stages of relaxation. We identify the mechanisms controlling the ultrafast dynamics, in particular the role of collinear scattering. This gives rise to Auger processes, including charge multiplication, which is key in photovoltage generation and photodetectors.

Mechanical design of multiple zone plates precision alignment apparatus for hard X-ray focusing in twenty-nanometer scale

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

Shu, Deming; Liu, Jie; Gleber, Sophie C.

An enhanced mechanical design of multiple zone plates precision alignment apparatus for hard x-ray focusing in a twenty-nanometer scale is provided. The precision alignment apparatus includes a zone plate alignment base frame; a plurality of zone plates; and a plurality of zone plate holders, each said zone plate holder for mounting and aligning a respective zone plate for hard x-ray focusing. At least one respective positioning stage drives and positions each respective zone plate holder. Each respective positioning stage is mounted on the zone plate alignment base frame. A respective linkage component connects each respective positioning stage and the respectivemore » zone plate holder. The zone plate alignment base frame, each zone plate holder and each linkage component is formed of a selected material for providing thermal expansion stability and positioning stability for the precision alignment apparatus.« less

Natural products as modulator of autophagy with potential clinical prospects.

PubMed

Wang, Peiqi; Zhu, Lingjuan; Sun, Dejuan; Gan, Feihong; Gao, Suyu; Yin, Yuanyuan; Chen, Lixia

2017-03-01

Natural compounds derived from living organisms are well defined for their remarkable biological and pharmacological properties likely to be translated into clinical use. Therefore, delving into the mechanisms by which natural compounds protect against diverse diseases may be of great therapeutic benefits for medical practice. Autophagy, an intricate lysosome-dependent digestion process, with implications in a wide variety of pathophysiological settings, has attracted extensive attention over the past few decades. Hitherto, accumulating evidence has revealed that a large number of natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways and transcriptional regulators. In this review, we summarize natural compounds regulating autophagy in multifarious diseases including cancer, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and immune diseases, hoping to inspire further investigation of the underlying mechanisms of natural compounds and to facilitate their clinical use for multiple human diseases.

Neuronal intrinsic regenerative capacity: The impact of microtubule organization and axonal transport.

PubMed

Murillo, Blanca; Sousa, Mónica Mendes

2018-05-08

In the adult vertebrate central nervous system, axons generally fail to regenerate. In contrast, peripheral nervous system axons are able to form a growth cone and regenerate upon lesion. Among the multiple intrinsic mechanisms leading to the formation of a new growth cone and to successful axon regrowth, cytoskeleton organization and dynamics is central. Here we discuss how multiple pathways that define the regenerative capacity converge into the regulation of the axonal microtubule cytoskeleton and transport. We further explore the use of dorsal root ganglion neurons as a model to study the neuronal regenerative ability. Finally, we address some of the unanswered questions in the field, including the mechanisms by which axonal transport might be modulated by injury, and the relationship between microtubule organization, dynamics, and axonal transport. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018. © 2018 Wiley Periodicals, Inc.

Small RNAs Reflect Grandparental Environments in Apomictic Dandelion

PubMed Central

Morgado, Lionel; Preite, Veronica; Oplaat, Carla; Anava, Sarit; Ferreira de Carvalho, Julie; Rechavi, Oded; Johannes, Frank; Verhoeven, Koen J.F.

2017-01-01

Abstract Plants can show long-term effects of environmental stresses and in some cases a stress “memory” has been reported to persist across generations, potentially mediated by epigenetic mechanisms. However, few documented cases exist of transgenerational effects that persist for multiple generations and it remains unclear if or how epigenetic mechanisms are involved. Here, we show that the composition of small regulatory RNAs in apomictic dandelion lineages reveals a footprint of drought stress and salicylic acid treatment experienced two generations ago. Overall proportions of 21 and 24 nt RNA pools were shifted due to grandparental treatments. While individual genes did not show strong up- or downregulation of associated sRNAs, the subset of genes that showed the strongest shifts in sRNA abundance was significantly enriched for several GO terms including stress-specific functions. This suggests that a stress-induced signal was transmitted across multiple unexposed generations leading to persistent changes in epigenetic gene regulation. PMID:28472380

Trophic compensation reinforces resistance: herbivory absorbs the increasing effects of multiple disturbances.

PubMed

Ghedini, Giulia; Russell, Bayden D; Connell, Sean D

2015-02-01

Disturbance often results in small changes in community structure, but the probability of transitioning to contrasting states increases when multiple disturbances combine. Nevertheless, we have limited insights into the mechanisms that stabilise communities, particularly how perturbations can be absorbed without restructuring (i.e. resistance). Here, we expand the concept of compensatory dynamics to include countervailing mechanisms that absorb disturbances through trophic interactions. By definition, 'compensation' occurs if a specific disturbance stimulates a proportional countervailing response that eliminates its otherwise unchecked effect. We show that the compounding effects of disturbances from local to global scales (i.e. local canopy-loss, eutrophication, ocean acidification) increasingly promote the expansion of weedy species, but that this response is countered by a proportional increase in grazing. Finally, we explore the relatively unrecognised role of compensatory effects, which are likely to maintain the resistance of communities to disturbance more deeply than current thinking allows. © 2015 John Wiley & Sons Ltd/CNRS.

Mechanical design of translocating motor proteins.

PubMed

Hwang, Wonmuk; Lang, Matthew J

2009-01-01

Translocating motors generate force and move along a biofilament track to achieve diverse functions including gene transcription, translation, intracellular cargo transport, protein degradation, and muscle contraction. Advances in single molecule manipulation experiments, structural biology, and computational analysis are making it possible to consider common mechanical design principles of these diverse families of motors. Here, we propose a mechanical parts list that include track, energy conversion machinery, and moving parts. Energy is supplied not just by burning of a fuel molecule, but there are other sources or sinks of free energy, by binding and release of a fuel or products, or similarly between the motor and the track. Dynamic conformational changes of the motor domain can be regarded as controlling the flow of free energy to and from the surrounding heat reservoir. Multiple motor domains are organized in distinct ways to achieve motility under imposed physical constraints. Transcending amino acid sequence and structure, physically and functionally similar mechanical parts may have evolved as nature's design strategy for these molecular engines.

Mechanical Design of Translocating Motor Proteins

PubMed Central

Lang, Matthew J.

2013-01-01

Translocating motors generate force and move along a biofilament track to achieve diverse functions including gene transcription, translation, intracellular cargo transport, protein degradation, and muscle contraction. Advances in single molecule manipulation experiments, structural biology, and computational analysis are making it possible to consider common mechanical design principles of these diverse families of motors. Here, we propose a mechanical parts list that include track, energy conversion machinery, and moving parts. Energy is supplied not just by burning of a fuel molecule, but there are other sources or sinks of free energy, by binding and release of a fuel or products, or similarly between the motor and the track. Dynamic conformational changes of the motor domain can be regarded as controlling the flow of free energy to and from the surrounding heat reservoir. Multiple motor domains are organized in distinct ways to achieve motility under imposed physical constraints. Transcending amino acid sequence and structure, physically and functionally similar mechanical parts may have evolved as nature’s design strategy for these molecular engines. PMID:19452133

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

PubMed Central

Shahheydari, Hamideh; Ragagnin, Audrey; Walker, Adam K.; Toth, Reka P.; Vidal, Marta; Jagaraj, Cyril J.; Perri, Emma R.; Konopka, Anna; Sultana, Jessica M.; Atkin, Julie D.

2017-01-01

Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials. PMID:28539871

Tribbles in normal and malignant haematopoiesis.

PubMed

Stein, Sarah J; Mack, Ethan A; Rome, Kelly S; Pear, Warren S

2015-10-01

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types. © 2015 Authors; published by Portland Press Limited.

Model of visual contrast gain control and pattern masking

NASA Technical Reports Server (NTRS)

Watson, A. B.; Solomon, J. A.

1997-01-01

We have implemented a model of contrast gain and control in human vision that incorporates a number of key features, including a contrast sensitivity function, multiple oriented bandpass channels, accelerating nonlinearities, and a devisive inhibitory gain control pool. The parameters of this model have been optimized through a fit to the recent data that describe masking of a Gabor function by cosine and Gabor masks [J. M. Foley, "Human luminance pattern mechanisms: masking experiments require a new model," J. Opt. Soc. Am. A 11, 1710 (1994)]. The model achieves a good fit to the data. We also demonstrate how the concept of recruitment may accommodate a variant of this model in which excitatory and inhibitory paths have a common accelerating nonlinearity, but which include multiple channels tuned to different levels of contrast.

Lysosomes as mediators of drug resistance in cancer.

PubMed

Zhitomirsky, Benny; Assaraf, Yehuda G

2016-01-01

Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Simultaneous Measurement of Multiple Mechanical Properties of Single Cells Using AFM by Indentation and Vibration.

PubMed

Zhang, Chuang; Shi, Jialin; Wang, Wenxue; Xi, Ning; Wang, Yuechao; Liu, Lianqing

2017-12-01

The mechanical properties of cells, which are the main characteristics determining their physical performance and physiological functions, have been actively studied in the fields of cytobiology and biomedical engineering and for the development of medicines. In this study, an indentation-vibration-based method is proposed to simultaneously measure the mechanical properties of cells in situ, including cellular mass (m), elasticity (k), and viscosity (c). The proposed measurement method is implemented based on the principle of forced vibration stimulated by simple harmonic force using an atomic force microscope (AFM) system integrated with a piezoelectric transducer as the substrate vibrator. The corresponding theoretical model containing the three mechanical properties is derived and used to perform simulations and calculations. Living and fixed human embryonic kidney 293 (HEK 293) cells were subjected to indentation and vibration to measure and compare their mechanical parameters and verify the proposed approach. The results that the fixed sample cells are more viscous and elastic than the living sample cells and the measured mechanical properties of cell are consistent within, but not outside of the central region of the cell, are in accordance with the previous studies. This work provides an approach to simultaneous measurement of the multiple mechanical properties of single cells using an integrated AFM system based on the principle force vibration and thickness-corrected Hertz model. This study should contribute to progress in biomedical engineering, cytobiology, medicine, early diagnosis, specific therapy and cell-powered robots.

Singular Isothermal Disks and the Formation of Multiple Stars

NASA Technical Reports Server (NTRS)

Galli, Daniele; Shu, Frank H.; Laughlin, Gregory; Lizano, Susana; DeVincenzi, Donald (Technical Monitor)

2000-01-01

A crucial missing ingredient in previous theoretical studies of fragmentation is the inclusion of dynamically important levels of magnetic fields. As a minimal model for a candidate presursor to the formation of binary and multiple stars, we therefore consider the equilibrium configuration of isopedically magnetized, scale-free, singular isothermal disks, without the assumption of axial symmetry. We find that lopsided (M = 1) configurations exist at any dimensionless rotation rate, including zero. Multiple-lobed (M = 2, 3, 4, ...) configurations bifurcate from an underlying axisymmetric sequence at progressively higher dimensionless rates of rotation, but such nonaxisymmetric sequences always terminate in shockwaves before they have a chance to fission into separate bodies. We advance the hypothesis that binary and multiple star-formation from smooth (i.e., not highly turbulent) starting states that are supercritical but in unstable mechanical balance requires the rapid (i.e., dynamical) loss of magnetic flux at some stage of the ensuing gravitational collapse.

Students' Difficulties With Multiple Representations in Introductory Mechanics

ERIC Educational Resources Information Center

Nguyen, Dong-Hai; Rebello, N. Sanjay

2011-01-01

Research in physics education indicates that the use of multiple representations in teaching and learning helps students become better problem-solvers. We report on a study to investigate students' difficulties in solving mechanics problems presented in multiple representations. We conducted teaching/learning interviews with 20 students in a…

Disconnection as a Mechanism for Cognitive Dysfunction in Multiple Sclerosis

ERIC Educational Resources Information Center

Dineen, R. A.; Vilisaar, J.; Hlinka, J.; Bradshaw, C. M.; Morgan, P. S.; Constantinescu, C. S.; Auer, D. P.

2009-01-01

Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been…

The Best Anticoagulation Therapy in Multiple-Trauma Patients with Mechanical Heart Valves: Evaluation of Latest Guidelines and Studies.

PubMed

Moeinipour, Aliasghar; Zarifian, Ahmadreza; Sheikh Andalibi, Mohammad Sobhan; Shamloo, Alireza Sepehri; Ahmadabadi, Ali; Amouzeshi, Ahmad; Hoseinikhah, Hamid

2015-12-22

It is common practice for patients with prosthetic cardiac devices, especially heart valve prosthesis, arterial stents, defibrillators, and pacemaker devices, to use anticoagulation treatment. When these patients suffer from multiple trauma after motor vehicle accidents, the best medical management for this challenging position is mandatory. This strategy should include a rapid diagnosis of all possible multiple organ injuries, with special attention to anticoagulation therapy so as to minimize the risk of thromboembolism complication in prosthetic devices. In this review, we describe the best medical management for patients with multiple trauma who use anticoagulants after heart valve replacement. We searched electronic databases PubMed/Medline, Scopus, Embase, and Google Scholar using the following terms: anticoagulant, warfarin, heparin, and multiple trauma. Also, similar studies suggested by the databases were included. Non-English articles were excluded from the review. For patients who use anticoagulation therapy, teamwork between cardiac surgeons, general surgeons, anesthesiologists, and cardiologists is essential. For optimal medical management, multiple consults between members of this team is mandatory for rapid diagnosis of all possible damaged organs, with special attention to the central nervous system, chest, and abdominal traumas. With this strategy, it is important to take note of anticoagulation drugs to minimize the risk of thromboembolism complications in cardiac devices. The best anticoagulant agents for emergency operations in patients with multiple trauma who are using an anticoagulant after heart valve replacement are fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC).

[Keys to preventing accidents in children in the school context].

PubMed

Gabari Gambarte, M Inés; Sáenz Mendía, Raquel

2016-11-02

To learn about children's perception of the causes and prevention strategies involved in school accidents. The sample included 584 school children aged 8-9 years from Navarra. A mixed design was chosen by questionnaire with three open-response questions and one multiple-choice assessment. Analysis was performed in two phases: 1) qualitative development of categories and dimensions of the responses of narrative content, and 2) quantitative variables for recoding correlational analysis. 22 categories emerged, which make up three perceptual dimensions: 1) attribution of causality (5), 2) identification of mechanisms of avoidance (11), and 3) development of coping strategies (6). The correlation intra-variables portray varying degrees: on the one hand, moderate positive numbers (r>0.5) in allocating and identifying causality avoidance mechanisms and, on the other hand, high positive correlation values (r>0.7) referred to developing coping strategies. Children are able to identify accidents as a health problem. They question the multiplicity of elements involved and relate the origin and kind of accident to prevention and support mechanisms. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

Design of Multistable Origami Structures

NASA Astrophysics Data System (ADS)

Gillman, Andrew; Fuchi, Kazuko; Bazzan, Giorgio; Reich, Gregory; Alyanak, Edward; Buskohl, Philip

Origami is being transformed from an art to a mathematically robust method for device design in a variety of scientific applications. These structures often require multiple stable configurations, e.g. efficient well-controlled deployment. However, the discovery of origami structures with mechanical instabilities is challenging given the complex geometric nonlinearities and the large design space to investigate. To address this challenge, we have developed a topology optimization framework for discovering origami fold patterns that realize stable and metastable positions. The objective function targets both the desired stable positions and nonlinear loading profiles of specific vertices in the origami structure. Multistable compliant structures have been shown to offer advantages in their stability and efficiency, and certain origami fold patterns exhibit multistable behavior. Building on this previous work of single vertex multistability analysis, e.g. waterbomb origami pattern, we are expanding the solution set of multistable mechanisms to include multiple vertices and a broader set of reference configurations. Collectively, these results enable an initial classification of geometry-induced mechanical instabilities that can be programmed into active material systems. This work was supported by the Air Force Office of Scientific Research.

Identification of diverse nerve growth factor-regulated genes by serial analysis of gene expression (SAGE) profiling

PubMed Central

Angelastro, James M.; Klimaschewski, Lars; Tang, Song; Vitolo, Ottavio V.; Weissman, Tamily A.; Donlin, Laura T.; Shelanski, Michael L.; Greene, Lloyd A.

2000-01-01

Neurotrophic factors such as nerve growth factor (NGF) promote a wide variety of responses in neurons, including differentiation, survival, plasticity, and repair. Such actions often require changes in gene expression. To identify the regulated genes and thereby to more fully understand the NGF mechanism, we carried out serial analysis of gene expression (SAGE) profiling of transcripts derived from rat PC12 cells before and after NGF-promoted neuronal differentiation. Multiple criteria supported the reliability of the profile. Approximately 157,000 SAGE tags were analyzed, representing at least 21,000 unique transcripts. Of these, nearly 800 were regulated by 6-fold or more in response to NGF. Approximately 150 of the regulated transcripts have been matched to named genes, the majority of which were not previously known to be NGF-responsive. Functional categorization of the regulated genes provides insight into the complex, integrated mechanism by which NGF promotes its multiple actions. It is anticipated that as genomic sequence information accrues the data derived here will continue to provide information about neurotrophic factor mechanisms. PMID:10984536

On Holo-Hilbert Spectral Analysis: A Full Informational Spectral Representation for Nonlinear and Non-Stationary Data

NASA Technical Reports Server (NTRS)

Huang, Norden E.; Hu, Kun; Yang, Albert C. C.; Chang, Hsing-Chih; Jia, Deng; Liang, Wei-Kuang; Yeh, Jia Rong; Kao, Chu-Lan; Juan, Chi-Huang; Peng, Chung Kang;

On Holo-Hilbert spectral analysis: a full informational spectral representation for nonlinear and non-stationary data

PubMed Central

Huang, Norden E.; Hu, Kun; Yang, Albert C. C.; Chang, Hsing-Chih; Jia, Deng; Liang, Wei-Kuang; Yeh, Jia Rong; Kao, Chu-Lan; Juan, Chi-Hung; Peng, Chung Kang; Meijer, Johanna H.; Wang, Yung-Hung; Long, Steven R.; Wu, Zhauhua

2016-01-01

The Holo-Hilbert spectral analysis (HHSA) method is introduced to cure the deficiencies of traditional spectral analysis and to give a full informational representation of nonlinear and non-stationary data. It uses a nested empirical mode decomposition and Hilbert–Huang transform (HHT) approach to identify intrinsic amplitude and frequency modulations often present in nonlinear systems. Comparisons are first made with traditional spectrum analysis, which usually achieved its results through convolutional integral transforms based on additive expansions of an a priori determined basis, mostly under linear and stationary assumptions. Thus, for non-stationary processes, the best one could do historically was to use the time–frequency representations, in which the amplitude (or energy density) variation is still represented in terms of time. For nonlinear processes, the data can have both amplitude and frequency modulations (intra-mode and inter-mode) generated by two different mechanisms: linear additive or nonlinear multiplicative processes. As all existing spectral analysis methods are based on additive expansions, either a priori or adaptive, none of them could possibly represent the multiplicative processes. While the earlier adaptive HHT spectral analysis approach could accommodate the intra-wave nonlinearity quite remarkably, it remained that any inter-wave nonlinear multiplicative mechanisms that include cross-scale coupling and phase-lock modulations were left untreated. To resolve the multiplicative processes issue, additional dimensions in the spectrum result are needed to account for the variations in both the amplitude and frequency modulations simultaneously. HHSA accommodates all the processes: additive and multiplicative, intra-mode and inter-mode, stationary and non-stationary, linear and nonlinear interactions. The Holo prefix in HHSA denotes a multiple dimensional representation with both additive and multiplicative capabilities. PMID:26953180

Multiple-hypothesis multiple-model line tracking

NASA Astrophysics Data System (ADS)

Pace, Donald W.; Owen, Mark W.; Cox, Henry

2000-07-01

Passive sonar signal processing generally includes tracking of narrowband and/or broadband signature components observed on a Lofargram or on a Bearing-Time-Record (BTR) display. Fielded line tracking approaches to date have been recursive and single-hypthesis-oriented Kalman- or alpha-beta filters, with no mechanism for considering tracking alternatives beyond the most recent scan of measurements. While adaptivity is often built into the filter to handle changing track dynamics, these approaches are still extensions of single target tracking solutions to multiple target tracking environment. This paper describes an application of multiple-hypothesis, multiple target tracking technology to the sonar line tracking problem. A Multiple Hypothesis Line Tracker (MHLT) is developed which retains the recursive minimum-mean-square-error tracking behavior of a Kalman Filter in a maximum-a-posteriori delayed-decision multiple hypothesis context. Multiple line track filter states are developed and maintained using the interacting multiple model (IMM) state representation. Further, the data association and assignment problem is enhanced by considering line attribute information (line bandwidth and SNR) in addition to beam/bearing and frequency fit. MHLT results on real sonar data are presented to demonstrate the benefits of the multiple hypothesis approach. The utility of the system in cluttered environments and particularly in crossing line situations is shown.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

PubMed

Correale, Jorge; Gaitán, María I; Ysrraelit, María C; Fiol, Marcela P

2017-03-01

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Orchestrating Distributed Resource Ensembles for Petascale Science

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

Baldin, Ilya; Mandal, Anirban; Ruth, Paul

2014-04-24

Distributed, data-intensive computational science applications of interest to DOE scientific com- munities move large amounts of data for experiment data management, distributed analysis steps, remote visualization, and accessing scientific instruments. These applications need to orchestrate ensembles of resources from multiple resource pools and interconnect them with high-capacity multi- layered networks across multiple domains. It is highly desirable that mechanisms are designed that provide this type of resource provisioning capability to a broad class of applications. It is also important to have coherent monitoring capabilities for such complex distributed environments. In this project, we addressed these problems by designing an abstractmore » API, enabled by novel semantic resource descriptions, for provisioning complex and heterogeneous resources from multiple providers using their native provisioning mechanisms and control planes: computational, storage, and multi-layered high-speed network domains. We used an extensible resource representation based on semantic web technologies to afford maximum flexibility to applications in specifying their needs. We evaluated the effectiveness of provisioning using representative data-intensive ap- plications. We also developed mechanisms for providing feedback about resource performance to the application, to enable closed-loop feedback control and dynamic adjustments to resource allo- cations (elasticity). This was enabled through development of a novel persistent query framework that consumes disparate sources of monitoring data, including perfSONAR, and provides scalable distribution of asynchronous notifications.« less

RCT of a Psychological Intervention for Patients With Cancer: I. Mechanisms of Change

PubMed Central

Andersen, Barbara L.; Shelby, Rebecca A.; Golden-Kreutz, Deanna M.

2008-01-01

Little is known about the therapeutic processes contributing to efficacy of psychological interventions for patients with cancer. Data from a randomized clinical trial yielding robust biobehavioral and health effects (B. L. Andersen et al., 2004, 2007) were used to examine associations between process variables, treatment utilization, and outcomes. Novel findings emerged. Patients were highly satisfied with the treatment, but their higher levels of felt support (group cohesion) covaried with lower distress and fewer symptoms. Also, specific. treatment strategies were associated with specific outcomes, including lower distress, improved dietary habits, reduced symptomatology, and higher chemotherapy dose intensity. These data provide a comprehensive test of multiple therapeutic processes and mechanisms for biobehavioral change with an intervention including both intensive and maintenance phases. PMID:18085909

Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration

PubMed Central

Bravo, Roberto; Parra, Valentina; Gatica, Damián; Rodriguez, Andrea E.; Torrealba, Natalia; Paredes, Felipe; Wang, Zhao V.; Zorzano, Antonio; Hill, Joseph A.; Jaimovich, Enrique; Quest, Andrew F.G.; Lavandero, Sergio

2013-01-01

The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of reestablishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies. PMID:23317820

Structural Bus and Release Mechanisms on the ST5 Satellites: Summary and Status

NASA Technical Reports Server (NTRS)

Rossoni, Peter

2007-01-01

The Space Technology 5 Mechanical System met the challenge of packaging a fully functional science and technology satellite system with its Deployer mechanism into a compact 0.07cu m volume. Three 25 kg satellites were orbited in constellation in March, 2006. The ST5 mechanical system is composed of 1) The Structural Bus; 2) Magnetometer Instrument Boom 3) Spacecraft Deployer Release Mechanism This system includes a highly integrated electronics enclosure as a multifunctional structure; a lightweight, magnetically clean Magnetometer Boom; the first use of Nitinol Shape-Memory Alloy trigger devices for deploying multiple spacecraft; an innovative compliant mount for the umbilical connector and a Deployer mechanism that imparts both separation velocity and mission spin rate to three constellation flying satellites These elements employed cutting-edge design and analysis tools, state-of-the-art testing facilities and proven engineering techniques to meet stringent performance criteria, enabling the mission s success.

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

PubMed Central

Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.

2015-01-01

SUMMARY Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR. PMID:25652543

Anthropometric characteristics and risk of multiple myeloma.

PubMed

Blair, Cindy K; Cerhan, James R; Folsom, Aaron R; Ross, Julie A

2005-09-01

Few studies have examined obesity and risk for multiple myeloma, and the results are inconsistent. Laboratory evidence suggests mechanisms through which obesity could influence carcinogenesis of this hematopoietic malignancy. We examined the association between anthropometric characteristics and incident multiple myeloma in a prospective, population-based sample of 37,083 postmenopausal women. In 1986, the women completed a mailed questionnaire that included self-report of height and weight, and friend measurement of waist and hip circumferences. During 16 years of follow up, 95 cases of multiple myeloma were identified through linkage to the Iowa Cancer Registry. In an age-adjusted model, women in the highest category of several anthropometric measurements compared with the lowest category were at increased risk of developing multiple myeloma. For body mass index (kg/m), the rate ratio (95% confidence interval) was 1.5 (0.92-2.6); for weight, 1.9 (1.1-3.4); for waist circumference, 2.0 (1.1-3.5); and for hip circumference, 1.8 (1.0-3.0). Greater adiposity may increase the risk of multiple myeloma.

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.

PubMed

Raelson, John V; Little, Randall D; Ruether, Andreas; Fournier, Hélène; Paquin, Bruno; Van Eerdewegh, Paul; Bradley, W E C; Croteau, Pascal; Nguyen-Huu, Quynh; Segal, Jonathan; Debrus, Sophie; Allard, René; Rosenstiel, Philip; Franke, Andre; Jacobs, Gunnar; Nikolaus, Susanna; Vidal, Jean-Michel; Szego, Peter; Laplante, Nathalie; Clark, Hilary F; Paulussen, René J; Hooper, John W; Keith, Tim P; Belouchi, Abdelmajid; Schreiber, Stefan

2007-09-11

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction.

PubMed

Arshad, Q; Roberts, R E; Ahmad, H; Lobo, R; Patel, M; Ham, T; Sharp, D J; Seemungal, B M

2017-04-01

We hypothesised that chronic vestibular symptoms (CVS) of imbalance and dizziness post-traumatic head injury (THI) may relate to: (i) the occurrence of multiple simultaneous vestibular diagnoses including both peripheral and central vestibular dysfunction in individual patients increasing the chance of missed diagnoses and suboptimal treatment; (ii) an impaired response to vestibular rehabilitation since the central mechanisms that mediate rehabilitation related brain plasticity may themselves be disrupted. We report the results of a retrospective analysis of both the comprehensive clinical and vestibular laboratory testing of 20 consecutive THI patients with prominent and persisting vestibular symptoms still present at least 6months post THI. Individual THI patients typically had multiple vestibular diagnoses and unique to this group of vestibular patients, often displayed both peripheral and central vestibular dysfunction. Despite expert neuro-otological management, at two years 20% of patients still had persisting vestibular symptoms. In summary, chronic vestibular dysfunction in THI could relate to: (i) the presence of multiple vestibular diagnoses, increasing the risk of 'missed' vestibular diagnoses leading to persisting symptoms; (ii) the impact of brain trauma which may impair brain plasticity mediated repair mechanisms. Apart from alerting physicians to the potential for multiple vestibular diagnoses in THI, future work to identify the specific deficits in brain function mediating poor recovery from post-THI vestibular dysfunction could provide the rationale for developing new therapy for head injury patients whose vestibular symptoms are resistant to treatment. Copyright © 2017. Published by Elsevier B.V.

Neural Cross-Frequency Coupling: Connecting Architectures, Mechanisms, and Functions.

PubMed

Hyafil, Alexandre; Giraud, Anne-Lise; Fontolan, Lorenzo; Gutkin, Boris

2015-11-01

Neural oscillations are ubiquitously observed in the mammalian brain, but it has proven difficult to tie oscillatory patterns to specific cognitive operations. Notably, the coupling between neural oscillations at different timescales has recently received much attention, both from experimentalists and theoreticians. We review the mechanisms underlying various forms of this cross-frequency coupling. We show that different types of neural oscillators and cross-frequency interactions yield distinct signatures in neural dynamics. Finally, we associate these mechanisms with several putative functions of cross-frequency coupling, including neural representations of multiple environmental items, communication over distant areas, internal clocking of neural processes, and modulation of neural processing based on temporal predictions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of Thermal and Mechanical Impact on Aluminum Honeycomb Structures

NASA Technical Reports Server (NTRS)

Robinson, Christen M.

2013-01-01

This study supports NASA Kennedy Space Center's research in the area of intelligent thermal management systems and multifunctional thermal systems. This project addresses the evaluation of the mechanical and thermal properties of metallic cellular solid (MCS) materials; those that are lightweight; high strength, tunable, multifunctional and affordable. A portion of the work includes understanding the mechanical properties of honeycomb structured cellular solids upon impact testing under ambient, water-immersed, liquid nitrogen-cooled, and liquid nitrogen-immersed conditions. Additionally, this study will address characterization techniques of the aluminum honeycomb's ability to resist multiple high-rate loadings or impacts in varying environmental conditions, using various techniques for the quantitative and qualitative determination for commercial applicability.

Elucidating PID Degradation Mechanisms and In Situ Dark I–V Monitoring for Modeling Degradation Rate in CdTe Thin-Film Modules

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

Hacke, Peter; Spataru, Sergiu; Johnston, Steve

A progression of potential-induced degradation (PID) mechanisms are observed in CdTe modules, including shunting/junction degradation and two different manifestations of series resistance depending on the stress level and water ingress. The dark I-V method for in-situ characterization of Pmax based on superposition was adapted for the thin-film modules undergoing PID in view of the degradation mechanisms observed. An exponential model based on module temperature and relative humidity was fit to the PID rate for multiple stress levels in chamber tests and validated by predicting the observed degradation of the module type in the field.

Cold-loving microbes, plants, and animals—fundamental and applied aspects

NASA Astrophysics Data System (ADS)

Margesin, R.; Neuner, G.; Storey, K. B.

2007-02-01

Microorganisms, plants, and animals have successfully colonized cold environments, which represent the majority of the biosphere on Earth. They have evolved special mechanisms to overcome the life-endangering influence of low temperature and to survive freezing. Cold adaptation includes a complex range of structural and functional adaptations at the level of all cellular constituents, such as membranes, proteins, metabolic activity, and mechanisms to avoid the destructive effect of intracellular ice formation. These strategies offer multiple biotechnological applications of cold-adapted organisms and/or their products in various fields. In this review, we describe the mechanisms of microorganisms, plants, and animals to cope with the cold and the resulting biotechnological perspectives.

An active locking mechanism for assembling 3D micro structures

NASA Astrophysics Data System (ADS)

Zhang, Ping; Mayyas, Mohammad; Lee, Woo Ho; Popa, Dan; Shiakolas, Panos; Stephanou, Harry; Chiao, J. C.

2007-01-01

Microassembly is an enabling technology to build 3D microsystems consisting of microparts made of different materials and processes. Multiple microparts can be connected together to construct complicated in-plane and out-of-plane microsystems by using compliant mechanical structures such as micro hinges and snap fasteners. This paper presents design, fabrication, and assembly of an active locking mechanism that provides mechanical and electrical interconnections between mating microparts. The active locking mechanism is composed of thermally actuated Chevron beams and sockets. Assembly by means of an active locking mechanism offers more flexibility in designing microgrippers as it reduces or minimizes mating force, which is one of the main reasons causing fractures in a microgripper during microassembly operation. Microgrippers, microparts, and active locking mechanisms were fabricated on a silicon substrate using the deep reactive ion etching (DRIE) processes with 100-um thick silicon on insulator (SOI) wafers. A precision robotic assembly platform with a dual microscope vision system was used to automate the manipulation and assembly processes of microparts. The assembly sequence includes (1) tether breaking and picking up of a micropart by using an electrothermally actuated microgripper, (2) opening of a socket area for zero-force insertion, (3) a series of translation and rotation of a mating micropart to align it onto the socket, (4) insertion of a micropart into the socket, and (5) deactivation and releasing of locking fingers. As a result, the micropart was held vertically to the substrate and locked by the compliance of Chevron beams. Microparts were successfully assembled using the active locking mechanism and the measured normal angle was 89.2°. This active locking mechanism provides mechanical and electrical interconnections, and it can potentially be used to implement a reconfigurable microrobot that requires complex assembly of multiple links and joints.

How do we make models that are useful in understanding partial epilepsies?

PubMed

Prince, David A

2014-01-01

The goals of constructing epilepsy models are (1) to develop approaches to prophylaxis of epileptogenesis following cortical injury; (2) to devise selective treatments for established epilepsies based on underlying pathophysiological mechanisms; and (3) use of a disease (epilepsy) model to explore brain molecular, cellular and circuit properties. Modeling a particular epilepsy syndrome requires detailed knowledge of key clinical phenomenology and results of human experiments that can be addressed in critically designed laboratory protocols. Contributions to understanding mechanisms and treatment of neurological disorders has often come from research not focused on a specific disease-relevant issue. Much of the foundation for current research in epilepsy falls into this category. Too strict a definition of the relevance of an experimental model to progress in preventing or curing epilepsy may, in the long run, slow progress. Inadequate exploration of the experimental target and basic laboratory results in a given model can lead to a failed effort and false negative or positive results. Models should be chosen based on the specific issues to be addressed rather than on convenience of use. Multiple variables including maturational age, species and strain, lesion type, severity and location, latency from injury to experiment and genetic background will affect results. A number of key issues in clinical and basic research in partial epilepsies remain to be addressed including the mechanisms active during the latent period following injury, susceptibility factors that predispose to epileptogenesis, injury - induced adaptive versus maladaptive changes, mechanisms of pharmaco-resistance and strategies to deal with multiple pathophysiological processes occurring in parallel.

Human T cell immunosenescence and inflammation in aging.

PubMed

Bektas, Arsun; Schurman, Shepherd H; Sen, Ranjan; Ferrucci, Luigi

2017-10-01

The aging process is driven by a finite number of inter-related mechanisms that ultimately lead to the emergence of characteristic phenotypes, including increased susceptibility to multiple chronic diseases, disability, and death. New assays and analytical tools have become available that start to unravel some of these mechanisms. A prevailing view is that aging leads to an imbalance between stressors and stress-buffering mechanisms that causes loss of compensatory reserve and accumulation of unrepaired damage. Central to this paradigm are changes in the immune system and the chronic low-grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of risk factors. Independent of chronological age, high circulating levels of proinflammatory markers are associated with a high risk of multiple adverse health outcomes in older persons. In this review, we discuss current theories about causes and consequences of the proinflammatory state of aging, with a focus on changes in T cell function. We examine the role of NF-κB activation and its dysregulation and how NF-κB activity differs among subgroups of T cells. We explore emerging hypotheses about immunosenescence and changes in T cell behavior with age, including consideration of the T cell antigen receptor and regulatory T cells (T regs ). We conclude by illustrating how research using advanced technology is uncovering clues at the core of inflammation and aging. Some of the preliminary work in this field is already improving our understanding of the complex mechanisms by which immunosenescence of T cells is intertwined during human aging. © Society for Leukocyte Biology.

Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014-2017).

PubMed

Helpman, Liat; Zhu, Xi; Suarez-Jimenez, Benjamin; Lazarov, Amit; Monk, Catherine; Neria, Yuval

2017-11-08

Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years. Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014-2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. While substantial number of published studies present preliminary evidence for neural mechanisms of sex-specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed.

Analysis of multiple instructional techniques on the understanding and retention of select mechanical topics

NASA Astrophysics Data System (ADS)

Fetsco, Sara Elizabeth

There are several topics that introductory physics students typically have difficulty understanding. The purpose of this thesis is to investigate if multiple instructional techniques will help students to better understand and retain the material. The three units analyzed in this study are graphing motion, projectile motion, and conservation of momentum. For each unit students were taught using new or altered instructional methods including online laboratory simulations, inquiry labs, and interactive demonstrations. Additionally, traditional instructional methods such as lecture and problem sets were retained. Effectiveness was measured through pre- and post-tests and student opinion surveys. Results suggest that incorporating multiple instructional techniques into teaching will improve student understanding and retention. Students stated that they learned well from all of the instructional methods used except the online simulations.

Neurotoxicity

MedlinePlus

... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ...

Colchicine--Update on mechanisms of action and therapeutic uses.

PubMed

Leung, Ying Ying; Yao Hui, Laura Li; Kraus, Virginia B

2015-12-01

To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiple Roles of Integrin-Linked Kinase in Epidermal Development, Maturation and Pigmentation Revealed by Molecular Profiling

PubMed Central

Judah, David; Rudkouskaya, Alena; Wilson, Ryan; Carter, David E.; Dagnino, Lina

2012-01-01

Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function. PMID:22574216

Multiple roles of integrin-linked kinase in epidermal development, maturation and pigmentation revealed by molecular profiling.

PubMed

Judah, David; Rudkouskaya, Alena; Wilson, Ryan; Carter, David E; Dagnino, Lina

2012-01-01

Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.

[Neural Mechanisms Underlying the Processing of Temporal Information in Episodic Memory and Its Disturbance].

PubMed

Iwata, Saeko; Tsukiura, Takashi

2017-11-01

Episodic memory is defined as memory for personally experienced events, and includes memory content and contextual information of time and space. Previous neuroimaging and neuropsychological studies have demonstrated three possible roles of the temporal context in episodic memory. First, temporal information contributes to the arrangement of temporal order for sequential events in episodic memory, and this process is involved in the lateral prefrontal cortex. The second possible role of temporal information in episodic memory is the segregation between memories of multiple events, which are segregated by cues of different time information. The role of segregation is associated with the orbitofrontal regions including the orbitofrontal cortex and basal forebrain region. Third, temporal information in episodic memory plays an important role in the integration of multiple components into a coherent episodic memory, in which episodic components in the different modalities are combined by temporal information as an index. The role of integration is mediated by the medial temporal lobe including the hippocampus and parahippocampal gyrus. Thus, temporal information in episodic memory could be represented in multiple stages, which are involved in a network of the lateral prefrontal, orbitofrontal, and medial temporal lobe regions.

Insertion device and method for accurate and repeatable target insertion

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

Gubeli, III, Joseph F.; Shinn, Michelle D.; Bevins, Michael E.

The present invention discloses a device and a method for inserting and positioning a target within a free electron laser, particle accelerator, or other such device that generates or utilizes a beam of energy or particles. The system includes a three-point registration mechanism that insures angular and translational accuracy and repeatability of positioning upon multiple insertions within the same structure.

Population genetic structure of Bromus tectorum in the mountains of western North America

Treesearch

Spencer Arnesen; Craig E. Coleman; Susan E. Meyer

2017-01-01

PREMISE OF THE STUDY: Invasive species are often initially restricted to a narrow range and may then expand through any of multiple mechanisms including phenotypic plasticity, in situ evolution, or selection on traits preadapted for new habitats. Our study used population genetics to explore possible processes by which the highly selfing invasive annual grass Bromus...

Multifield Galileons and higher codimension branes

DOE PAGES

Hinterbichler, Kurt; Trodden, Mark; Wesley, Daniel

2010-12-07

We studied a multi-field generalizations of the galileon - a popular idea of how to modify gravity to account for the acceleration of the universe. We derived an extremely restrictive theory of multiple galileon fields, and explored some properties of this theory, including proving a general non-renormalization theorem: multi-field galileons are not renormalized quantum mechanically to any loop in perturbation theory.

The osteoblastic niche in the context of multiple myeloma.

PubMed

Toscani, Denise; Bolzoni, Marina; Accardi, Fabrizio; Aversa, Franco; Giuliani, Nicola

2015-01-01

The osteoblastic niche has a critical role in the regulation of hemopoietic stem cell (HSC) quiescence and self-renewal and in the support of hematopoiesis. Several mechanisms are involved in the crosstalk between stem cells and osteoblasts, including soluble cytokines, adhesion molecules, and signal pathways such as the wingless-Int (Wnt), Notch, and parathyroid hormone pathways. According to the most recent evidence, there is an overlap between osteoblastic and perivascular niches that affects HSC function involving mesenchymal stromal and endothelial cells and a gradient of oxygen regulated by hypoxia inducible factor (HIF)-1α. Derived from plasma cells, multiple myeloma (MM) is a hematopoietic malignancy characterized by a peculiar dependency on the bone microenvironment. Quiescent MM cells may reside in the osteoblastic niche for protection from apoptotic stimuli; in turn, MM cells suppress osteoblast formation and function, leading to impairment of bone formation and the development of osteolytic lesions. Several recent studies have investigated the mechanisms involved in the relationship between osteoblasts and MM cells and identified potential therapeutic targets in the osteoblastic niche, including the HIF-1α, Runx2, and Wnt (both canonical and noncanonical) signaling pathways. © 2014 New York Academy of Sciences.

Bacterial killing in macrophages and amoeba: do they all use a brass dagger?

PubMed

German, Nadezhda; Doyscher, Dominik; Rensing, Christopher

2013-10-01

Macrophages are immune cells that are known to engulf pathogens and destroy them by employing several mechanisms, including oxidative burst, induction of Fe(II) and Mn(II) efflux, and through elevation of Cu(I) and Zn(II) concentrations in the phagosome ('brass dagger'). The importance of the latter mechanism is supported by the presence of multiple counteracting efflux systems in bacteria, responsible for the efflux of toxic metals. We hypothesize that similar bacteria-killing mechanisms are found in predatory protozoa/amoeba species. Here, we present a brief summary of soft metal-related mechanisms used by macrophages, and perhaps amoeba, to inactivate and destroy bacteria. Based on this, we think it is likely that copper resistance is also selected for by protozoan grazing in the environment.

Dynamics of Implementation and Maintenance of Organizational Health Interventions.

PubMed

Jalali, Mohammad S; Rahmandad, Hazhir; Bullock, Sally Lawrence; Ammerman, Alice

2017-08-15

In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes.

Expert opinion on emerging drugs: chronic low back pain.

PubMed

Hsu, Eugene; Murphy, Sunberri; Chang, David; Cohen, Steven P

2015-03-01

It is difficult to overestimate the personal and socioeconomic impact of chronic low back pain (CLBP). It is the leading cause of years lost to disability and poses the highest economic toll among chronic illnesses. Despite the strong need for extensive research efforts, few drugs have consistently demonstrated effectiveness for this condition. In this review, the epidemiology, rationale for mechanism-based treatment, competitive environment and market trends, and the preclinical and clinical evidence supporting over 15 different classes of analgesic medications studied for CLBP or related pain conditions are discussed. Treatments are divided by drug category, type of CLBP they are likely to treat (e.g., neuropathic or mechanical), and whether they are new formulations of existing treatments, new indications for existing treatments or represent novel mechanisms of action. Databases searched included MEDLINE, Embase, Pharmaprojects and various clinical trial registries. Many barriers exist for the development of medications for CLBP including difficulties in identifying pathophysiological mechanisms, biologic resiliency secondary to multiple concurrent pain pathways and off-target and sometimes serious side effects. Nevertheless, the volume and diversity of novel molecular entities has continued to surge and includes possible disease-modifying therapies such as gene and stem cell therapy.

Improving ecosystem-scale modeling of evapotranspiration using ecological mechanisms that account for compensatory responses following disturbance

NASA Astrophysics Data System (ADS)

Millar, David J.; Ewers, Brent E.; Mackay, D. Scott; Peckham, Scott; Reed, David E.; Sekoni, Adewale

2017-09-01

Mountain pine beetle outbreaks in western North America have led to extensive forest mortality, justifiably generating interest in improving our understanding of how this type of ecological disturbance affects hydrological cycles. While observational studies and simulations have been used to elucidate the effects of mountain beetle mortality on hydrological fluxes, an ecologically mechanistic model of forest evapotranspiration (ET) evaluated against field data has yet to be developed. In this work, we use the Terrestrial Regional Ecosystem Exchange Simulator (TREES) to incorporate the ecohydrological impacts of mountain pine beetle disturbance on ET for a lodgepole pine-dominated forest equipped with an eddy covariance tower. An existing degree-day model was incorporated that predicted the life cycle of mountain pine beetles, along with an empirically derived submodel that allowed sap flux to decline as a function of temperature-dependent blue stain fungal growth. The eddy covariance footprint was divided into multiple cohorts for multiple growing seasons, including representations of recently attacked trees and the compensatory effects of regenerating understory, using two different spatial scaling methods. Our results showed that using a multiple cohort approach matched eddy covariance-measured ecosystem-scale ET fluxes well, and showed improved performance compared to model simulations assuming a binary framework of only areas of live and dead overstory. Cumulative growing season ecosystem-scale ET fluxes were 8 - 29% greater using the multicohort approach during years in which beetle attacks occurred, highlighting the importance of including compensatory ecological mechanism in ET models.

MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

PubMed Central

Mao, Peizhong; Manczak, Maria; Shirendeb, Ulziibat P.; Reddy, P. Hemachandra

2013-01-01

Oxidative stress and mitochondrial dysfunction are involved in the progression and pathogenesis of multiple sclerosis (MS). MitoQ is a mitochondria-targeted antioxidant that has a neuroprotective role in several mitochondrial and neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Here we sought to determine the possible effects of a systematic administration of MitoQ as a therapy, using an experimental autoimmune encephalomyelitis (EAE) mouse model. We studied the beneficial effects of MitoQ in EAE mice that mimic MS like symptoms by treating EAE mice with MitoQ and pretreated C57BL6 mice MitoQ plus EAE induction. We found that pretreatment and treatment of EAE mice with MitoQ reduced neurological disabilities associated with EAE. We also found that both pretreatment and treatment of the EAE mice with MitoQ significantly suppressed inflammatory markers of EAE, including the inhibition of inflammatory cytokines and chemokines. MitoQ treatments reduced neuronal cell loss in the spinal cord, a factor underlying motor disability in EAE mice. The neuroprotective role of MitoQ was confirmed by a neuron-glia co-culture system designed to mimic the mechanism of MS and EAE in vitro. We found that axonal inflammation and oxidative stress are associated with impaired behavioral functions in the EAE mouse model and that treatment with MitoQ can exert protective effects on neurons and reduce axonal inflammation and oxidative stress. These protective effects are likely via multiple mechanisms, including the attenuation of the robust immune response. These results suggest that MitoQ may be a new candidate for the treatment of MS. PMID:24055980

MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

PubMed

Mao, Peizhong; Manczak, Maria; Shirendeb, Ulziibat P; Reddy, P Hemachandra

2013-12-01

Oxidative stress and mitochondrial dysfunction are involved in the progression and pathogenesis of multiple sclerosis (MS). MitoQ is a mitochondria-targeted antioxidant that has a neuroprotective role in several mitochondrial and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Here we sought to determine the possible effects of a systematic administration of MitoQ as a therapy, using an experimental autoimmune encephalomyelitis (EAE) mouse model. We studied the beneficial effects of MitoQ in EAE mice that mimic MS like symptoms by treating EAE mice with MitoQ and pretreated C57BL6 mice with MitoQ plus EAE induction. We found that pretreatment and treatment of EAE mice with MitoQ reduced neurological disabilities associated with EAE. We also found that both pretreatment and treatment of the EAE mice with MitoQ significantly suppressed inflammatory markers of EAE, including the inhibition of inflammatory cytokines and chemokines. MitoQ treatments reduced neuronal cell loss in the spinal cord, a factor underlying motor disability in EAE mice. The neuroprotective role of MitoQ was confirmed by a neuron-glia co-culture system designed to mimic the mechanism of MS and EAE in vitro. We found that axonal inflammation and oxidative stress are associated with impaired behavioral functions in the EAE mouse model and that treatment with MitoQ can exert protective effects on neurons and reduce axonal inflammation and oxidative stress. These protective effects are likely via multiple mechanisms, including the attenuation of the robust immune response. These results suggest that MitoQ may be a new candidate for the treatment of MS. © 2013.

Mechanosensation is evolutionarily tuned to locomotor mechanics

PubMed Central

Aiello, Brett R.; Westneat, Mark W.; Hale, Melina E.

2017-01-01

The biomechanics of animal limbs has evolved to meet the functional demands for movement associated with different behaviors and environments. Effective movement relies not only on limb mechanics but also on appropriate mechanosensory feedback. By comparing sensory ability and mechanics within a phylogenetic framework, we show that peripheral mechanosensation has evolved with limb biomechanics, evolutionarily tuning the neuromechanical system to its functional demands. We examined sensory physiology and mechanics of the pectoral fins, forelimb homologs, in the fish family Labridae. Labrid fishes exhibit extraordinary morphological and behavioral diversity and use pectoral fin-based propulsion with fins ranging in shape from high aspect ratio (AR) wing-like fins to low AR paddle-like fins. Phylogenetic character analysis demonstrates that high AR fins evolved independently multiple times in this group. Four pairs of species were examined; each included a plesiomorphic low AR and a high AR species. Within each species pair, the high AR species demonstrated significantly stiffer fin rays in comparison with the low AR species. Afferent sensory nerve activity was recorded during fin ray bending. In all cases, afferents of stiffer fins were more sensitive at lower displacement amplitudes, demonstrating mechanosensory tuning to fin mechanics and a consistent pattern of correlated evolution. We suggest that these data provide a clear example of parallel evolution in a complex neuromechanical system, with a strong link between multiple phenotypic characters: pectoral fin shape, swimming behavior, fin ray stiffness, and mechanosensory sensitivity. PMID:28396411

Dynamic Binding of Identity and Location Information: A Serial Model of Multiple Identity Tracking

ERIC Educational Resources Information Center

Oksama, Lauri; Hyona, Jukka

2008-01-01

Tracking of multiple moving objects is commonly assumed to be carried out by a fixed-capacity parallel mechanism. The present study proposes a serial model (MOMIT) to explain performance accuracy in the maintenance of multiple moving objects with distinct identities. A serial refresh mechanism is postulated, which makes recourse to continuous…

Hypothesis: neoplasms in myotonic dystrophy

PubMed Central

Hilbert, James E.; Martens, William; Thornton, Charles A.; Moxley, Richard T.; Greene, Mark H.

2011-01-01

Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities. PMID:19642006

Cellular mechanisms contributing to multiple stress tolerance in Saccharomyces cerevisiae strains with potential use in high-temperature ethanol fermentation.

PubMed

Kitichantaropas, Yasin; Boonchird, Chuenchit; Sugiyama, Minetaka; Kaneko, Yoshinobu; Harashima, Satoshi; Auesukaree, Choowong

2016-12-01

High-temperature ethanol fermentation has several benefits including a reduction in cooling cost, minimizing risk of bacterial contamination, and enabling simultaneous saccharification and fermentation. To achieve the efficient ethanol fermentation at high temperature, yeast strain that tolerates to not only high temperature but also the other stresses present during fermentation, e.g., ethanol, osmotic, and oxidative stresses, is indispensable. The C3253, C3751, and C4377 Saccharomyces cerevisiae strains, which have been previously isolated as thermotolerant yeasts, were found to be multiple stress-tolerant. In these strains, continuous expression of heat shock protein genes and intracellular trehalose accumulation were induced in response to stresses causing protein denaturation. Compared to the control strains, these multiple stress-tolerant strains displayed low intracellular reactive oxygen species levels and effective cell wall remodeling upon exposures to almost all stresses tested. In response to simultaneous multi-stress mimicking fermentation stress, cell wall remodeling and redox homeostasis seem to be the primary mechanisms required for protection against cell damage. Moreover, these strains showed better performances of ethanol production than the control strains at both optimal and high temperatures, suggesting their potential use in high-temperature ethanol fermentation.

Epigenomics of Hypertension

PubMed Central

Liang, Mingyu; Cowley, Allen W.; Mattson, David L.; Kotchen, Theodore A.; Liu, Yong

2013-01-01

Multiple genes and pathways are involved in the pathogenesis of hypertension. Epigenomic studies of hypertension are beginning to emerge and hold great promise of providing novel insights into the mechanisms underlying hypertension. Epigenetic marks or mediators including DNA methylation, histone modifications, and non-coding RNA can be studied at a genome or near-genome scale using epigenomic approaches. At the single gene level, several studies have identified changes in epigenetic modifications in genes expressed in the kidney that correlate with the development of hypertension. Systematic analysis and integration of epigenetic marks at the genome scale, demonstration of cellular and physiological roles of specific epigenetic modifications, and investigation of inheritance are among the major challenges and opportunities for future epigenomic and epigenetic studies of hypertension. Essential hypertension is a multifactorial disease involving multiple genetic and environmental factors and mediated by alterations in multiple biological pathways. Because the non-genetic mechanisms may involve epigenetic modifications, epigenomics is one of the latest concepts and approaches brought to bear on hypertension research. In this article, we summarize briefly the concepts and techniques for epigenomics, discuss the rationale for applying epigenomic approaches to study hypertension, and review the current state of this research area. PMID:24011581

Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants.

PubMed

Degenhardt, Jörg; Köllner, Tobias G; Gershenzon, Jonathan

2009-01-01

The multitude of terpene carbon skeletons in plants is formed by enzymes known as terpene synthases. This review covers the monoterpene and sesquiterpene synthases presenting an up-to-date list of enzymes reported and evidence for their ability to form multiple products. The reaction mechanisms of these enzyme classes are described, and information on how terpene synthase proteins mediate catalysis is summarized. Correlations between specific amino acid motifs and terpene synthase function are described, including an analysis of the relationships between active site sequence and cyclization type and a discussion of whether specific protein features might facilitate multiple product formation.

[New drugs in the treatment of multiple myeloma].

PubMed

Oriol, Albert; Motlló, Cristina

2014-09-15

Progress in the treatment of multiple myeloma in the last decade has been able to delay, but ultimately not to prevent, the development of resistances and most patients still die of the disease or its related complications. New drugs have been developed including new alkylating agents, proteasome inhibitors and immunomodulators but also monoclonal antibodies and drugs with new mechanisms of action. Hopefully, this new generation of targeted agents will improve the results of the initial therapy, avoid relapses and development of resistances and provide better and less toxic options for the relapsed and refractory patient. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Multiple Mechanisms are Responsible for Transactivation of the Epidermal Growth Factor Receptor in Mammary Epithelial Cells

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

Rodland, Karin D.; Bollinger, Nikki; Ippolito, Danielle L.

2008-11-14

REVIEW ENTIRE DOCUMENT AT: https://pnlweb.pnl.gov/projects/bsd/ERICA%20Manuscripts%20for%20Review/KD%20Rodland%20D7E80/HMEC_transactivation_ms01_15+Figs.pdf ABSTRACT: Using a single nontransformed strain of human mammary epithelial cells, we found that the ability of multiple growth factors and cytokines to induce ERK phosphorylation was dependent on EGFR activity. These included lysophosphatidic acid (LPA), uridine triphosphate, growth hormone, vascular endothelial growth factor, insulin-like growth factor-1 (IGF-1), and tumor necrosis factoralpha. In contrast, hepatocyte growth factor could stimulate ERK phosphorylation independent of EGFR activity...

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells*

PubMed Central

Borahay, Mostafa A.; Kilic, Gokhan S.; Yallampalli, Chandrasekha; Snyder, Russell R.; Hankins, Gary D. V.; Al-Hendy, Ayman; Boehning, Darren

2014-01-01

Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well known lipid-lowering properties, they possess broad-reaching effects in vivo, including antitumor effects. Statins inhibit the growth of multiple tumors. However, the mechanisms remain incompletely understood. Here we show that simvastatin inhibits the proliferation of human leiomyoma cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently stimulated leiomyoma cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from voltage-gated calcium channels. Therefore, simvastatin possesses antitumor effects that are dependent upon the apoptotic calcium release machinery. PMID:25359773

Severe disease exacerbations in patients with multiple sclerosis after discontinuing fingolimod.

PubMed

Członkowska, Anna; Smoliński, Łukasz; Litwin, Tomasz

Discontinuation of fingolimod in patients with multiple sclerosis (MS) can lead to disease reactivation. In this review, we describe cases of severe exacerbations in patients with MS following discontinuation of fingolimod, including three cases from our center. We consider potential mechanisms of disease reactivation after cessation of fingolimod, and the evidence supporting this rebound effect. We conclude that discontinuation of fingolimod results in the return of disease activity, which then leads to severe exacerbations (i.e., rebounds) in a clinically significant proportion of patients. Lastly, we consider disease-modifying treatment options for patients who discontinue fingolimod. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

Floating point only SIMD instruction set architecture including compare, select, Boolean, and alignment operations

DOEpatents

Gschwind, Michael K [Chappaqua, NY

2011-03-01

Mechanisms for implementing a floating point only single instruction multiple data instruction set architecture are provided. A processor is provided that comprises an issue unit, an execution unit coupled to the issue unit, and a vector register file coupled to the execution unit. The execution unit has logic that implements a floating point (FP) only single instruction multiple data (SIMD) instruction set architecture (ISA). The floating point vector registers of the vector register file store both scalar and floating point values as vectors having a plurality of vector elements. The processor may be part of a data processing system.

Dissection of Biological Property of Chinese Acupuncture Point Zusanli Based on Long-Term Treatment via Modulating Multiple Metabolic Pathways.

PubMed

Yan, Guangli; Zhang, Aihua; Sun, Hui; Cheng, Weiping; Meng, Xiangcai; Liu, Li; Zhang, Yingzhi; Xie, Ning; Wang, Xijun

2013-01-01

Acupuncture has a history of over 3000 years and is a traditional Chinese medical therapy that uses hair-thin metal needles to puncture the skin at specific points on the body to promote wellbeing, while its molecular mechanism and ideal biological pathways are still not clear. High-throughput metabolomics is the global assessment of endogenous metabolites within a biologic system and can potentially provide a more accurate snap shot of the actual physiological state. We hypothesize that acupuncture-treated human would produce unique characterization of metabolic phenotypes. In this study, UPLC/ESI-HDMS coupled with pattern recognition methods and system analysis were carried out to investigate the mechanism and metabolite biomarkers for acupuncture treatment at "Zusanli" acupoint (ST-36) as a case study. The top 5 canonical pathways including alpha-linolenic acid metabolism, d-glutamine and d-glutamate metabolism, citrate cycle, alanine, aspartate, and glutamate metabolism, and vitamin B6 metabolism pathways were acutely perturbed, and 53 differential metabolites were identified by chemical profiling and may be useful to clarify the physiological basis and mechanism of ST-36. More importantly, network construction has led to the integration of metabolites associated with the multiple perturbation pathways. Urine metabolic profiling might be a promising method to investigate the molecular mechanism of acupuncture.

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

PubMed Central

Zhu, Yuan Xiao; Kortuem, K. Martin; Stewart, A. Keith

2014-01-01

Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. PMID:22966948

Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP

PubMed Central

Mukherjee, Rajarshi; Mareninova, Olga A; Odinokova, Irina V; Huang, Wei; Murphy, John; Chvanov, Michael; Javed, Muhammad A; Wen, Li; Booth, David M; Cane, Matthew C; Awais, Muhammad; Gavillet, Bruno; Pruss, Rebecca M; Schaller, Sophie; Molkentin, Jeffery D; Tepikin, Alexei V; Petersen, Ole H; Pandol, Stephen J; Gukovsky, Ilya; Criddle, David N; Gukovskaya, Anna S

2016-01-01

Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease. PMID:26071131

How PV system ownership can impact the market value of residential homes

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

Klise, Geoffrey Taylor; Johnson, Jamie L.

2014-01-01

There are multiple ways for a homeowner to obtain the electricity generating and savings benefits offered by a photovoltaic (PV) system. These include purchasing a PV system through various financing mechanisms, or by leasing the PV system from a third party with multiple options that may include purchase, lease renewal or PV system removal. The different ownership options available to homeowners presents a challenge to appraisal and real estate professionals during a home sale or refinance in terms of how to develop a value that is reflective of the PV systems operational characteristics, local market conditions, and lender and underwritermore » requirements. This paper presents these many PV system ownership options with a discussion of what considerations an appraiser must make when developing the contributory value of a PV system to a residential property.« less

Comparison of sedation strategies for critically ill patients: a protocol for a systematic review incorporating network meta-analyses.

PubMed

Hutton, Brian; Burry, Lisa D; Kanji, Salmaan; Mehta, Sangeeta; Guenette, Melanie; Martin, Claudio M; Fergusson, Dean A; Adhikari, Neill K; Egerod, Ingrid; Williamson, David; Straus, Sharon; Moher, David; Ely, E Wesley; Rose, Louise

2016-09-20

Sedatives and analgesics are administered to provide sedation and manage agitation and pain in most critically ill mechanically ventilated patients. Various sedation administration strategies including protocolized sedation and daily sedation interruption are used to mitigate drug pharmacokinetic limitations and minimize oversedation, thereby shortening the duration of mechanical ventilation. At present, it is unclear which strategy is most effective, as few have been directly compared. Our review will use network meta-analysis (NMA) to compare and rank sedation strategies to determine their efficacy and safety for mechanically ventilated patients. We will search the following from 1980 to March 2016: Ovid MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science. We will also search the Cochrane Library, gray literature, and the International Clinical Trials Registry Platform. We will use a validated randomized control trial search filter to identify studies evaluating any strategy to optimize sedation in mechanically ventilated adult patients. Authors will independently extract data from eligible studies in duplicate and complete the Cochrane Risk of Bias tool. Our outcomes of interest include duration of mechanical ventilation, time to first extubation, ICU and hospital length of stay, re-intubation, tracheostomy, mortality, total sedative and opioid exposure, health-related quality of life, and adverse events. To inform our NMA, we will first conduct conventional pair-wise meta-analyses using random-effects models. Where appropriate, we will perform Bayesian NMA using WinBUGS software. There are multiple strategies to optimize sedation for mechanically ventilated patients. Current ICU guidelines recommend protocolized sedation or daily sedation interruption. Our systematic review incorporating NMA will provide a unified analysis of all sedation strategies to determine the relative efficacy and safety of interventions that may not have been compared directly. We will provide knowledge users, decision makers, and professional societies with ranking of multiple sedation strategies to inform future sedation guidelines. PROSPERO CRD42016037480.

Medication effects on sleep and breathing.

PubMed

Seda, Gilbert; Tsai, Sheila; Lee-Chiong, Teofilo

2014-09-01

Sleep respiration is regulated by circadian, endocrine, mechanical and chemical factors, and characterized by diminished ventilatory drive and changes in Pao2 and Paco2 thresholds. Hypoxemia and hypercapnia are more pronounced during rapid eye movement. Breathing is influenced by sleep stage and airway muscle tone. Patient factors include medical comorbidities and body habitus. Medications partially improve obstructive sleep apnea and stabilize periodic breathing at altitude. Potential adverse consequences of medications include precipitation or worsening of disorders. Risk factors for adverse medication effects include aging, medical disorders, and use of multiple medications that affect respiration. Published by Elsevier Inc.

Experimental comparison of residual stresses for a thermomechanical model for the simulation of selective laser melting

DOE PAGES

Hodge, N. E.; Ferencz, R. M.; Vignes, R. M.

2016-05-30

Selective laser melting (SLM) is an additive manufacturing process in which multiple, successive layers of metal powders are heated via laser in order to build a part. Modeling of SLM requires consideration of the complex interaction between heat transfer and solid mechanics. Here, the present work describes the authors initial efforts to validate their first generation model. In particular, the comparison of model-generated solid mechanics results, including both deformation and stresses, is presented. Additionally, results of various perturbations of the process parameters and modeling strategies are discussed.

Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

PubMed Central

Zhou, Shuang; Wang, Fengfei; Hsieh, Tze-Chen; Wu, Joseph M.; Wu, Erxi

2014-01-01

In the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug inducing birth defects into a highly effective therapy for treating leprosy and multiple myeloma. Today, most notably, thalidomide and its analogs have shown efficacy against a wide variety of diseases, including inflammation and cancer. The mechanism underlying its teratogenicity as well as its anticancer activities has been intensively studied. This review summarizes the biological effects and therapeutic uses of thalidomide and its analogs, and the underlying mechanisms of thalidomide’s action with a focus on its suppression of tumor growth. PMID:23931282

Effects of sterilization on optical and mechanical reliability of specialty optical fibers and terminations

NASA Astrophysics Data System (ADS)

Stolov, Andrei A.; Warych, Edward T.; Smith, William P.; Fournier, Paula L.; Hokansson, Adam S.; Li, Jie; Allen, R. Steve

2014-02-01

Optical fibers and terminations were subjected to different sterilization techniques, including multiple autoclaving and treatments with peracetic acid, E-beam and UV radiation. Effects of different sterilization techniques on key optical and mechanical properties of the fibers and the terminations were revealed. The primary attention was given to behavior of the coatings on the fibers and adhesives used in the terminations in harsh sterilization environments. The optical fibers with following four coating/buffer types were investigated: (i) dual acrylate, (ii) polyimide, (iii) silicone/PEEK and (iv) fluoroacrylate hard cladding/ETFE.

[Progress on mechanism of cell apoptosis induced by rubella virus].

PubMed

Li, Zhen-mei; Chu, Fu-lu; Liu, Ying; Wang, Zhi-yu

2013-09-01

Rubella virus (RV), a member of the family Togaviridae, can induce apoptosis of host cells in vitro. Protein kinases of the Ras-Raf-MEK-ERK pathway and PI3K-Akt pathway play essential roles in virus multiplication, cell survival and apoptosis. Proteins p53 and TAp63 that bind to specific DNA sequences stimulate Bax in a manner to produce functional pores that facilitate release of mitochondrial cytochrome c and downstream caspase activation. In this review, the molecular mechanisms of RV-induced cell apoptosis, including RV-infected cell lines, pathological changes in cell components and apoptosis signaling pathways are summarized.

Future directions of multiple behavior change research.

PubMed

Geller, Karly; Lippke, Sonia; Nigg, Claudio R

2017-02-01

Non-communicable diseases (i.e., chronic diseases including cardiovascular disease, cancer, chronic respiratory disease, diabetes and obesity) result in 36 million deaths each year. Individuals' habitual participation in a single health-risk behaviors substantially contribute to morbidity and mortality (e.g., tobacco use, daily fast food intake, etc.); however, more concerning is the impact of typically co-occurring or clustering of multiple health-risk behaviors. This burden can be minimized through successful cessation of health-risk behaviors and adoption of healthy behaviors; namely healthy lifestyle adoption or multiple health behavior change (MHBC). MHBC is a developing field and future research recommendations are provided to advance MHBC research. A valid measure of MHBC (i.e., lifestyle) is warranted to provide the needed basis for MHBC investigations and evaluations. MHBC is thought to occur through shared co-variation of underlying motivating mechanisms, but how these relationships influence behavior remains unclear. A better understanding of the relationship between behaviors and the related motivating mechanisms (and potential cross-relationship of influences) is needed. Future research should also aim to improve lifestyles through understanding how to change multiple health behaviors. Finally, MHBC research should target the development of sustainable interventions which result in lasting effects (e.g., capacity, systems, policy and environmental changes), with dissemination considered during development. Focusing MHBC research in these areas will increase our understanding and maximize the impact on the health of populations.

Factors promoting survival of bacteria in chlorinated water supplies.

PubMed Central

LeChevallier, M W; Cawthon, C D; Lee, R G

1988-01-01

Results of our experiments showed that the attachment of bacteria to surfaces provided the greatest increase in disinfection resistance. Attachment of unencapsulated Klebsiella pneumoniae grown in medium with high levels of nutrients to glass microscope slides afforded the microorganisms as much as a 150-fold increase in disinfection resistance. Other mechanisms which increased disinfection resistance included the age of the biofilm, bacterial encapsulation, and previous growth conditions (e.g., growth medium and growth temperature). These factors increased resistance to chlorine from 2- to 10-fold. The choice of disinfectant residual was shown to influence the type of resistance mechanism observed. Disinfection by free chlorine was affected by surfaces, age of the biofilm, encapsulation, and nutrient effects. Disinfection by monochloramine, however, was only affected by surfaces. Importantly, results showed that these resistance mechanisms were multiplicative (i.e., the resistance provided by one mechanism could be multiplied by the resistance provided by a second mechanism). PMID:3288119

RCRA, superfund and EPCRA hotline training module. Introduction to: RCRA financial assurance (40 cfr parts 264/265, subpart h) updated July 1996

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

NONE

1996-07-01

The module addresses financial assurance standards explaining first mechanisms and then the extent of coverage required. It describes the applicability of financial assurance for closure and post-closure and identifies necessary factors for calculating cost estimates. It explains allowable mechanisms for financial assurance, including which mechanisms can be used together and under what conditions. It explains how financial assurance works when a company owns several facilities or when a company is owned by one or more larger companies. It presents the financial assurance requirements for accident liability coverage. It identifies who is subject to sudden versus nonsudden liability provisions and citesmore » applicable definitions. It specifies the amount of liability coverage required for single and multiple facilities. It lists allowable mechanisms and combinations of mechanisms that can be used to satisfy financial assurance liability requirements.« less

Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked.

PubMed

Evan, Gerard I; Hah, Nasun; Littlewood, Trevor D; Sodir, Nicole M; Campos, Tania; Downes, Michael; Evans, Ronald M

2017-04-01

The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer-driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease. Clin Cancer Res; 23(7); 1647-55. ©2017 AACR See all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration." ©2017 American Association for Cancer Research.

Probabilistic tsunami hazard analysis: Multiple sources and global applications

USGS Publications Warehouse

Grezio, Anita; Babeyko, Andrey; Baptista, Maria Ana; Behrens, Jörn; Costa, Antonio; Davies, Gareth; Geist, Eric L.; Glimsdal, Sylfest; González, Frank I.; Griffin, Jonathan; Harbitz, Carl B.; LeVeque, Randall J.; Lorito, Stefano; Løvholt, Finn; Omira, Rachid; Mueller, Christof; Paris, Raphaël; Parsons, Thomas E.; Polet, Jascha; Power, William; Selva, Jacopo; Sørensen, Mathilde B.; Thio, Hong Kie

2017-01-01

Applying probabilistic methods to infrequent but devastating natural events is intrinsically challenging. For tsunami analyses, a suite of geophysical assessments should be in principle evaluated because of the different causes generating tsunamis (earthquakes, landslides, volcanic activity, meteorological events, and asteroid impacts) with varying mean recurrence rates. Probabilistic Tsunami Hazard Analyses (PTHAs) are conducted in different areas of the world at global, regional, and local scales with the aim of understanding tsunami hazard to inform tsunami risk reduction activities. PTHAs enhance knowledge of the potential tsunamigenic threat by estimating the probability of exceeding specific levels of tsunami intensity metrics (e.g., run-up or maximum inundation heights) within a certain period of time (exposure time) at given locations (target sites); these estimates can be summarized in hazard maps or hazard curves. This discussion presents a broad overview of PTHA, including (i) sources and mechanisms of tsunami generation, emphasizing the variety and complexity of the tsunami sources and their generation mechanisms, (ii) developments in modeling the propagation and impact of tsunami waves, and (iii) statistical procedures for tsunami hazard estimates that include the associated epistemic and aleatoric uncertainties. Key elements in understanding the potential tsunami hazard are discussed, in light of the rapid development of PTHA methods during the last decade and the globally distributed applications, including the importance of considering multiple sources, their relative intensities, probabilities of occurrence, and uncertainties in an integrated and consistent probabilistic framework.

Probabilistic Tsunami Hazard Analysis: Multiple Sources and Global Applications

NASA Astrophysics Data System (ADS)

Grezio, Anita; Babeyko, Andrey; Baptista, Maria Ana; Behrens, Jörn; Costa, Antonio; Davies, Gareth; Geist, Eric L.; Glimsdal, Sylfest; González, Frank I.; Griffin, Jonathan; Harbitz, Carl B.; LeVeque, Randall J.; Lorito, Stefano; Løvholt, Finn; Omira, Rachid; Mueller, Christof; Paris, Raphaël.; Parsons, Tom; Polet, Jascha; Power, William; Selva, Jacopo; Sørensen, Mathilde B.; Thio, Hong Kie

2017-12-01

Applying probabilistic methods to infrequent but devastating natural events is intrinsically challenging. For tsunami analyses, a suite of geophysical assessments should be in principle evaluated because of the different causes generating tsunamis (earthquakes, landslides, volcanic activity, meteorological events, and asteroid impacts) with varying mean recurrence rates. Probabilistic Tsunami Hazard Analyses (PTHAs) are conducted in different areas of the world at global, regional, and local scales with the aim of understanding tsunami hazard to inform tsunami risk reduction activities. PTHAs enhance knowledge of the potential tsunamigenic threat by estimating the probability of exceeding specific levels of tsunami intensity metrics (e.g., run-up or maximum inundation heights) within a certain period of time (exposure time) at given locations (target sites); these estimates can be summarized in hazard maps or hazard curves. This discussion presents a broad overview of PTHA, including (i) sources and mechanisms of tsunami generation, emphasizing the variety and complexity of the tsunami sources and their generation mechanisms, (ii) developments in modeling the propagation and impact of tsunami waves, and (iii) statistical procedures for tsunami hazard estimates that include the associated epistemic and aleatoric uncertainties. Key elements in understanding the potential tsunami hazard are discussed, in light of the rapid development of PTHA methods during the last decade and the globally distributed applications, including the importance of considering multiple sources, their relative intensities, probabilities of occurrence, and uncertainties in an integrated and consistent probabilistic framework.

Endocannabinoid system: potential novel targets for treatment of schizophrenia.

PubMed

Saito, Atsushi; Ballinger, Michael D L; Pletnikov, Mikhail V; Wong, Dean F; Kamiya, Atsushi

2013-05-01

Accumulating epidemiological evidences suggest that cannabis use during adolescence is a potential environmental risk for the development of psychosis, including schizophrenia. Consistently, clinical and preclinical studies, using pharmacological approaches and genetically engineered animals to target endocannabinoid signaling, reveal the multiple varieties of endocannabinoid system-mediated human and animal behaviors, including cognition and emotion. Recently, there has been substantial progress in understanding the molecular mechanisms of the endocannabinoid system for synaptic communications in the central nervous system. Furthermore, the impact of endocannabinoid signaling on diverse cellular processes during brain development has emerged. Thus, although schizophrenia has etiological complexities, including genetic heterogeneities and multiple environmental factors, it now becomes crucial to explore molecular pathways of convergence of genetic risk factors and endocannabinoid signaling, which may provide us with clues to find novel targets for therapeutic intervention. In this review, epidemiological, clinical, and pathological evidences on the role of the endocannabinoid system in the pathophysiologies of schizophrenia will be presented. We will also make a brief overview of the recent progress in understanding molecular mechanisms of the endocannabinoid system for brain development and function, with particular focus on cannabinoid receptor type 1 (CB1R)-mediated cascade, the most well-characterized cannabinoid receptor. Lastly, we will discuss the potential of the endocannabinoid system in finding novel therapeutic targets for prevention and treatment of schizophrenia. Copyright © 2012 Elsevier Inc. All rights reserved.

Sedentary behavior and sleep: paradoxical effects in association with childhood obesity.

PubMed

Must, A; Parisi, S M

2009-04-01

Sedentary behavior and sleep may be working in concert to increase the likelihood of a child becoming overweight, but in paradoxical ways. Reduction of sedentary behavior (that is, media screen time) has been extensively researched and touted as an intervention target. Inadequate sleep as a putative risk factor for obesity is only beginning to be explored. In this paper, we review the current state of research regarding these factors, and describe the existing evidence and mechanisms proposed to explain these relationships. Whereas the association between weight and sedentary behavior has been consistently shown in observational studies, effect sizes are small, and multiple mechanisms appear to be operating. Recent cross-sectional and longitudinal evidence suggests a link between short sleep duration and weight. Possible mechanisms here include direct metabolic effects as well as indirect behavioral pathways, including the presence of electronic media in children's bedrooms. Measurement issues present a challenge to both areas of research. Prospective studies that include more accurate measures of both sedentary behavior and of sleep will be needed to clarify causal pathways.

Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action

PubMed Central

Rusnati, Marco; Urbinati, Chiara; Bonifacio, Silvia; Presta, Marco; Taraboletti, Giulia

2010-01-01

Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents. PMID:27713299

Tripolar mitosis in human cells and embryos: occurrence, pathophysiology and medical implications.

PubMed

Kalatova, Beata; Jesenska, Renata; Hlinka, Daniel; Dudas, Marek

2015-01-01

Tripolar mitosis is a specific case of cell division driven by typical molecular mechanisms of mitosis, but resulting in three daughter cells instead of the usual count of two. Other variants of multipolar mitosis show even more mitotic poles and are relatively rare. In nature, this phenomenon was frequently observed or suspected in multiple common cancers, infected cells, the placenta, and in early human embryos with impaired pregnancy-yielding potential. Artificial causes include radiation and various toxins. Here we combine several pieces of the most recent evidence for the existence of different types of multipolar mitosis in preimplantation embryos together with a detailed review of the literature. The related molecular and cellular mechanisms are discussed, including the regulation of centriole duplication, mitotic spindle biology, centromere functions, cell cycle checkpoints, mitotic autocorrection mechanisms, and the related complicating factors in healthy and affected cells, including post-mitotic cell-cell fusion often associated with multipolar cell division. Clinical relevance for oncology and embryo selection in assisted reproduction is also briefly discussed in this context. Copyright © 2014 Elsevier GmbH. All rights reserved.

Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma

PubMed Central

Zhou, Yunli; Zhang, Xun; Klibanski, Anne

2013-01-01

Human pituitary adenomas are the most common intracranial neoplasms. Approximately 5% of them are familial adenomas. Patients with familial tumors carry germline mutations in predisposition genes, including AIP, MEN1 and PRKAR1A. These mutations are extremely rare in sporadic pituitary adenomas, which therefore are caused by different mechanisms. Multiple tumor suppressive genes linked to sporadic tumors have been identified. Their inactivation is caused by epigenetic mechanisms, mainly promoter hypermethylation, and can be placed into two groups based on their functional interaction with tumor suppressors RB or p53. The RB group includes CDKN2A, CDKN2B, CDKN2C, RB1, BMP4, CDH1, CDH13, GADD45B and GADD45G; AIP and MEN1 genes also belong to this group. The p53 group includes MEG3, MGMT, PLAGL1, RASSF1, RASSF3 and SOCS1. We propose that the tumor suppression function of these genes is mainly mediated by the RB and p53 pathways. We also discuss possible tumor suppression mechanisms for individual genes. PMID:24035864

Impaired neurosteroid synthesis in multiple sclerosis

PubMed Central

Noorbakhsh, Farshid; Ellestad, Kristofor K.; Maingat, Ferdinand; Warren, Kenneth G.; Han, May H.; Steinman, Lawrence; Baker, Glen B.

2011-01-01

High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription–polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis. PMID:21908875

Heterogeneity of reward mechanisms.

PubMed

Lajtha, A; Sershen, H

2010-06-01

The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms. The system is variable, is changed during development, is sex-dependent, and is influenced by genetic differences. Not all of the elements participate in the reward of all stimuli. Different set of mechanisms are involved in the reward of different drugs of abuse, yet different mechanisms in the reward of natural stimuli such as food or sexual activity; thus there are different systems that distinguish different stimuli. Separate functions of the reward system such as anticipation, evaluation, consummation and identification; all contain function-specific elements. The level of the stimulus also influences the participation of the elements of the reward system, there are possible reactions to even below threshold stimuli, and excessive stimuli can change reward to aversion involving parts of the system. Learning and memory of past reward is an important integral element of reward and addictive behavior. Many of the reward elements are altered by repeated or chronic stimuli, and chronic exposure to one drug is likely to alter the response to another stimulus. To evaluate and identify the reward stimulus thus requires heterogeneity of the reward components in the brain.

Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior.

PubMed

Ludwig, V; Mihov, Y; Schwarting, R K W

2008-05-16

Using the elevated plus-maze (EPM), Wistar rats can be distinguished into high (HA) or low anxiety (LA) subjects. These differences seem to reflect traits, since HA and LA rats vary also in other anxiety-dependent tasks, neurochemical mechanisms, and psychopharmacological reactivity, including lasting consequences after single treatment with 3,4-methylenedioxymethamphetamine (MDMA). Here, we tested whether multiple MDMA treatments also have subject-dependent effects. Based on routine EPM screening, male Wistar rats were divided into HA and LA sub-groups, which received five (i.e. multiple) daily injections of MDMA (5 mg/kg) or saline, followed by a test battery, including a challenge test with MDMA, a retest in the EPM, a novel-object test, and a final neurochemical analysis. Acutely, MDMA led to comparable hyperactivity in HA and LA rats. After multiple MDMA, behavioral sensitization was observed, especially in LA rats. Open arm time during the EPM retest (min 0-5) correlated with that of the initial one only in those rats, which had received a single injection of MDMA. Rats with multiple MDMA, especially LA-rats, showed more open-arm time and locomotion during the subsequent 5-10 min of the retest. In a novel-object test, rats with multiple MDMA, again especially LA subjects, showed more exploratory bouts towards the novel object. Neurochemically, multiple MDMA led to moderately lower serotonin in the ventral striatum, and higher dopamine levels in the frontal cortex as compared to single MDMA; these effects were also moderated by subject-dependent factors. Our data show that low-dosed multiple MDMA can lead to behavioral sensitization and outlasting consequences, which affect behavior in the EPM and a novel object task. Detecting such sequels partly requires consideration of individual differences.

New Integrated Modeling Capabilities: MIDAS' Recent Behavioral Enhancements

NASA Technical Reports Server (NTRS)

Gore, Brian F.; Jarvis, Peter A.

2005-01-01

The Man-machine Integration Design and Analysis System (MIDAS) is an integrated human performance modeling software tool that is based on mechanisms that underlie and cause human behavior. A PC-Windows version of MIDAS has been created that integrates the anthropometric character "Jack (TM)" with MIDAS' validated perceptual and attention mechanisms. MIDAS now models multiple simulated humans engaging in goal-related behaviors. New capabilities include the ability to predict situations in which errors and/or performance decrements are likely due to a variety of factors including concurrent workload and performance influencing factors (PIFs). This paper describes a new model that predicts the effects of microgravity on a mission specialist's performance, and its first application to simulating the task of conducting a Life Sciences experiment in space according to a sequential or parallel schedule of performance.

Update on Multiple Ovulations in Dairy Cattle.

PubMed

Macmillan, Kira; Kastelic, John P; Colazo, Marcos G

2018-04-24

This review updates the causal mechanisms and risk factors for multiple ovulations (MOV) in cattle. Clearly, MOV can lead to twin pregnancies, which negatively affects the health, production, and reproduction of cows. Therefore, a better understanding of the factors causing MOV may help to reduce twinning. Multiple ovulations occur after two or more follicles deviate and achieve codominance. The MOV rate is influenced by a complex network of hormones. For example, MOV is more common during periods of low progesterone (P4), that is, in anovulatory cattle or when luteolysis coincides with the selection of the future ovulatory follicle. There is also strong evidence for the luteinizing hormone (LH) being the primary factor leading to codominance, as high P4 concentrations suppress the transient LH surges and can reduce the ovulation rate in cattle or even inhibit deviation. Rates of MOV are increased in older and higher-producing dairy cows. Increased milk production and dry matter intake (DMI) increases hormone clearance, including P4; however, the association between milk yield and MOV has not been consistent. Additional risk factors for MOV include ovarian cysts, diet, season, and genetics.

Applications That Participate in Their Own Defense (APOD)

DTIC Science & Technology

2003-05-01

bandwidth requirements from multiple applications and uses ssh to directly login the RSVP routers to reconfigure the priority queues. This approach...detect flooding. 3 Emerald makes use of some signature matching techniques on BSM logs, but the unique strength of Emerald technology is in event...mechanisms that provide awareness, and IDSs form an important class of these4. We investigated several COTS and research IDSs including Emerald

Writing a Writing Assessment: Saying What You Want to Say Isn't as Simple as It Seems.

ERIC Educational Resources Information Center

Escoe, Adrienne

Since acceptable writing is essential to success in job training programs and in many entry-level jobs, a writing sample was included in the Training and Employment Prerequisites Survey, a multiple-choice test about skills like mechanics, usage, and spelling. The two writing prompts asked students to give directions for finding a location in a…

Evaluating the status of individuals and populations: Advantages of multiple approaches and time scales: Chapter 6

USGS Publications Warehouse

Monson, Daniel H.; Bowen, Lizabeth

2015-01-01

Overall, a variety of indices used to measure population status throughout the sea otter’s range have provided insights for understanding the mechanisms driving the trajectory of various sea otter populations, which a single index could not, and we suggest using multiple methods to measure a population’s status at multiple spatial and temporal scales. The work described here also illustrates the usefulness of long-term data sets and/or approaches that can be used to assess population status retrospectively, providing information otherwise not available. While not all systems will be as amenable to using all the approaches presented here, we expect innovative researchers could adapt analogous multi-scale methods to a broad range of habitats and species including apex predators occupying the top trophic levels, which are often of conservation concern.

Multiple Exciton Generation in Colloidal Nanocrystals

PubMed Central

Smith, Charles; Binks, David

2013-01-01

In a conventional solar cell, the energy of an absorbed photon in excess of the band gap is rapidly lost as heat, and this is one of the main reasons that the theoretical efficiency is limited to ~33%. However, an alternative process, multiple exciton generation (MEG), can occur in colloidal quantum dots. Here, some or all of the excess energy is instead used to promote one or more additional electrons to the conduction band, potentially increasing the photocurrent of a solar cell and thereby its output efficiency. This review will describe the development of this field over the decade since the first experimental demonstration of multiple exciton generation, including the controversies over experimental artefacts, comparison with similar effects in bulk materials, and the underlying mechanisms. We will also describe the current state-of-the-art and outline promising directions for further development. PMID:28348283

Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation.

PubMed

Choi, Dongsic; Lee, Tae Hoon; Spinelli, Cristiana; Chennakrishnaiah, Shilpa; D'Asti, Esterina; Rak, Janusz

2017-07-01

Pathogenesis of human cancers bridges intracellular oncogenic driver events and their impact on intercellular communication. Among multiple mediators of this 'pathological connectivity' the role of extracellular vesicles (EVs) and their subsets (exosomes, ectosomes, oncosomes) is of particular interest for several reasons. The release of EVs from cancer cells represents a unique mechanism of regulated expulsion of bioactive molecules, a process that also mediates cell-to-cell transfer of lipids, proteins, and nucleic acids. Biological effects of these processes have been implicated in several aspects of cancer-related pathology, including tumour growth, invasion, angiogenesis, metastasis, immunity and thrombosis. Notably, the emerging evidence suggests that oncogenic mutations may impact several aspects of EV-mediated cell-cell communication including: (i) EV release rate and protein content; (ii) molecular composition of cancer EVs; (iii) the inclusion of oncogenic and mutant macromolecules in the EV cargo; (iv) EV-mediated release of genomic DNA; (v) deregulation of mechanisms responsible for EV biogenesis (vesiculome) and (vi) mechanisms of EV uptake by cancer cells. Intriguingly, EV-mediated intercellular transfer of mutant and oncogenic molecules between subpopulations of cancer cells, their indolent counterparts and stroma may exert profound biological effects that often resemble (but are not tantamount to) oncogenic transformation, including changes in cell growth, clonogenicity and angiogenic phenotype, or cause cell stress and death. However, several biological barriers likely curtail a permanent horizontal transformation of normal cells through EV-mediated mechanisms. The ongoing analysis and targeting of EV-mediated intercellular communication pathways can be viewed as a new therapeutic paradigm in cancer, while the analysis of oncogenic cargo contained in EVs released from cancer cells into biofluids is being developed for clinical use as a biomarker and companion diagnostics. Indeed, studies are underway to further explore the multiple links between molecular causality in cancer and various aspects of cellular vesiculation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence.

PubMed

Lenain, Christelle; de Graaf, Carolyn A; Pagie, Ludo; Visser, Nils L; de Haas, Marcel; de Vries, Sandra S; Peric-Hupkes, Daniel; van Steensel, Bas; Peeper, Daniel S

2017-10-01

Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging. It interacts with multiple regions of the genome called lamina-associated domains (LADs). Some LADs are cell-type specific, whereas others are conserved between cell types and are referred to as constitutive LADs (cLADs). Here, we used DamID to investigate the changes in genome-NL interactions in a model of OIS triggered by the expression of the common BRAF V600E oncogene. We found that OIS cells lose most of their cLADS, suggesting the loss of a specific mechanism that targets cLADs to the NL. In addition, multiple genes relocated to the NL. Unexpectedly, they were not repressed, implying the abrogation of the repressive activity of the NL during OIS. Finally, OIS cells displayed an increased association of telomeres with the NL. Our study reveals that senescent cells acquire a new type of LAD organization and suggests the existence of as yet unknown mechanisms that tether cLADs to the NL and repress gene expression at the NL. © 2017 Lenain et al.; Published by Cold Spring Harbor Laboratory Press.

A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2.

PubMed

Lavik, Andrew R; Zhong, Fei; Chang, Ming-Jin; Greenberg, Edward; Choudhary, Yuvraj; Smith, Mitchell R; McColl, Karen S; Pink, John; Reu, Frederic J; Matsuyama, Shigemi; Distelhorst, Clark W

2015-09-29

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction.

Microarray profiling analysis uncovers common molecular mechanisms of rubella virus, human cytomegalovirus, and herpes simplex virus type 2 infections in ECV304 cells.

PubMed

Mo, X; Xu, L; Yang, Q; Feng, H; Peng, J; Zhang, Y; Yuan, W; Wang, Y; Li, Y; Deng, Y; Wan, Y; Chen, Z; Li, F; Wu, X

2011-08-01

To study the common molecular mechanisms of various viruses infections that might result in congential cardiovascular diseases in perinatal period, changes in mRNA expression levels of ECV304 cells infected by rubella virus (RUBV), human cytomegalovirus (HCMV), and herpes simplex virus type 2 (HSV-2) were analyzed using a microarray system representing 18,716 human genes. 99 genes were found to exhibit differential expression (80 up-regulated and 19 down-regulated). Biological process analysis showed that 33 signaling pathways including 22 genes were relevant significantly to RV, HCMV and HSV-II infections. Of these 33 biological processes, 28 belong to one-gene biological processes and 5 belong to multiple-gene biological processes. Gene annotation indicated that the 5 multiple-gene biological processes including regulation of cell growth, collagen fibril organization, mRNA transport, cell adhesion and regulation of cell shape, and seven down- or up-regulated genes [CRIM1 (cysteine rich transmembrane BMP regulator 1), WISP2 (WNT1 inducible signaling pathway protein 2), COL12A1 (collagen, type XII, alpha 1), COL11A2 (collagen, type XI, alpha 2), CNTN5 (contactin 5), DDR1 (discoidin domain receptor tyrosine kinase 1), VEGF (vascular endothelial growth factor precursor)], are significantly correlated to RUBV, HCMV and HSV-2 infections in ECV304 cells. The results obtained in this study suggested the common molecular mechanisms of viruses infections that might result in congential cardiovascular diseases.

Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: friends or foes?

PubMed

Chang, Ting-Ting; Chen, Jaw-Wen

2016-08-24

Chemokines are critical components in pathology. The roles of chemokine CC motif ligand 4 (CCL4) and its receptor are associated with diabetes mellitus (DM) and atherosclerosis cardiovascular diseases. However, due to the complexity of these diseases, the specific effects of CCL4 remain unclear, although recent reports have suggested that multiple pathways are related to CCL4. In this review, we provide an overview of the role and potential mechanisms of CCL4 and one of its major receptors, fifth CC chemokine receptor (CCR5), in DM and cardiovascular diseases. CCL4-related mechanisms, including CCL4 and CCR5, might provide potential therapeutic targets in DM and/or atherosclerosis cardiovascular diseases.

Integrated analysis of error detection and recovery

NASA Technical Reports Server (NTRS)

Shin, K. G.; Lee, Y. H.

1985-01-01

An integrated modeling and analysis of error detection and recovery is presented. When fault latency and/or error latency exist, the system may suffer from multiple faults or error propagations which seriously deteriorate the fault-tolerant capability. Several detection models that enable analysis of the effect of detection mechanisms on the subsequent error handling operations and the overall system reliability were developed. Following detection of the faulty unit and reconfiguration of the system, the contaminated processes or tasks have to be recovered. The strategies of error recovery employed depend on the detection mechanisms and the available redundancy. Several recovery methods including the rollback recovery are considered. The recovery overhead is evaluated as an index of the capabilities of the detection and reconfiguration mechanisms.

The intricate mechanisms of neurodegeneration in prion diseases

PubMed Central

Soto, Claudio; Satani, Nikunj

2010-01-01

Prion diseases are a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission, involving a protein-only infectious agent that propagates the disease by transmitting protein conformational changes. The disease results from extensive and progressive brain degeneration. The molecular mechanisms involved in neurodegeneration are not entirely known but involve multiple processes operating simultaneously and synergistically in the brain, including spongiform degeneration, synaptic alterations, brain inflammation, neuronal death and the accumulation of protein aggregates. Here, we review the pathways implicated in prion-induced brain damage and put the pieces together into a possible model of neurodegeneration in prion disorders. A more comprehensive understanding of the molecular basis of brain degeneration is essential to develop a much needed therapy for these devastating diseases. PMID:20889378

Neurobiology of dysregulated motivational systems in drug addiction

PubMed Central

Edwards, Scott; Koob, George F

2010-01-01

The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention. PMID:20563312

Hot Spots from Generated Defects in HMX Crystals

NASA Astrophysics Data System (ADS)

Sorensen, Christian; Cummock, Nicholas; O'Grady, Caitlin; Gunduz, I. Emre; Son, Steven

2017-06-01

There are several hot spot initiation mechanisms that have been proposed. However, direct observation of shock or impact compression of these mechanisms at macroscopic scale in explosives is difficult. Phase contrast imaging (PCI) may be applied to these systems. Here, high-speed video was used to record optical spectrum and for x-ray Phase Contrast Imaging (PCI) of shockwave interaction with low defect HMX crystals and crystals with engineered defects. Additionally, multiple crystals were arranged and observed under shock loading with PCI and optical high-speed video. Sample preparation techniques for generating voids and other engineered defects will be discussed. These methods include drilled holes and laser machined samples. Insight into hot spot mechanisms was obtained. Funding from ONR's PC@Xtreme MURI.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke.

PubMed

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke

PubMed Central

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects against cerebral ischemia. This review introduces multiple paradigms of inhalational anesthetic treatments that have been investigated in the setting of cerebral ischemia, such as preconditioning, proconditioning and postconditioning with a variety of inhalational anesthetics. The pleiotropic mechanisms underlying these inhalational anesthetics-afforded neuroprotection against stroke are also discussed in detail, including the common pathways shared by most of the inhalational anesthetic paradigms, such as anti-excitotoxicity, anti-apoptosis and anti-inflammation. There are also distinct mechanisms involved in specific paradigms, such as preserving blood brain barrier integrity, regulating cerebral blood flow and catecholamine release. The ready availability of these inhalational anesthetics bedside and renders them a potentially translatable stroke therapy attracting great efforts for understanding of the underlying mechanisms. PMID:28217291

Missing continuous outcomes under covariate dependent missingness in cluster randomised trials

PubMed Central

Diaz-Ordaz, Karla; Bartlett, Jonathan W

2016-01-01

Attrition is a common occurrence in cluster randomised trials which leads to missing outcome data. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. This paper compares the performance of unadjusted cluster-level analysis, baseline covariate adjusted cluster-level analysis and linear mixed model analysis, under baseline covariate dependent missingness in continuous outcomes, in terms of bias, average estimated standard error and coverage probability. The methods of complete records analysis and multiple imputation are used to handle the missing outcome data. We considered four scenarios, with the missingness mechanism and baseline covariate effect on outcome either the same or different between intervention groups. We show that both unadjusted cluster-level analysis and baseline covariate adjusted cluster-level analysis give unbiased estimates of the intervention effect only if both intervention groups have the same missingness mechanisms and there is no interaction between baseline covariate and intervention group. Linear mixed model and multiple imputation give unbiased estimates under all four considered scenarios, provided that an interaction of intervention and baseline covariate is included in the model when appropriate. Cluster mean imputation has been proposed as a valid approach for handling missing outcomes in cluster randomised trials. We show that cluster mean imputation only gives unbiased estimates when missingness mechanism is the same between the intervention groups and there is no interaction between baseline covariate and intervention group. Multiple imputation shows overcoverage for small number of clusters in each intervention group. PMID:27177885

Missing continuous outcomes under covariate dependent missingness in cluster randomised trials.

PubMed

Hossain, Anower; Diaz-Ordaz, Karla; Bartlett, Jonathan W

2017-06-01

Attrition is a common occurrence in cluster randomised trials which leads to missing outcome data. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. This paper compares the performance of unadjusted cluster-level analysis, baseline covariate adjusted cluster-level analysis and linear mixed model analysis, under baseline covariate dependent missingness in continuous outcomes, in terms of bias, average estimated standard error and coverage probability. The methods of complete records analysis and multiple imputation are used to handle the missing outcome data. We considered four scenarios, with the missingness mechanism and baseline covariate effect on outcome either the same or different between intervention groups. We show that both unadjusted cluster-level analysis and baseline covariate adjusted cluster-level analysis give unbiased estimates of the intervention effect only if both intervention groups have the same missingness mechanisms and there is no interaction between baseline covariate and intervention group. Linear mixed model and multiple imputation give unbiased estimates under all four considered scenarios, provided that an interaction of intervention and baseline covariate is included in the model when appropriate. Cluster mean imputation has been proposed as a valid approach for handling missing outcomes in cluster randomised trials. We show that cluster mean imputation only gives unbiased estimates when missingness mechanism is the same between the intervention groups and there is no interaction between baseline covariate and intervention group. Multiple imputation shows overcoverage for small number of clusters in each intervention group.

Electromagnetic energy coupling mechanism with matrix architecture control

NASA Technical Reports Server (NTRS)

Hughes, Eli (Inventor); Knowles, Gareth (Inventor)

2006-01-01

The present invention relates generally to reconfigurable, solid-state matrix arrays comprising multiple rows and columns of reconfigurable secondary mechanisms that are independently tuned. Specifically, the invention relates to reconfigurable devices comprising multiple, solid-state mechanisms characterized by at least one voltage-varied parameter disposed within a flexible, multi-laminate film, which are suitable for use as magnetic conductors, ground surfaces, antennas, varactors, ferrotunable substrates, or other active or passive electronic mechanisms.

Dynamics of Implementation and Maintenance of Organizational Health Interventions

PubMed Central

Rahmandad, Hazhir; Bullock, Sally Lawrence; Ammerman, Alice

2017-01-01

In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes. PMID:28809807

The Molecular Basis of Memory

PubMed Central

2012-01-01

We propose a tripartite biochemical mechanism for memory. Three physiologic components are involved, namely, the neuron (individual and circuit), the surrounding neural extracellular matrix, and the various trace metals distributed within the matrix. The binding of a metal cation affects a corresponding nanostructure (shrinking, twisting, expansion) and dielectric sensibility of the chelating node (address) within the matrix lattice, sensed by the neuron. The neural extracellular matrix serves as an electro-elastic lattice, wherein neurons manipulate multiple trace metals (n > 10) to encode, store, and decode coginive information. The proposed mechanism explains brains low energy requirements and high rates of storage capacity described in multiples of Avogadro number (NA = 6 × 1023). Supportive evidence correlates memory loss to trace metal toxicity or deficiency, or breakdown in the delivery/transport of metals to the matrix, or its degradation. Inherited diseases revolving around dysfunctional trace metal metabolism and memory dysfunction, include Alzheimer's disease (Al, Zn, Fe), Wilson’s disease (Cu), thalassemia (Fe), and autism (metallothionein). The tripartite mechanism points to the electro-elastic interactions of neurons with trace metals distributed within the neural extracellular matrix, as the molecular underpinning of “synaptic plasticity” affecting short-term memory, long-term memory, and forgetting. PMID:23050060

Restriction of the Xenopus DEADSouth mRNA to the primordial germ cells is ensured by multiple mechanisms.

PubMed

Yamaguchi, Takeshi; Kataoka, Kensuke; Watanabe, Kenji; Orii, Hidefumi

2014-02-01

DEADSouth mRNA encoding the RNA helicase DDX25 is a component of the germ plasm in Xenopus laevis. We investigated the mechanisms underlying its specific mRNA expression in primordial germ cells (PGCs). Based on our previous findings of several microRNA miR-427 recognition elements (MREs) in the 3' untranslated region of the mRNA, we first examined whether DEADSouth mRNA was degraded by miR-427 targeting in somatic cells. Injection of antisense miR-427 oligomer and reporter mRNA for mutated MREs revealed that DEADSouth mRNA was potentially degraded in somatic cells via miR-427 targeting, but not in PGCs after the mid-blastula transition (MBT). The expression level of miR-427 was very low in PGCs, which probably resulted in the lack of miR-427-mediated degradation. In addition, the DEADSouth gene was expressed zygotically after MBT. Thus, the predominant expression of DEADSouth mRNA in the PGCs is ensured by multiple mechanisms including zygotic expression and prohibition from miR-427-mediated degradation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems

PubMed Central

Herrando-Grabulosa, Mireia; Mulet, Roger; Pujol, Albert; Mas, José Manuel; Navarro, Xavier; Aloy, Patrick; Coma, Mireia; Casas, Caty

2016-01-01

Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis. PMID:26807587

Insights on persistent airway infection by non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease

PubMed Central

Ahearn, Christian P.; Gallo, Mary C.

2017-01-01

Abstract Non-typeable Haemophilus influenzae (NTHi) is the most common bacterial cause of infection of the lower airways in adults with chronic obstructive pulmonary disease (COPD). Infection of the COPD airways causes acute exacerbations, resulting in substantial morbidity and mortality. NTHi has evolved multiple mechanisms to establish infection in the hostile environment of the COPD airways, allowing the pathogen to persist in the airways for months to years. Persistent infection of the COPD airways contributes to chronic airway inflammation that increases symptoms and accelerates the progressive loss of pulmonary function, which is a hallmark of the disease. Persistence mechanisms of NTHi include the expression of multiple redundant adhesins that mediate binding to host cellular and extracellular matrix components. NTHi evades host immune recognition and clearance by invading host epithelial cells, forming biofilms, altering gene expression and displaying surface antigenic variation. NTHi also binds host serum factors that confer serum resistance. Here we discuss the burden of COPD and the role of NTHi infections in the course of the disease. We provide an overview of NTHi mechanisms of persistence that allow the pathogen to establish a niche in the hostile COPD airways. PMID:28449098

Effects of axial compression and rotation angle on torsional mechanical properties of bovine caudal discs.

PubMed

Bezci, Semih E; Klineberg, Eric O; O'Connell, Grace D

2018-01-01

The intervertebral disc is a complex joint that acts to support and transfer large multidirectional loads, including combinations of compression, tension, bending, and torsion. Direct comparison of disc torsion mechanics across studies has been difficult, due to differences in loading protocols. In particular, the lack of information on the combined effect of multiple parameters, including axial compressive preload and rotation angle, makes it difficult to discern whether disc torsion mechanics are sensitive to the variables used in the test protocol. Thus, the objective of this study was to evaluate compression-torsion mechanical behavior of healthy discs under a wide range of rotation angles. Bovine caudal discs were tested under a range of compressive preloads (150, 300, 600, and 900N) and rotation angles (± 1, 2, 3, 4, or 5°) applied at a rate of 0.5°/s. Torque-rotation data were used to characterize shape changes in the hysteresis loop and to calculate disc torsion mechanics. Torsional mechanical properties were described using multivariate regression models. The rate of change in torsional mechanical properties with compression depended on the maximum rotation angle applied, indicating a strong interaction between compressive stress and maximum rotation angle. The regression models reported here can be used to predict disc torsion mechanics under axial compression for a given disc geometry, compressive preload, and rotation angle. Copyright © 2017 Elsevier Ltd. All rights reserved.

Flash memory management system and method utilizing multiple block list windows

NASA Technical Reports Server (NTRS)

Chow, James (Inventor); Gender, Thomas K. (Inventor)

2005-01-01

The present invention provides a flash memory management system and method with increased performance. The flash memory management system provides the ability to efficiently manage and allocate flash memory use in a way that improves reliability and longevity, while maintaining good performance levels. The flash memory management system includes a free block mechanism, a disk maintenance mechanism, and a bad block detection mechanism. The free block mechanism provides efficient sorting of free blocks to facilitate selecting low use blocks for writing. The disk maintenance mechanism provides for the ability to efficiently clean flash memory blocks during processor idle times. The bad block detection mechanism provides the ability to better detect when a block of flash memory is likely to go bad. The flash status mechanism stores information in fast access memory that describes the content and status of the data in the flash disk. The new bank detection mechanism provides the ability to automatically detect when new banks of flash memory are added to the system. Together, these mechanisms provide a flash memory management system that can improve the operational efficiency of systems that utilize flash memory.

Gibberellin DELLA signaling targets the retromer complex to redirect protein trafficking to the plasma membrane

PubMed Central

Salanenka, Yuliya; Verstraeten, Inge; Löfke, Christian; Tabata, Kaori; Naramoto, Satoshi; Glanc, Matouš; Friml, Jiří

2018-01-01

The plant hormone gibberellic acid (GA) is a crucial regulator of growth and development. The main paradigm of GA signaling puts forward transcriptional regulation via the degradation of DELLA transcriptional repressors. GA has also been shown to regulate tropic responses by modulation of the plasma membrane incidence of PIN auxin transporters by an unclear mechanism. Here we uncovered the cellular and molecular mechanisms by which GA redirects protein trafficking and thus regulates cell surface functionality. Photoconvertible reporters revealed that GA balances the protein traffic between the vacuole degradation route and recycling back to the cell surface. Low GA levels promote vacuolar delivery and degradation of multiple cargos, including PIN proteins, whereas high GA levels promote their recycling to the plasma membrane. This GA effect requires components of the retromer complex, such as Sorting Nexin 1 (SNX1) and its interacting, microtubule (MT)-associated protein, the Cytoplasmic Linker-Associated Protein (CLASP1). Accordingly, GA regulates the subcellular distribution of SNX1 and CLASP1, and the intact MT cytoskeleton is essential for the GA effect on trafficking. This GA cellular action occurs through DELLA proteins that regulate the MT and retromer presumably via their interaction partners Prefoldins (PFDs). Our study identified a branching of the GA signaling pathway at the level of DELLA proteins, which, in parallel to regulating transcription, also target by a nontranscriptional mechanism the retromer complex acting at the intersection of the degradation and recycling trafficking routes. By this mechanism, GA can redirect receptors and transporters to the cell surface, thus coregulating multiple processes, including PIN-dependent auxin fluxes during tropic responses. PMID:29463731

Anticancer Properties of Capsaicin Against Human Cancer.

PubMed

Clark, Ruth; Lee, Seong-Ho

2016-03-01

There is persuasive epidemiological and experimental evidence that dietary phytochemicals have anticancer activity. Capsaicin is a bioactive phytochemical abundant in red and chili peppers. While the preponderance of the data strongly indicates significant anticancer benefits of capsaicin, more information to highlight molecular mechanisms of its action is required to improve our knowledge to be able to propose a potential therapeutic strategy for use of capsaicin against cancer. Capsaicin has been shown to alter the expression of several genes involved in cancer cell survival, growth arrest, angiogenesis and metastasis. Recently, many research groups, including ours, found that capsaicin targets multiple signaling pathways, oncogenes and tumor-suppressor genes in various types of cancer models. In this review article, we highlight multiple molecular targets responsible for the anticancer mechanism of capsaicin. In addition, we deal with the benefits of combinational use of capsaicin with other dietary or chemotherapeutic compounds, focusing on synergistic anticancer activities. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Accelerated hydrolysis of substituted cellulose for potential biofuel production: kinetic study and modeling.

PubMed

Mu, Bingnan; Xu, Helan; Yang, Yiqi

2015-11-01

In this work, kinetics of substitution accelerated cellulose hydrolysis with multiple reaction stages was investigated to lay foundation for mechanism study and molecular design of substituting compounds. High-efficiency hydrolysis of cellulose is critical for cellulose-based bioethanol production. It is known that, substitution could substantially decrease activation energy and increase reaction rate of acidic hydrolysis of glycosidic bonds in cellulose. However, reaction kinetics and mechanism of the accelerated hydrolysis were not fully revealed. In this research, it was proved that substitution therefore accelerated hydrolysis only occurred in amorphous regions of cellulose fibers, and was a process with multiple reaction stages. With molar ratio of substitution less than 1%, the overall hydrolysis rate could be increased for around 10 times. We also quantified the relationship between the hydrolysis rate of individual reaction stage and its major influences, including molar ratio of substitution, activation energy of acidic hydrolysis, pH and temperature. Copyright © 2015 Elsevier Ltd. All rights reserved.

The multiple functions of plant serine protease inhibitors

PubMed Central

Giri, Ashok P; Kaur, Harleen; Baldwin, Ian T

2011-01-01

Plant protease inhibitors (PIs) are a diverse group of proteins which have been intensely investigated due to their potential function in protecting plants against herbivorous insects by inhibiting digestive proteases. Although this mechanism has been well documented for a number of single PIs and their target enzymes, whether this mechanism protects plants in nature remains unclear. Moreover, many plants express a number of different PIs and it was unknown if these proteins work synergistically as defenses or if they also have other functions. We recently identified four serine PIs (SPI) of Solanum nigrum and demonstrated that they differ substantially in substrate specificity, accumulation patterns, and their effect against different natural herbivorous insects in field- and glasshouse experiments. These differences suggest that SPIs have at least partially diversified to provide protection against different attackers. Although we could not detect effects on plant development or growth when silencing SPIs, gene- and tissue-specific expression patterns suggest multiple functions in generative tissues, including a possible involvement in development. PMID:22004998

Inhibitory activity and mechanism of inhibition of the N-[[(4-benzoylamino)phenyl]sulfonyl]amino acid aldose reductase inhibitors.

PubMed

DeRuiter, J; Mayfield, C A

1990-11-15

A series of substituted N-[[(4-benzoylamino)phenyl]sulfonyl]amino acids (BAPS-amino acids) were synthesized by established methods, and the stereochemistry of the products was confirmed by HPLC analysis after chiral derivatization. When tested against aldose reductase (alditol:NADP+ oxidoreductase; EC 1.1.1.21; ALR2) isolated from rat lens, all of the BAPS-amino acids were determined to be significantly more inhibitory than the corresponding N-(phenylsulfonyl)amino acids. Structure-inhibition and enzyme kinetic analyses suggest that the BAPS-amino acids inhibit ALR2 by a mechanism similar to the N-(phenylsulfonyl)amino acids. However, multiple inhibition analyses indicate that the increased inhibitory activity of the BAPS-amino acids is a result of interaction with multiple sites present on ALR2. Enzyme specificity studies with several of the BAPS-amino acids demonstrated that these compounds do not produce significant inhibition of other nucleotide-requiring enzymes including aldehyde reductase (alcohol: NADP+ oxidoreductase; EC 1.1.1.2; ALR1).

Multiple levels of bilingual language control: evidence from language intrusions in reading aloud.

PubMed

Gollan, Tamar H; Schotter, Elizabeth R; Gomez, Joanne; Murillo, Mayra; Rayner, Keith

2014-02-01

Bilinguals rarely produce words in an unintended language. However, we induced such intrusion errors (e.g., saying el instead of he) in 32 Spanish-English bilinguals who read aloud single-language (English or Spanish) and mixed-language (haphazard mix of English and Spanish) paragraphs with English or Spanish word order. These bilinguals produced language intrusions almost exclusively in mixed-language paragraphs, and most often when attempting to produce dominant-language targets (accent-only errors also exhibited reversed language-dominance effects). Most intrusion errors occurred for function words, especially when they were not from the language that determined the word order in the paragraph. Eye movements showed that fixating a word in the nontarget language increased intrusion errors only for function words. Together, these results imply multiple mechanisms of language control, including (a) inhibition of the dominant language at both lexical and sublexical processing levels, (b) special retrieval mechanisms for function words in mixed-language utterances, and (c) attentional monitoring of the target word for its match with the intended language.

Effects of filler type and content on mechanical properties of photopolymerizable composites measured across two-dimensional combinatorial arrays.

PubMed

Lin-Gibson, Sheng; Sung, Lipiin; Forster, Aaron M; Hu, Haiqing; Cheng, Yajun; Lin, Nancy J

2009-07-01

Multicomponent formulations coupled with complex processing conditions govern the final properties of photopolymerizable dental composites. In this study, a single test substrate was fabricated to support multiple formulations with a gradient in degree of conversion (DC), allowing the evaluation of multiple processing conditions and formulations on one specimen. Mechanical properties and damage response were evaluated as a function of filler type/content and irradiation. DC, surface roughness, modulus, hardness, scratch deformation and cytotoxicity were quantified using techniques including near-infrared spectroscopy, laser confocal scanning microscopy, depth-sensing indentation, scratch testing and cell viability. Scratch parameters (depth, width, percent recovery) were correlated to composite modulus and hardness. Total filler content, nanofiller and irradiation time/intensity all affected the final properties, with the dominant factor for improved properties being a higher DC. This combinatorial platform accelerates the screening of dental composites through the direct comparison of properties and processing conditions across the same sample.

Tracking planets and moons: mechanisms of object tracking revealed with a new paradigm

PubMed Central

Tombu, Michael

2014-01-01

People can attend to and track multiple moving objects over time. Cognitive theories of this ability emphasize location information and differ on the importance of motion information. Results from several experiments have shown that increasing object speed impairs performance, although speed was confounded with other properties such as proximity of objects to one another. Here, we introduce a new paradigm to study multiple object tracking in which object speed and object proximity were manipulated independently. Like the motion of a planet and moon, each target–distractor pair rotated about both a common local point as well as the center of the screen. Tracking performance was strongly affected by object speed even when proximity was controlled. Additional results suggest that two different mechanisms are used in object tracking—one sensitive to speed and proximity and the other sensitive to the number of distractors. These observations support models of object tracking that include information about object motion and reject models that use location alone. PMID:21264704

Evaluating oversight of human drugs and medical devices: a case study of the FDA and implications for nanobiotechnology.

PubMed

Paradise, Jordan; Tisdale, Alison W; Hall, Ralph F; Kokkoli, Efrosini

2009-01-01

This article evaluates the oversight of drugs and medical devices by the U.S. Food and Drug Administration (FDA) using an integration of public policy, law, and bioethics approaches and employing multiple assessment criteria, including economic, social, safety, and technological. Criteria assessment and expert elicitation are combined with existing literature, case law, and regulations in an integrative historical case studies approach. We then use our findings as a tool to explore possibilities for effective oversight and regulatory mechanisms for nanobiotechnology. Section I describes oversight mechanisms for human drugs and medical devices and presents current nanotechnology products. Section II describes the results of expert elicitation research. Section III highlights key criteria and relates them to the literature and larger debate. We conclude with broad lessons for the oversight of nanobiotechnology informed by Sections I-III in order to provide useful analysis from multiple disciplines and perspectives to guide discussions regarding appropriate FDA oversight.

Tracking planets and moons: mechanisms of object tracking revealed with a new paradigm.

PubMed

Tombu, Michael; Seiffert, Adriane E

2011-04-01

People can attend to and track multiple moving objects over time. Cognitive theories of this ability emphasize location information and differ on the importance of motion information. Results from several experiments have shown that increasing object speed impairs performance, although speed was confounded with other properties such as proximity of objects to one another. Here, we introduce a new paradigm to study multiple object tracking in which object speed and object proximity were manipulated independently. Like the motion of a planet and moon, each target-distractor pair rotated about both a common local point as well as the center of the screen. Tracking performance was strongly affected by object speed even when proximity was controlled. Additional results suggest that two different mechanisms are used in object tracking--one sensitive to speed and proximity and the other sensitive to the number of distractors. These observations support models of object tracking that include information about object motion and reject models that use location alone.

Transmedia Storytelling in Science Communication: One Subject, Multiple Media, Multiple Stories

NASA Astrophysics Data System (ADS)

Unger, M.; Moloney, K.

2012-12-01

Each communication medium has particular storytelling strengths. For example, video is particularly good at illustrating a progression of events, text at background and context, and games at describing systems. In what USC's Prof. Henry Jenkins described as "transmedia storytelling," multiple media are used simultaneously, in an expansive rather than repetitive way, to better tell a single, complex story. The audience is given multiple entry points to the story, and the story is exposed to diverse and dispersed audiences, ultimately engaging a broader public. We will examine the effectiveness of a transmedia approach to communicating scientific and other complex concepts to a broad and diverse audience. Using the recently developed Educational Visitor Center at the NCAR-Wyoming Supercomputing Center as a case study, we will evaluate the reach of various means of presenting information about the geosciences, climate change and computational science. These will include an assessment of video, mechanical and digital interactive elements, animated movie segments, web-based content, photography, scientific visualizations, printed material and docent-led activities.

Root Cause Investigation of Lead-Free Solder Joint Interfacial Failures After Multiple Reflows

NASA Astrophysics Data System (ADS)

Li, Yan; Hatch, Olen; Liu, Pilin; Goyal, Deepak

2017-03-01

Solder joint interconnects in three-dimensional (3D) packages with package stacking configurations typically must undergo multiple reflow cycles during the assembly process. In this work, interfacial open joint failures between the bulk solder and the intermetallic compound (IMC) layer were found in Sn-Ag-Cu (SAC) solder joints connecting a small package to a large package after multiple reflow reliability tests. Systematic progressive 3D x-ray computed tomography experiments were performed on both incoming and assembled parts to reveal the initiation and evolution of the open failures in the same solder joints before and after the reliability tests. Characterization studies, including focused ion beam cross-sections, scanning electron microscopy, and energy-dispersive x-ray spectroscopy, were conducted to determine the correlation between IMC phase transformation and failure initiation in the solder joints. A comprehensive failure mechanism, along with solution paths for the solder joint interfacial failures after multiple reflow cycles, is discussed in detail.

Experimental models of demyelination and remyelination.

PubMed

Torre-Fuentes, L; Moreno-Jiménez, L; Pytel, V; Matías-Guiu, J A; Gómez-Pinedo, U; Matías-Guiu, J

2017-08-29

Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Immunonutrition - fact or fad.

PubMed

Schneider, H; Atkinson, S W

2000-01-01

Suggestions that modifications to the diet may have a beneficial effect on health are not new. recent work demonstrates that nutritional supplements may effect immune function. This review examines the evidence for the effects of these supplements including arginine, glutamine, nucleotides and omega - 3 fatty acids. In particular, clinical trials with patients in multiple organ failure are discussed. The evidence published thus far suggests that immunonutrition, if absorbed in adequate amounts both pre- and post-operatively, reduces septic complications and improves surrogate measures of ourcome, including length of stay and requirements for mechanical ventilation.

Design Concept for a Reusable/Propellantless MXER Tether Space Transportation System

NASA Technical Reports Server (NTRS)

McCandless, B., II; Kustas, F. m.; Marshall, L. S.; Lytle, W. B.; Hansen, N. P.

2005-01-01

The Momentum Exchange/Electrodynamic Reboost (MXER) tether facility is a transformational concept that significantly reduces the fuel requirements (and associated costs) in transferring payloads above low earth orbit (LEO). Facility reboost is accomplished without propellant by driving current against a voltage created by a conducting tether's interaction with the Earth's magnetic field (electrodynamic reboost). This system can be used for transferring a variety of payloads (scientific, cargo, and human space vehicles) to multiple destinations including geosynchronous transfer orbit, the Moon or Mars. MXER technology advancement requires development in two key areas: survivable, high tensile strength non-conducting tethers and reliable, lightweight payload catch/release mechanisms. Fundamental requirements associated with the MXER non-conducting strength tether and catch mechanism designs will be presented. Key requirements for the tether design include high specific-strength (tensile strength/material density), material survivability to the space environment (atomic oxygen and ultraviolet radiation), and structural survivability to micrometeoroid/orbital debris (MM/OD) impacts. The driving mechanism key,gequirements include low mass-to-capture-volume ratio, positional and velocity error tolerance, and operational reliability. Preliminary tether and catch mechanism design criteria are presented, which have been used as guidelines to "screen" and down-select initial concepts. Candidate tether materials and protective coatings are summarized along with their performance in simulated space environments (e.g., oxygen plasma, thermal cycling). A candidate catch mechanism design concept is presented along with examples of demonstration hardware.

Sonodynamic therapy--a review of the synergistic effects of drugs and ultrasound.

PubMed

Rosenthal, Ionel; Sostaric, Joe Z; Riesz, Peter

2004-09-01

Sonodynamic therapy, the ultrasound dependent enhancement of cytotoxic activities of certain compounds (sonosensitizers) in studies with cells in vitro and in tumor bearing animals, is reviewed. The attractive features of this modality for cancer treatment emerges from the ability to focus the ultrasound energy on malignancy sites buried deep in tissues and to locally activate a preloaded sonosensitizer. Possible mechanisms of sonodynamic therapy include generation of sonosensitizer derived radicals which initiate chain peroxidation of membrane lipids via peroxyl and/or alkoxyl radicals, the physical destabilization of the cell membrane by the sonosensitizer thereby rendering the cell more susceptible to shear forces or ultrasound enhanced drug transport across the cell membrane (sonoporation). Evidence against the role of singlet oxygen in sonodynamic therapy is discussed. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound parameters. The current review emphasizes the effect of ultrasound induced free radicals in sonodynamic therapy.

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

PubMed Central

Yang, Lili; Rozenfeld, Raphael; Wu, Defeng; Devi, Lakshmi A.; Zhang, Zhenfeng; Cederbaum, Arthur

2014-01-01

Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy. PMID:24398069

Discovering Hematopoietic Mechanisms Through Genome-Wide Analysis of GATA Factor Chromatin Occupancy

PubMed Central

Fujiwara, Tohru; O'Geen, Henriette; Keles, Sunduz; Blahnik, Kimberly; Linnemann, Amelia K.; Kang, Yoon-A; Choi, Kyunghee; Farnham, Peggy J.; Bresnick, Emery H.

2009-01-01

SUMMARY GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction, and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for cross-regulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2 negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis. PMID:19941826

Post-transplantation Development of Food Allergies.

PubMed

Newman, Erik N; Firszt, Rafael

2018-01-29

The development of food allergies is increasingly being recognized as a post-solid organ transplant complication. In this article, we review the spectrum of post-transplant food allergy development and the proposed mechanisms for de novo food allergies and the clinical significance they pose. The development of new food allergies is disproportionately associated with pediatric liver transplants, where it occurs in up to 38% of select populations. The mechanism of food allergy development is not completely understood; however, it is likely promoted by unbalanced immune suppression. De novo food allergy development is a common complication of solid organ transplants with the highest risk occurring in pediatric liver transplant recipients. There are likely multiple mechanisms for food allergy development including passive transfer of membrane-bound IgE and lymphocytes from donor to recipient, as well as loss of food tolerance and active development of new food allergies. The optimal management of food allergies following organ transplants has not been well researched but may include changing the immune suppression regimen if the food allergy does not resolve without intervention.

Material mechanical characterization method for multiple strains and strain rates

DOEpatents

Erdmand, III, Donald L.; Kunc, Vlastimil; Simunovic, Srdjan; Wang, Yanli

2016-01-19

A specimen for measuring a material under multiple strains and strain rates. The specimen including a body having first and second ends and a gage region disposed between the first and second ends, wherein the body has a central, longitudinal axis passing through the first and second ends. The gage region includes a first gage section and a second gage section, wherein the first gage section defines a first cross-sectional area that is defined by a first plane that extends through the first gage section and is perpendicular to the central, longitudinal axis. The second gage section defines a second cross-sectional area that is defined by a second plane that extends through the second gage section and is perpendicular to the central, longitudinal axis and wherein the first cross-sectional area is different in size than the second cross-sectional area.

Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements

PubMed Central

Liu, Pengfei; Erez, Ayelet; Sreenath Nagamani, Sandesh C.; Dhar, Shweta U.; Kołodziejska, Katarzyna E.; Dharmadhikari, Avinash V.; Cooper, M. Lance; Wiszniewska, Joanna; Zhang, Feng; Withers, Marjorie A.; Bacino, Carlos A.; Campos-Acevedo, Luis Daniel; Delgado, Mauricio R.; Freedenberg, Debra; Garnica, Adolfo; Grebe, Theresa A.; Hernández-Almaguer, Dolores; Immken, LaDonna; Lalani, Seema R.; McLean, Scott D.; Northrup, Hope; Scaglia, Fernando; Strathearn, Lane; Trapane, Pamela; Kang, Sung-Hae L.; Patel, Ankita; Cheung, Sau Wai; Hastings, P. J.; Stankiewicz, Paweł; Lupski, James R.; Bi, Weimin

2011-01-01

SUMMARY Complex genomic rearrangements (CGR) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated we observed localization and multiple copy number changes including deletions, duplications and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism’s life cycle. PMID:21925314

Managing renal complications in multiple myeloma.

PubMed

Fotiou, Despoina; Dimopoulos, Meletios A; Kastritis, Efstathios

2016-09-01

About 20-40% of patients with multiple myeloma (MM) will present with some degree of renal impairment (RI) and about 25% of patients will experience RI at later disease stages. Patients with MM and RI have poorer overall survival and are at higher risk of early death. The mechanisms of acute renal damage in MM are covered and the issues around diagnosis and renal evaluation response are discussed. The importance of optimal supportive care is stressed and the role and effectiveness of different anti-myeloma agents covered including the role of high cut-off hemodialysis, autologous stem cell transplantation and kidney transplant. Expert commentary: Outcomes of patients with RI and rates of renal recovery have improved with the use of novel anti-myeloma agents. Bortezomib-dexamethasone backbone regimes (±third agent) are the current first choice in newly diagnosed patients. In relapsed/refractory disease additional treatment options include newer novel agents.

Scalable Lunar Surface Networks and Adaptive Orbit Access

NASA Technical Reports Server (NTRS)

Wang, Xudong

2015-01-01

Teranovi Technologies, Inc., has developed innovative network architecture, protocols, and algorithms for both lunar surface and orbit access networks. A key component of the overall architecture is a medium access control (MAC) protocol that includes a novel mechanism of overlaying time division multiple access (TDMA) and carrier sense multiple access with collision avoidance (CSMA/CA), ensuring scalable throughput and quality of service. The new MAC protocol is compatible with legacy Institute of Electrical and Electronics Engineers (IEEE) 802.11 networks. Advanced features include efficiency power management, adaptive channel width adjustment, and error control capability. A hybrid routing protocol combines the advantages of ad hoc on-demand distance vector (AODV) routing and disruption/delay-tolerant network (DTN) routing. Performance is significantly better than AODV or DTN and will be particularly effective for wireless networks with intermittent links, such as lunar and planetary surface networks and orbit access networks.

Diseases Associated with Defective Responses to DNA Damage

PubMed Central

O’Driscoll, Mark

2012-01-01

Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways. PMID:23209155

Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma.

PubMed

Luczkowska, K; Litwinska, Z; Paczkowska, E; Machalinski, B

2018-04-01

Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.

Pancreatic trauma: demographics, diagnosis, and management.

PubMed

Stawicki, Stanislaw Peter; Schwab, C William

2008-12-01

Pancreatic injuries are rare, with penetrating mechanisms being causative in majority of cases. They can create major diagnostic and therapeutic challenges and require multiple diagnostic modalities, including multislice high-definition computed tomography, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, ultrasonography, and at times, surgery and direct visualization of the pancreas. Pancreatic trauma is frequently associated with duodenal and other severe vascular and visceral injuries. Mortality is high and usually related to the concomitant vascular injury. Surgical management of pancreatic and pancreatic-duodenal trauma is challenging, and multiple surgical approaches and techniques have been described, up to and including pancreatic damage control and later resection and reconstruction. Wide surgical drainage is a key to any surgical trauma technique and access for enteral nutrition, or occasionally parenteral nutrition, are important adjuncts. Morbidity associated with pancreatic trauma is high and can be quite severe. Treatment of pancreatic trauma-related complications often requires a combination of interventional, endoscopic, and surgical approaches.

Current perspectives on the mechanism of action of artemisinins.

PubMed

Golenser, Jacob; Waknine, Judith H; Krugliak, Miriam; Hunt, Nicholas H; Grau, Georges E

2006-12-01

Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.

Chemo-mechanical modeling of tumor growth in elastic epithelial tissue

NASA Astrophysics Data System (ADS)

Bratsun, Dmitry A.; Zakharov, Andrey P.; Pismen, Len

2016-08-01

We propose a multiscale chemo-mechanical model of the cancer tumor development in the epithelial tissue. The epithelium is represented by an elastic 2D array of polygonal cells with its own gene regulation dynamics. The model allows the simulation of the evolution of multiple cells interacting via the chemical signaling or mechanically induced strain. The algorithm includes the division and intercalation of cells as well as the transformation of normal cells into a cancerous state triggered by a local failure of the spatial synchronization of the cellular rhythms driven by transcription/translation processes. Both deterministic and stochastic descriptions of the system are given for chemical signaling. The transformation of cells means the modification of their respective parameters responsible for chemo-mechanical interactions. The simulations reproduce a distinct behavior of invasive and localized carcinoma. Generally, the model is designed in such a way that it can be readily modified to take account of any newly understood gene regulation processes and feedback mechanisms affecting chemo-mechanical properties of cells.

Spline-Screw Multiple-Rotation Mechanism

NASA Technical Reports Server (NTRS)

Vranish, John M.

1994-01-01

Mechanism functions like combined robotic gripper and nut runner. Spline-screw multiple-rotation mechanism related to spline-screw payload-fastening system described in (GSC-13454). Incorporated as subsystem in alternative version of system. Mechanism functions like combination of robotic gripper and nut runner; provides both secure grip and rotary actuation of other parts of system. Used in system in which no need to make or break electrical connections to payload during robotic installation or removal of payload. More complicated version needed to make and break electrical connections. Mechanism mounted in payload.

Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases.

PubMed

Nakayama, Hiroyuki; Otsu, Kinya

2018-03-06

Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection - termed sterile inflammation - is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP-AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases. © 2018 The Author(s).

Repeated cis-regulatory tuning of a metabolic bottleneck gene during evolution.

PubMed

Kuang, Meihua Christina; Kominek, Jacek; Alexander, William G; Cheng, Jan-Fang; Wrobel, Russell L; Hittinger, Chris Todd

2018-05-21

Repeated evolutionary events imply underlying genetic constraints that can make evolutionary mechanisms predictable. Morphological traits are thought to evolve frequently through cis-regulatory changes because these mechanisms bypass constraints in pleiotropic genes that are reused during development. In contrast, the constraints acting on metabolic traits during evolution are less well studied. Here we show how a metabolic bottleneck gene has repeatedly adopted similar cis-regulatory solutions during evolution, likely due to its pleiotropic role integrating flux from multiple metabolic pathways. Specifically, the genes encoding phosphoglucomutase activity (PGM1/PGM2), which connect GALactose catabolism to glycolysis, have gained and lost direct regulation by the transcription factor Gal4 several times during yeast evolution. Through targeted mutations of predicted Gal4-binding sites in yeast genomes, we show this galactose-mediated regulation of PGM1/2 supports vigorous growth on galactose in multiple yeast species, including Saccharomyces uvarum and Lachancea kluyveri. Furthermore, the addition of galactose-inducible PGM1 alone is sufficient to improve the growth on galactose of multiple species that lack this regulation, including Saccharomyces cerevisiae. The strong association between regulation of PGM1/2 by Gal4 even enables remarkably accurate predictions of galactose growth phenotypes between closely related species. This repeated mode of evolution suggests that this specific cis-regulatory connection is a common way that diverse yeasts can govern flux through the pathway, likely due to the constraints imposed by this pleiotropic bottleneck gene. Since metabolic pathways are highly interconnected, we argue that cis-regulatory evolution might be widespread at pleiotropic genes that control metabolic bottlenecks and intersections.

Multidrug resistance: prospects for clinical management.

PubMed

Mansouri, A; Henle, K J; Nagle, W A

1992-01-01

Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.

Ultra-accelerated natural sunlight exposure testing

DOEpatents

Jorgensen, Gary J.; Bingham, Carl; Goggin, Rita; Lewandowski, Allan A.; Netter, Judy C.

2000-06-13

Process and apparatus for providing ultra accelerated natural sunlight exposure testing of samples under controlled weathering without introducing unrealistic failure mechanisms in exposed materials and without breaking reciprocity relationships between flux exposure levels and cumulative dose that includes multiple concurrent levels of temperature and relative humidity at high levels of natural sunlight comprising: a) concentrating solar flux uniformly; b) directing the controlled uniform sunlight onto sample materials in a chamber enclosing multiple concurrent levels of temperature and relative humidity to allow the sample materials to be subjected to accelerated irradiance exposure factors for a sufficient period of time in days to provide a corresponding time of about at least a years worth of representative weathering of the sample materials.

Highly efficient multiple-layer CdS quantum dot sensitized III-V solar cells.

PubMed

Lin, Chien-Chung; Han, Hau-Vei; Chen, Hsin-Chu; Chen, Kuo-Ju; Tsai, Yu-Lin; Lin, Wein-Yi; Kuo, Hao-Chung; Yu, Peichen

2014-02-01

In this review, the concept of utilization of solar spectrum in order to increase the solar cell efficiency is discussed. Among the three mechanisms, down-shifting effect is investigated in detail. Organic dye, rare-earth minerals and quantum dots are three most popular down-shift materials. While the enhancement of solar cell efficiency was not clearly observed in the past, the advances in quantum dot fabrication have brought strong response out of the hybrid platform of a quantum dot solar cell. A multiple layer structure, including PDMS as the isolation layer, is proposed and demonstrated. With the help of pulse spray system, precise control can be achieved and the optimized concentration can be found.

Alternative splicing mechanisms orchestrating post-transcriptional gene expression: intron retention and the intron-rich genome of apicomplexan parasites.

PubMed

Lunghi, Matteo; Spano, Furio; Magini, Alessandro; Emiliani, Carla; Carruthers, Vern B; Di Cristina, Manlio

2016-02-01

Apicomplexan parasites including Toxoplasma gondii and Plasmodium species have complex life cycles that include multiple hosts and differentiation through several morphologically distinct stages requiring marked changes in gene expression. This review highlights emerging evidence implicating regulation of mRNA splicing as a mechanism to prime these parasites for rapid gene expression upon differentiation. We summarize the most important insights in alternative splicing including its role in regulating gene expression by decreasing mRNA abundance via 'Regulated Unproductive Splicing and Translation'. As a related but less well-understood mechanism, we discuss also our recent work suggesting a role for intron retention for precluding translation of stage specific isoforms of T. gondii glycolytic enzymes. We additionally provide new evidence that intron retention might be a widespread mechanism during parasite differentiation. Supporting this notion, recent genome-wide analysis of Toxoplasma and Plasmodium suggests intron retention is more pervasive than heretofore thought. These findings parallel recent emergence of intron retention being more prevalent in mammals than previously believed, thereby adding to the established roles in plants, fungi and unicellular eukaryotes. Deeper mechanistic studies of intron retention will provide important insight into its role in regulating gene expression in apicomplexan parasites and more general in eukaryotic organisms.

Mechanisms of termination and prevention of atrial fibrillation by drug therapy

PubMed Central

Workman, AJ; Smith, GL; Rankin, AC

2011-01-01

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. PMID:21334377

Principle, design and validation of a power-generated magnetorheological energy absorber with velocity self-sensing capability

NASA Astrophysics Data System (ADS)

Bai, Xian-Xu; Zhong, Wei-Min; Zou, Qi; Zhu, An-Ding; Sun, Jun

2018-07-01

Based on the structural design concept of ‘functional integration’, this paper proposes the principle of a power-generated magnetorheological energy absorber with velocity self-sensing capability (PGMREA), which realizes the integration of controllable damping mechanism and mechanical energy-electrical energy conversion mechanism in structure profile and multiple functions in function profile, including controllable damping, power generation and velocity self-sensing. The controllable damping mechanism consists of an annular gap and a ball screw. The annular gap fulfilled with MR fluid that operates in pure shear mode under controllable electromagnetic field. The rotational damping torque generated from the controllable damping mechanism is translated to a linear damping force via the ball screw. The mechanical energy-electrical energy conversion mechanism is realized by the ball screw and a generator composed of a permanent magnet rotor and a generator stator. The ball screw based mechanical energy-electrical energy conversion mechanism converts the mechanical energy of excitations to electrical energy for storage or directly to power the controllable damping mechanism of the PGMREA. The velocity self-sensing capability of the PGMREA is achieved via signal processing using the mechanical energy-electrical energy conversion information. Based on the principle of the proposed PGMREA, the mathematical model of the PGMREA is established, including the damping force, generated power and self-sensing velocity. The electromagnetic circuit of the PGMREA is simulated and verified via a finite element analysis software ANSYS. The developed PGMREA prototype is experimentally tested on a servo-hydraulic testing system. The model-based predicted results and the experimental results are compared and analyzed.

A soft and dexterous motor

NASA Astrophysics Data System (ADS)

Anderson, Iain A.; Tse, Tony Chun Hin; Inamura, Tokushu; O'Brien, Benjamin M.; McKay, Thomas; Gisby, Todd

2011-03-01

We present a soft, bearing-free artificial muscle motor that cannot only turn a shaft but also grip and reposition it through a flexible gear. The bearing-free operation provides a foundation for low complexity soft machines, with multiple degree-of-freedom actuation, that can act simultaneously as motors and manipulators. The mechanism also enables an artificial muscle controlled gear change. Future work will include self-sensing feedback for precision, multidegree-of-freedom operation.

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties.

PubMed

Dulla, Balakrishna; Kirla, Krishna Tulasi; Rathore, Vandana; Deora, Girdhar Singh; Kavela, Sridhar; Maddika, Subbareddy; Chatti, Kiranam; Reiser, Oliver; Iqbal, Javed; Pal, Manojit

2013-05-21

A series of functionalized phenyl oxazole derivatives was designed, synthesized and screened in vitro for their activities against LSD1 and for effects on viability of cervical and breast cancer cells, and in vivo for effects using zebrafish embryos. These compounds are likely to act via multiple epigenetic mechanisms specific to cancer cells including LSD1 inhibition.

Neurocomputation by Reaction Diffusion

NASA Astrophysics Data System (ADS)

Liang, Ping

1995-08-01

This Letter demonstrates the possible role nonsynaptic diffusion neurotransmission may play in neurocomputation using an artificial neural network model. A reaction-diffusion neural network model with field-based information-processing mechanisms is proposed. The advantages of nonsynaptic field neurotransmission from a computational viewpoint demonstrated in this Letter include long-range inhibition using only local interaction, nonhardwired and changeable (target specific) long-range communication pathways, and multiple simultaneous spatiotemporal organization processes in the same medium.

The Belmont Forum - Facilitating International Collaboration through New Funding Opportunities

NASA Astrophysics Data System (ADS)

von Schneidemesser, E.

2012-12-01

The Belmont Forum is an international group of the world's main funders of environmental change research and international science councils, committed to 'delivering knowledge needed for action to avoid and adapt to detrimental environmental change, including extreme hazardous events.' It aims to do so by mobilizing international resources at a scale that matches this challenge 'in order to catalyze delivery of the environmental science-derived solutions that society needs.' To achieve this goal, the member countries of the Belmont Forum have formed a new working partnership that launched the International Opportunities Fund (IOF) - an open call for proposals with focus themes and the intention of new themes for a new funding round each year. The IOF effectively lowers the activation energy needed for international collaboration while preserving national control over funding monies that stay within borders. This mechanism enables international collaboration to tackle global problems, while removing barriers such as the uncertainty of multiple proposal review processes for funding when partners from multiple countries wish to collaborate. During this presentation, perspectives on the Belmont Forum process will be shared, including the development of research themes for the IOF calls, mechanisms for collaboration, methods of information dissemination to various communities, lessons learned, and plans for future cooperation.

Development of a Whole-Body Haptic Sensor with Multiple Supporting Points and Its Application to a Manipulator

NASA Astrophysics Data System (ADS)

Hanyu, Ryosuke; Tsuji, Toshiaki

This paper proposes a whole-body haptic sensing system that has multiple supporting points between the body frame and the end-effector. The system consists of an end-effector and multiple force sensors. Using this mechanism, the position of a contact force on the surface can be calculated without any sensor array. A haptic sensing system with a single supporting point structure has previously been developed by the present authors. However, the system has drawbacks such as low stiffness and low strength. Therefore, in this study, a mechanism with multiple supporting points was proposed and its performance was verified. In this paper, the basic concept of the mechanism is first introduced. Next, an evaluation of the proposed method, performed by conducting some experiments, is presented.

A first principles calculation and statistical mechanics modeling of defects in Al-H system

NASA Astrophysics Data System (ADS)

Ji, Min; Wang, Cai-Zhuang; Ho, Kai-Ming

2007-03-01

The behavior of defects and hydrogen in Al was investigated by first principles calculations and statistical mechanics modeling. The formation energy of different defects in Al+H system such as Al vacancy, H in institution and multiple H in Al vacancy were calculated by first principles method. Defect concentration in thermodynamical equilibrium was studied by total free energy calculation including configuration entropy and defect-defect interaction from low concentration limit to hydride limit. In our grand canonical ensemble model, hydrogen chemical potential under different environment plays an important role in determing the defect concentration and properties in Al-H system.

Wilms' tumour 1 (WT1) in development, homeostasis and disease.

PubMed

Hastie, Nicholas D

2017-08-15

The study of genes mutated in human disease often leads to new insights into biology as well as disease mechanisms. One such gene is Wilms' tumour 1 ( WT1 ), which plays multiple roles in development, tissue homeostasis and disease. In this Primer, I summarise how this multifaceted gene functions in various mammalian tissues and organs, including the kidney, gonads, heart and nervous system. This is followed by a discussion of our current understanding of the molecular mechanisms by which WT1 and its two major isoforms regulate these processes at the transcriptional and post-transcriptional levels. © 2017. Published by The Company of Biologists Ltd.

From Fibrils to Toughness: Multi-Scale Mechanics of Fibrillating Interfaces in Stretchable Electronics

PubMed Central

van der Sluis, Olaf; Vossen, Bart; Geers, Marc

2018-01-01

Metal-elastomer interfacial systems, often encountered in stretchable electronics, demonstrate remarkably high interface fracture toughness values. Evidently, a large gap exists between the rather small adhesion energy levels at the microscopic scale (‘intrinsic adhesion’) and the large measured macroscopic work-of-separation. This energy gap is closed here by unravelling the underlying dissipative mechanisms through a systematic numerical/experimental multi-scale approach. This self-containing contribution collects and reviews previously published results and addresses the remaining open questions by providing new and independent results obtained from an alternative experimental set-up. In particular, the experimental studies on Cu-PDMS (Poly(dimethylsiloxane)) samples conclusively reveal the essential role of fibrillation mechanisms at the micro-meter scale during the metal-elastomer delamination process. The micro-scale numerical analyses on single and multiple fibrils show that the dynamic release of the stored elastic energy by multiple fibril fracture, including the interaction with the adjacent deforming bulk PDMS and its highly nonlinear behaviour, provide a mechanistic understanding of the high work-of-separation. An experimentally validated quantitative relation between the macroscopic work-of-separation and peel front height is established from the simulation results. Finally, it is shown that a micro-mechanically motivated shape of the traction-separation law in cohesive zone models is essential to describe the delamination process in fibrillating metal-elastomer systems in a physically meaningful way. PMID:29393908

Possible designs of medication monitors. Final report

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

Moulding, T.S.

A medication monitor is a device which utilizes radioactive material and photographic film to determine when patients remove medication from a dispenser. The material presents multiple, largely mechanical, ideas for making this type of dispenser so it can be used for a wide range of medication regimens. The description includes using the idea of a digital clock and memory chips for the time recording system. It also includes details on (1) choice of radioactive source and method of sealing source, (2) methods of locking or sealing medication monitors, (3) detailed instructions for using existing devices, (4) a simplified film developmentmore » system, (5) a mechanical and electronic means for creating a dispenser to reduce the chance of suicidal overdosage, and (6) an electronic means to allow a patient to compensate for medication forgotten without taking an excessive dose of medication.« less

Numerical Modeling, Thermomechanical Testing, and NDE Procedures for Prediction of Microcracking Induced Permeability of Cryogenic Composites

NASA Technical Reports Server (NTRS)

Noh, Jae; Whitcomb, John; Oh, Bongtaek; Lagoudas, Dimitris; Maslov, Konstatin; Ganpatyre, Atul; Kinra, Vikram

2003-01-01

Reusable Space Vehicles will include light cryogenic composite fuel tanks that must not leak excessively even after multiple launches. Damage in cryogenic composite fuel tanks induced during manufacturing and advanced by thermomechanical cycling can accelerate leakage of the propellant. Whether the leakage exceeds tolerable levels depends on many factors, including pressure gradients, microcrack density, other damage such as delamination, connectivity of the cracks, residual stresses from manufacture, service-induced stresses from thermal and mechanical loads, and composite lay-up. Although it is critical to experimentally characterize permeability during various thermal and mechanical load histories, optimal design depends on having analytical models that can predict the effect of various parameters on performance. Our broad goal is to develop such models that are experimentally validated by destructive and non-destructive evaluation means.

Initial genome sequencing and analysis of multiple myeloma

PubMed Central

Chapman, Michael A.; Lawrence, Michael S.; Keats, Jonathan J.; Cibulskis, Kristian; Sougnez, Carrie; Schinzel, Anna C.; Harview, Christina L.; Brunet, Jean-Philippe; Ahmann, Gregory J.; Adli, Mazhar; Anderson, Kenneth C.; Ardlie, Kristin G.; Auclair, Daniel; Baker, Angela; Bergsagel, P. Leif; Bernstein, Bradley E.; Drier, Yotam; Fonseca, Rafael; Gabriel, Stacey B.; Hofmeister, Craig C.; Jagannath, Sundar; Jakubowiak, Andrzej J.; Krishnan, Amrita; Levy, Joan; Liefeld, Ted; Lonial, Sagar; Mahan, Scott; Mfuko, Bunmi; Monti, Stefano; Perkins, Louise M.; Onofrio, Robb; Pugh, Trevor J.; Vincent Rajkumar, S.; Ramos, Alex H.; Siegel, David S.; Sivachenko, Andrey; Trudel, Suzanne; Vij, Ravi; Voet, Douglas; Winckler, Wendy; Zimmerman, Todd; Carpten, John; Trent, Jeff; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.

2013-01-01

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. PMID:21430775

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

PubMed

Dadhania, Vivekkumar P; Trivedi, Priyanka P; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight

PubMed Central

Dadhania, Vivekkumar P.; Trivedi, Priyanka P.; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways. PMID:26725888

A space-frequency multiplicative regularization for force reconstruction problems

NASA Astrophysics Data System (ADS)

Aucejo, M.; De Smet, O.

2018-05-01

Dynamic forces reconstruction from vibration data is an ill-posed inverse problem. A standard approach to stabilize the reconstruction consists in using some prior information on the quantities to identify. This is generally done by including in the formulation of the inverse problem a regularization term as an additive or a multiplicative constraint. In the present article, a space-frequency multiplicative regularization is developed to identify mechanical forces acting on a structure. The proposed regularization strategy takes advantage of one's prior knowledge of the nature and the location of excitation sources, as well as that of their spectral contents. Furthermore, it has the merit to be free from the preliminary definition of any regularization parameter. The validity of the proposed regularization procedure is assessed numerically and experimentally. It is more particularly pointed out that properly exploiting the space-frequency characteristics of the excitation field to identify can improve the quality of the force reconstruction.

Noncoding Subgenomic Flavivirus RNA: Multiple Functions in West Nile Virus Pathogenesis and Modulation of Host Responses

PubMed Central

Roby, Justin A.; Pijlman, Gorben P.; Wilusz, Jeffrey; Khromykh, Alexander A.

2014-01-01

Flaviviruses are a large group of positive strand RNA viruses transmitted by arthropods that include many human pathogens such as West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus, dengue virus, and tick-borne encephalitis virus. All members in this genus tested so far are shown to produce a unique subgenomic flavivirus RNA (sfRNA) derived from the 3' untranslated region (UTR). sfRNA is a product of incomplete degradation of genomic RNA by the cell 5'–3' exoribonuclease XRN1 which stalls at highly ordered secondary RNA structures at the beginning of the 3'UTR. Generation of sfRNA results in inhibition of XRN1 activity leading to an increase in stability of many cellular mRNAs. Mutant WNV deficient in sfRNA generation was highly attenuated displaying a marked decrease in cytopathicity in cells and pathogenicity in mice. sfRNA has also been shown to inhibit the antiviral activity of IFN-α/β by yet unknown mechanism and of the RNAi pathway by likely serving as a decoy substrate for Dicer. Thus, sfRNA is involved in modulating multiple cellular pathways to facilitate viral pathogenicity; however the overlying mechanism linking all these multiple functions of sfRNA remains to be elucidated. PMID:24473339

New developments in the treatment of multiple myeloma - clinical utility of daratumumab.

PubMed

McEllistrim, Cian; Krawczyk, Janusz; O'Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups.

New developments in the treatment of multiple myeloma – clinical utility of daratumumab

PubMed Central

McEllistrim, Cian; Krawczyk, Janusz; O’Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups. PMID:28442888

Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis.

PubMed

Heidker, Rebecca M; Emerson, Mitchell R; LeVine, Steven M

2017-08-01

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc . Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g. , oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g. , ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

Efficient Assignment of Multiple E-MBMS Sessions towards LTE

NASA Astrophysics Data System (ADS)

Alexiou, Antonios; Bouras, Christos; Kokkinos, Vasileios

One of the major prerequisites for Long Term Evolution (LTE) networks is the mass provision of multimedia services to mobile users. To this end, Evolved - Multimedia Broadcast/Multicast Service (E-MBMS) is envisaged to play an instrumental role during LTE standardization process and ensure LTE’s proliferation in mobile market. E-MBMS targets at the economic delivery, in terms of power and spectral efficiency, of multimedia data from a single source entity to multiple destinations. This paper proposes a novel mechanism for efficient radio bearer selection during E-MBMS transmissions in LTE networks. The proposed mechanism is based on the concept of transport channels combination in any cell of the network. Most significantly, the mechanism manages to efficiently deliver multiple E-MBMS sessions. The performance of the proposed mechanism is evaluated and compared with several radio bearer selection mechanisms in order to highlight the enhancements that it provides.

Theory of chromatic noise masking applied to testing linearity of S-cone detection mechanisms.

PubMed

Giulianini, Franco; Eskew, Rhea T

2007-09-01

A method for testing the linearity of cone combination of chromatic detection mechanisms is applied to S-cone detection. This approach uses the concept of mechanism noise, the noise as seen by a postreceptoral neural mechanism, to represent the effects of superposing chromatic noise components in elevating thresholds and leads to a parameter-free prediction for a linear mechanism. The method also provides a test for the presence of multiple linear detectors and off-axis looking. No evidence for multiple linear mechanisms was found when using either S-cone increment or decrement tests. The results for both S-cone test polarities demonstrate that these mechanisms combine their cone inputs nonlinearly.

Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure

PubMed Central

Kubicek-Sutherland, Jessica Z.; Heithoff, Douglas M.; Ersoy, Selvi C.; Shimp, William R.; House, John K.; Marth, Jamey D.; Smith, Jeffrey W.; Mahan, Michael J.

2015-01-01

Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host–pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies. PMID:26501114

Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

PubMed

Kubicek-Sutherland, Jessica Z; Heithoff, Douglas M; Ersoy, Selvi C; Shimp, William R; House, John K; Marth, Jamey D; Smith, Jeffrey W; Mahan, Michael J

2015-09-01

Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

The Role of Inhibition in Avoiding Distraction by Salient Stimuli.

PubMed

Gaspelin, Nicholas; Luck, Steven J

2018-01-01

Researchers have long debated whether salient stimuli can involuntarily 'capture' visual attention. We review here evidence for a recently discovered inhibitory mechanism that may help to resolve this debate. This evidence suggests that salient stimuli naturally attempt to capture attention, but capture can be avoided if the salient stimulus is suppressed before it captures attention. Importantly, the suppression process can be more or less effective as a result of changing task demands or lapses in cognitive control. Converging evidence for the existence of this suppression mechanism comes from multiple sources, including psychophysics, eye-tracking, and event-related potentials (ERPs). We conclude that the evidence for suppression is strong, but future research will need to explore the nature and limits of this mechanism. Copyright © 2017 Elsevier Ltd. All rights reserved.

3D-printing and mechanics of bio-inspired articulated and multi-material structures.

PubMed

Porter, Michael M; Ravikumar, Nakul; Barthelat, Francois; Martini, Roberto

2017-09-01

3D-printing technologies allow researchers to build simplified physical models of complex biological systems to more easily investigate their mechanics. In recent years, a number of 3D-printed structures inspired by the dermal armors of various fishes have been developed to study their multiple mechanical functionalities, including flexible protection, improved hydrodynamics, body support, or tail prehensility. Natural fish armors are generally classified according to their shape, material and structural properties as elasmoid scales, ganoid scales, placoid scales, carapace scutes, or bony plates. Each type of dermal armor forms distinct articulation patterns that facilitate different functional advantages. In this paper, we highlight recent studies that developed 3D-printed structures not only to inform the design and application of some articulated and multi-material structures, but also to explain the mechanics of the natural biological systems they mimic. Copyright © 2017 Elsevier Ltd. All rights reserved.

Plastic deformation mechanisms in polyimide resins and their semi-interpenetrating networks

NASA Technical Reports Server (NTRS)

Jang, Bor Z.

1990-01-01

High-performance thermoset resins and composites are critical to the future growth of space, aircraft, and defense industries in the USA. However, the processing-structure-property relationships in these materials remain poorly understood. In the present ASEE/NASA Summer Research Program, the plastic deformation modes and toughening mechanisms in single-phase and multiphase thermoset resins were investigated. Both thermoplastic and thermoset polyimide resins and their interpenetrating networks (IPNs and semi-IPNs) were included. The fundamental tendency to undergo strain localization (crazing and shear banding) as opposed to a more diffuse (or homogeneous) deformation in these polymers were evaluated. Other possible toughening mechanisms in multiphase thermoset resins were also examined. The topological features of network chain configuration/conformation and the multiplicity of phase morphology in INPs and semi-IPNs provide unprecedented opportunities for studying the toughening mechanisms in multiphase thermoset polymers and their fiber composites.

Elevated-CO2 Response of Stomata and Its Dependence on Environmental Factors

PubMed Central

Xu, Zhenzhu; Jiang, Yanling; Jia, Bingrui; Zhou, Guangsheng

2016-01-01

Stomata control the flow of gases between plants and the atmosphere. This review is centered on stomatal responses to elevated CO2 concentration and considers other key environmental factors and underlying mechanisms at multiple levels. First, an outline of general responses in stomatal conductance under elevated CO2 is presented. Second, stomatal density response, its development, and the trade-off with leaf growth under elevated CO2 conditions are depicted. Third, the molecular mechanism regulating guard cell movement at elevated CO2 is suggested. Finally, the interactive effects of elevated CO2 with other factors critical to stomatal behavior are reviewed. It may be useful to better understand how stomata respond to elevated CO2 levels while considering other key environmental factors and mechanisms, including molecular mechanism, biochemical processes, and ecophysiological regulation. This understanding may provide profound new insights into how plants cope with climate change. PMID:27242858

Genes and signaling pathways involved in memory enhancement in mutant mice

PubMed Central

2014-01-01

Mutant mice have been used successfully as a tool for investigating the mechanisms of memory at multiple levels, from genes to behavior. In most cases, manipulating a gene expressed in the brain impairs cognitive functions such as memory and their underlying cellular mechanisms, including synaptic plasticity. However, a remarkable number of mutations have been shown to enhance memory in mice. Understanding how to improve a system provides valuable insights into how the system works under normal conditions, because this involves understanding what the crucial components are. Therefore, more can be learned about the basic mechanisms of memory by studying mutant mice with enhanced memory. This review will summarize the genes and signaling pathways that are altered in the mutants with enhanced memory, as well as their roles in synaptic plasticity. Finally, I will discuss how knowledge of memory-enhancing mechanisms could be used to develop treatments for cognitive disorders associated with impaired plasticity. PMID:24894914

Plasmid-mediated quinolone resistance: Two decades on.

PubMed

Rodríguez-Martínez, José Manuel; Machuca, Jesús; Cano, María Eliecer; Calvo, Jorge; Martínez-Martínez, Luis; Pascual, Alvaro

2016-11-01

After two decades of the discovery of plasmid-mediated quinolone resistance (PMQR), three different mechanisms have been associated to this phenomenon: target protection (Qnr proteins, including several families with multiple alleles), active efflux pumps (mainly QepA and OqxAB pumps) and drug modification [AAC(6')-Ib-cr acetyltransferase]. PMQR genes are usually associated with mobile or transposable elements on plasmids, and, in the case of qnr genes, are often incorporated into sul1-type integrons. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. Although the three PMQR mechanisms alone cause only low-level resistance to quinolones, they can complement other mechanisms of chromosomal resistance to reach clinical resistance level and facilitate the selection of higher-level resistance, raising a threat to the treatment of infections by microorganisms that host these mechanisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coagulation and complement system in critically ill patients.

PubMed

Helling, H; Stephan, B; Pindur, G

2015-01-01

Activation of coagulation and inflammatory response including the complement system play a major role in the pathogenesis of critical illness. However, only limited data are available addressing the relationship of both pathways and its assessment of a predictive value for the clinical outcome in intense care medicine. Therefore, parameters of the coagulation and complement system were studied in patients with septicaemia and multiple trauma regarded as being exemplary for critical illness. 34 patients (mean age: 51.38 years (±16.57), 15 females, 19 males) were investigated at day 1 of admittance to the intensive care unit (ICU). Leukocytes, complement factors C3a and C5a were significantly (p <  0.0500) higher in sepsis than in trauma, whereas platelet count and plasma fibrinogen were significantly lower in multiple trauma. Activation markers of coagulation were elevated in both groups, however, thrombin-antithrombin-complex was significantly higher in multiple trauma. DIC scores of 5 were not exceeded in any of the two groups. Analysing the influences on mortality (11/34; 32.35% ), which was not different in both groups, non-survivors were significantly older, had significantly higher multiple organ failure (MOF) scores, lactate, abnormal prothrombin times and lower C1-inhibitor activities, even more pronounced in early deaths, than survivors. In septic non-survivors protein C was significantly lower than in trauma. We conclude from these data that activation of the complement system as part of the inflammatory response is a significant mechanism in septicaemia, whereas loss and consumption of blood components including parts of the coagulation and complement system is more characteristic for multiple trauma. Protein C in case of severe reduction might be of special concern for surviving in sepsis. Activation of haemostasis was occurring in both diseases, however, overt DIC was not confirmed in this study to be a leading mechanism in critically ill patients. MOF score, lactate, C1-inhibitor and prothrombin time have been the only statistically significant predictors for lethal outcome suggesting that organ function, microcirculation, haemostasis and inflammatory response are essential elements of the pathomechanism and clinical course of diseases among critically ill patients.

Omega-3 fatty acids and dementia

PubMed Central

Cole, Greg M.; Ma, Qiu-Lan; Frautschy, Sally A.

2014-01-01

More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid β peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Aβ, including two major kinases that phosphorylate the microtubule associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline—with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants. PMID:19523795

Multiplicity of mechanisms govern efficacy of anaerobic soil disinfestation for soil-borne disease control

USDA-ARS?s Scientific Manuscript database

Studies demonstrated that carbon input type influenced control of various fungi, oomycetes and plant parasitic nematodes with anaerobic soil disinfestation (ASD). Findings implicated multiple mechanisms may contribute to the overall level of disease control attained. In strawberry field trials, ASD ...

DNA Damage Repair and the Emerging Role of Poly(ADP-ribose) Polymerase Inhibition in Cancer Therapeutics.

PubMed

Rabenau, Karen; Hofstatter, Erin

2016-07-01

As a result of improved understanding of DNA repair mechanisms, poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly recognized to play an important therapeutic role in the treatment of cancer. The aim of this article is to provide a review of PARPi function in DNA damage repair and synthetic lethality and to demonstrate how these mechanisms can be exploited to provide new PARPi-based therapies to patients with solid tumors. Literature from a range of sources, including PubMed and MEDLINE, were searched to identify recent reports regarding DNA damage repair and PARPi. DNA damage repair is central to cellular viability. The family of poly(ADP-ribose) polymerase proteins play multiple intracellular roles in DNA repair, but function primarily in the resolution of repair of single-strand DNA breaks. Insights through the discovery of germline BRCA1/2 mutations led to the understanding of synthetic lethality and the potential therapeutic role of PARPi in the treatment of cancer. Further understanding of DNA damage repair and the concept of BRCA-like tumors have catalyzed PARPi clinical investigation in multiple oncologic settings. PARPi hold great promise in the treatment of solid tumors, both as monotherapy and in combination with other cancer therapeutics. Multiple PARPi clinical trials are currently underway. Further understanding of aberrant DNA repair mechanisms in the germline and in the tumor genome will allow clinicians and researchers to apply PARPi most strategically in the era of personalized medicine. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Resistance of the Extreme Halophile Halobacterium sp. NRC-1 to Multiple Stresses

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

Gygli, Patrick E.; Prajapati, Surendra; DeVeaux, Linda C.

2009-03-10

The model Archaeon Halobacterium sp. NRC-1 is an extreme halophile known for its resistance to multiple stressors, including electron-beam and ultraviolet radiation. It is a well-developed system with a completely sequenced genome and extensive post-genomic tools for the study of a variety of biological processes. To further understand the mechanisms of Halobacterium's, radiation resistance, we previously reported the selection for multiple independent highly resistant mutants using repeated exposure to high doses of 18-20 MeV electrons using a medical S-band Linac. Molecular analysis of the transcriptional profile of several of these mutants revealed a single common change: upregulation of the rfa3more » operon. These genes encode proteins homologous to the subunits of eukaryotic Replication Protein A (RPA), a DNA binding protein with major roles in DNA replication, recombination, and repair. This operon has also been implicated in a somewhat lesser role in resistance of wild type Halobacterium to ultraviolet radiation, suggesting common mechanisms for resistance. To further understand the mechanism of radiation resistance in the mutant strains, we measured the survival after exposure to both electron-beam and ultraviolet radiation, UV-A, B, and C All mutant strains showed increased resistance to electrons when compared with the parent. However, the mutant strains do not display increased UV resistance, and in one case is more sensitive than the parent strain. Thus, the protective role of increased RPA expression within a cell may be specific to the DNA damage caused by the different physical effects induced by high energy electron-beam radiation.« less

A service brokering and recommendation mechanism for better selecting cloud services.

PubMed

Gui, Zhipeng; Yang, Chaowei; Xia, Jizhe; Huang, Qunying; Liu, Kai; Li, Zhenlong; Yu, Manzhu; Sun, Min; Zhou, Nanyin; Jin, Baoxuan

2014-01-01

Cloud computing is becoming the new generation computing infrastructure, and many cloud vendors provide different types of cloud services. How to choose the best cloud services for specific applications is very challenging. Addressing this challenge requires balancing multiple factors, such as business demands, technologies, policies and preferences in addition to the computing requirements. This paper recommends a mechanism for selecting the best public cloud service at the levels of Infrastructure as a Service (IaaS) and Platform as a Service (PaaS). A systematic framework and associated workflow include cloud service filtration, solution generation, evaluation, and selection of public cloud services. Specifically, we propose the following: a hierarchical information model for integrating heterogeneous cloud information from different providers and a corresponding cloud information collecting mechanism; a cloud service classification model for categorizing and filtering cloud services and an application requirement schema for providing rules for creating application-specific configuration solutions; and a preference-aware solution evaluation mode for evaluating and recommending solutions according to the preferences of application providers. To test the proposed framework and methodologies, a cloud service advisory tool prototype was developed after which relevant experiments were conducted. The results show that the proposed system collects/updates/records the cloud information from multiple mainstream public cloud services in real-time, generates feasible cloud configuration solutions according to user specifications and acceptable cost predication, assesses solutions from multiple aspects (e.g., computing capability, potential cost and Service Level Agreement, SLA) and offers rational recommendations based on user preferences and practical cloud provisioning; and visually presents and compares solutions through an interactive web Graphical User Interface (GUI).

The ASYMMETRIC LEAVES Complex Employs Multiple Modes of Regulation to Affect Adaxial-Abaxial Patterning and Leaf Complexity[OPEN

PubMed Central

Husbands, Aman Y.; Benkovics, Anna H.; Nogueira, Fabio T.S.; Lodha, Mukesh; Timmermans, Marja C.P.

2015-01-01

Flattened leaf architecture is not a default state but depends on positional information to precisely coordinate patterns of cell division in the growing primordium. This information is provided, in part, by the boundary between the adaxial (top) and abaxial (bottom) domains of the leaf, which are specified via an intricate gene regulatory network whose precise circuitry remains poorly defined. Here, we examined the contribution of the ASYMMETRIC LEAVES (AS) pathway to adaxial-abaxial patterning in Arabidopsis thaliana and demonstrate that AS1-AS2 affects this process via multiple, distinct regulatory mechanisms. AS1-AS2 uses Polycomb-dependent and -independent mechanisms to directly repress the abaxial determinants MIR166A, YABBY5, and AUXIN RESPONSE FACTOR3 (ARF3), as well as a nonrepressive mechanism in the regulation of the adaxial determinant TAS3A. These regulatory interactions, together with data from prior studies, lead to a model in which the sequential polarization of determinants, including AS1-AS2, explains the establishment and maintenance of adaxial-abaxial leaf polarity. Moreover, our analyses show that the shared repression of ARF3 by the AS and trans-acting small interfering RNA (ta-siRNA) pathways intersects with additional AS1-AS2 targets to affect multiple nodes in leaf development, impacting polarity as well as leaf complexity. These data illustrate the surprisingly multifaceted contribution of AS1-AS2 to leaf development showing that, in conjunction with the ta-siRNA pathway, AS1-AS2 keeps the Arabidopsis leaf both flat and simple. PMID:26589551

Nrf2 and Nrf2-Related Proteins in Development and Developmental Toxicity: Insights from studies in Zebrafish (Danio rerio)

PubMed Central

Hahn, Mark E.; Timme-Laragy, Alicia R.; Karchner, Sibel I.; Stegeman, John J.

2015-01-01

Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap’n’collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects. PMID:26130508

Emergence of the interplay between hierarchy and contact splitting in biological adhesion highlighted through a hierarchical shear lag model.

PubMed

Brely, Lucas; Bosia, Federico; Pugno, Nicola M

2018-06-20

Contact unit size reduction is a widely studied mechanism as a means to improve adhesion in natural fibrillar systems, such as those observed in beetles or geckos. However, these animals also display complex structural features in the way the contact is subdivided in a hierarchical manner. Here, we study the influence of hierarchical fibrillar architectures on the load distribution over the contact elements of the adhesive system, and the corresponding delamination behaviour. We present an analytical model to derive the load distribution in a fibrillar system loaded in shear, including hierarchical splitting of contacts, i.e. a "hierarchical shear-lag" model that generalizes the well-known shear-lag model used in mechanics. The influence on the detachment process is investigated introducing a numerical procedure that allows the derivation of the maximum delamination force as a function of the considered geometry, including statistical variability of local adhesive energy. Our study suggests that contact splitting generates improved adhesion only in the ideal case of extremely compliant contacts. In real cases, to produce efficient adhesive performance, contact splitting needs to be coupled with hierarchical architectures to counterbalance high load concentrations resulting from contact unit size reduction, generating multiple delamination fronts and helping to avoid detrimental non-uniform load distributions. We show that these results can be summarized in a generalized adhesion scaling scheme for hierarchical structures, proving the beneficial effect of multiple hierarchical levels. The model can thus be used to predict the adhesive performance of hierarchical adhesive structures, as well as the mechanical behaviour of composite materials with hierarchical reinforcements.

Numerical solution of fractured horizontal wells in shale gas reservoirs considering multiple transport mechanisms

NASA Astrophysics Data System (ADS)

Zhao, Yu-long; Tang, Xu-chuan; Zhang, Lie-hui; Tang, Hong-ming; Tao, Zheng-Wu

2018-06-01

The multiscale pore size and specific gas storage mechanism in organic-rich shale gas reservoirs make gas transport in such reservoirs complicated. Therefore, a model that fully incorporates all transport mechanisms and employs an accurate numerical method is urgently needed to simulate the gas production process. In this paper, a unified model of apparent permeability was first developed, which took into account multiple influential factors including slip flow, Knudsen diffusion (KD), surface diffusion, effects of the adsorbed layer, permeability stress sensitivity, and ad-/desorption phenomena. Subsequently, a comprehensive mathematical model, which included the model of apparent permeability, was derived to describe gas production behaviors. Thereafter, on the basis of unstructured perpendicular bisection grids and finite volume method, a fully implicit numerical simulator was developed using Matlab software. The validation and application of the new model were confirmed using a field case reported in the literature. Finally, the impacts of related influencing factors on gas production were analyzed. The results showed that KD resulted in a negligible impact on gas production in the proposed model. The smaller the pore size was, the more obvious the effects of the adsorbed layer on the well production rate would be. Permeability stress sensitivity had a slight effect on well cumulative production in shale gas reservoirs. Adsorbed gas made a major contribution to the later flow period of the well; the greater the adsorbed gas content, the greater the well production rate would be. This paper can improve the understanding of gas production in shale gas reservoirs for petroleum engineers.

Efficient Exploration of Membrane-Associated Phenomena at Atomic Resolution.

PubMed

Vermaas, Josh V; Baylon, Javier L; Arcario, Mark J; Muller, Melanie P; Wu, Zhe; Pogorelov, Taras V; Tajkhorshid, Emad

2015-06-01

Biological membranes constitute a critical component in all living cells. In addition to providing a conducive environment to a wide range of cellular processes, including transport and signaling, mounting evidence has established active participation of specific lipids in modulating membrane protein function through various mechanisms. Understanding lipid-protein interactions underlying these mechanisms at a sufficiently high resolution has proven extremely challenging, partly due to the semi-fluid nature of the membrane. In order to address this challenge computationally, multiple methods have been developed, including an alternative membrane representation termed highly mobile membrane mimetic (HMMM) in which lateral lipid diffusion has been significantly enhanced without compromising atomic details. The model allows for efficient sampling of lipid-protein interactions at atomic resolution, thereby significantly enhancing the effectiveness of molecular dynamics simulations in capturing membrane-associated phenomena. In this review, after providing an overview of HMMM model development, we will describe briefly successful application of the model to study a variety of membrane processes, including lipid-dependent binding and insertion of peripheral proteins, the mechanism of phospholipid insertion into lipid bilayers, and characterization of optimal tilt angle of transmembrane helices. We conclude with practical recommendations for proper usage of the model in simulation studies of membrane processes.

Immunotherapeutics in Pediatric Autoimmune Central Nervous System Disease: Agents and Mechanisms.

PubMed

Nosadini, Margherita; Sartori, Stefano; Sharma, Suvasini; Dale, Russell C

2017-08-01

Beyond the major advances produced by careful clinical-radiological phenotyping and biomarker development in autoimmune central nervous system disorders, a comprehensive knowledge of the range of available immune therapies and a deeper understanding of their action should benefit therapeutic decision-making. This review discusses the agents used in neuroimmunology and their mechanisms of action. First-line treatments typically include corticosteroids, intravenous immunoglobulin, and plasmapheresis, while for severe disease second-line "induction" agents such as rituximab or cyclophosphamide are used. Steroid-sparing agents such as mycophenolate, azathioprine, or methotrexate are often used in potentially relapsing or corticosteroid-dependent diseases. Lessons from adult neuroimmunology and rheumatology could be translated into pediatric autoimmune central nervous system disease in the future, including the potential utility of monoclonal antibodies targeting lymphocytes, adhesion molecules for lymphocytic migration, cytokines or their receptors, or complement. Finally, many agents used in other fields have multiple mechanisms of action, including immunomodulation, with potential usefulness in neuroimmunology, such as antibiotics, psychotropic drugs, probiotics, gut health, and ketogenic diet. All currently accepted and future potential agents have adverse effects, which can be severe; therefore, a "risk-versus-benefit" determination should guide therapeutic decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

Progressive Damage Modeling of Durable Bonded Joint Technology

NASA Technical Reports Server (NTRS)

Leone, Frank A.; Davila, Carlos G.; Lin, Shih-Yung; Smeltzer, Stan; Girolamo, Donato; Ghose, Sayata; Guzman, Juan C.; McCarville, Duglas A.

2013-01-01

The development of durable bonded joint technology for assembling composite structures for launch vehicles is being pursued for the U.S. Space Launch System. The present work is related to the development and application of progressive damage modeling techniques to bonded joint technology applicable to a wide range of sandwich structures for a Heavy Lift Launch Vehicle. The joint designs studied in this work include a conventional composite splice joint and a NASA-patented Durable Redundant Joint. Both designs involve a honeycomb sandwich with carbon/epoxy facesheets joined with adhesively bonded doublers. Progressive damage modeling allows for the prediction of the initiation and evolution of damage. For structures that include multiple materials, the number of potential failure mechanisms that must be considered increases the complexity of the analyses. Potential failure mechanisms include fiber fracture, matrix cracking, delamination, core crushing, adhesive failure, and their interactions. The joints were modeled using Abaqus parametric finite element models, in which damage was modeled with user-written subroutines. Each ply was meshed discretely, and layers of cohesive elements were used to account for delaminations and to model the adhesive layers. Good correlation with experimental results was achieved both in terms of load-displacement history and predicted failure mechanisms.

B cell biology: implications for treatment of systemic lupus erythematosus.

PubMed

Anolik, J H

2013-04-01

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Mechanisms of behavior modification in clinical behavioral medicine in China.

PubMed

Yang, Zhiyin; Su, Zhonghua; Ji, Feng; Zhu, Min; Bai, Bo

2014-08-01

Behavior modification, as the core of clinical behavioral medicine, is often used in clinical settings. We seek to summarize behavior modification techniques that are commonly used in clinical practice of behavioral medicine in China and discuss possible biobehavioral mechanisms. We reviewed common behavior modification techniques in clinical settings in China, and we reviewed studies that explored possible biobehavioral mechanisms. Commonly used clinical approaches of behavior modification in China include behavior therapy, cognitive therapy, cognitive-behavioral therapy, health education, behavior management, behavioral relaxation training, stress management intervention, desensitization therapy, biofeedback therapy, and music therapy. These techniques have been applied in the clinical treatment of a variety of diseases, such as chronic diseases, psychosomatic diseases, and psychological disorders. The biobehavioral mechanisms of these techniques involve the autonomic nervous system, neuroendocrine system, neurobiochemistry, and neuroplasticity. Behavior modification techniques are commonly used in the treatment of a variety of somatic and psychological disorders in China. Multiple biobehavioral mechanisms are involved in successful behavior modification.

Effects of the space flight environment on the immune system

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Butel, Janet S.; Shearer, William T.

2003-01-01

Space flight conditions have a dramatic effect on a variety of physiologic functions of mammals, including muscle, bone, and neurovestibular function. Among the physiological functions that are affected when humans or animals are exposed to space flight conditions is the immune response. The focus of this review is on the function of the immune system in space flight conditions during actual space flights, as well as in models of space flight conditions on the earth. The experiments were carried out in tissue culture systems, in animal models, and in human subjects. The results indicate that space flight conditions alter cell-mediated immune responses, including lymphocyte proliferation and subset distribution, and cytokine production. The mechanism(s) of space flight-induced alterations in immune system function remain(s) to be established. It is likely, however, that multiple factors, including microgravity, stress, neuroendocrine factors, sleep disruption, and nutritional factors, are involved in altering certain functions of the immune system. Such alterations could lead to compromised defenses against infections and tumors.

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

DOE PAGES

Liu, Shizhong; White, Michael G.; Liu, Ping

2018-01-25

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

Oxygen Reduction Reaction on Ag(111) in Alkaline Solution: A Combined Density Functional Theory and Kinetic Monte Carlo Study

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

Liu, Shizhong; White, Michael G.; Liu, Ping

We reported a detailed mechanistic study of the oxygen reduction reaction (ORR) on the model Ag(111) surface in alkaline solution by using density functional theory (DFT) and Kinetic Monte Carlo (KMC) simulations, in which multiple pathways involving either 2 e - or 4 e - mechanisms were included. The theoretical modelling presented here is able to reproduce the experimentally measured polarization curves in both low and high potential regions. An electrochemical 4 e - network including both a chemisorbed water (*H 2O)-mediated 4 e - associative pathway and the conventional associative pathway was identified to dominate the ORR mechanism. Onmore » the basis of the mechanistic understanding derived from these calculations, the ways to promote the ORR on Ag(111) were provided, including facilitating *OH removal, **O 2 reduction by *H 2O, and suppressing **O 2 desorption. Finally, the origin of the different ORR behaviors of Ag(111) and Pt(111) was also discussed in detail.« less

Incremental benefit of 3D transesophageal echocardiography: a case of a mass overlying a prosthetic mitral valve.

PubMed

Tauras, James M; Zhang, Zhihang; Taub, Cynthia C

2011-05-01

A young woman with a mechanical mitral valve and prosthetic mitral stenosis underwent multiple imaging modalities (including transthoracic ECHO, fluoroscopy, and two-dimensional transesophageal ECHO) to determine the cause of her stenosis. Only three-dimensional transesophageal echocardiography demonstrated the full size and extent of an obstructing mass on the strut and sewing ring of the prosthetic mitral valve. © 2011, Wiley Periodicals, Inc.

Review on antibacterial biocomposites of structural laminated veneer lumber

PubMed Central

Chen, Zi-xiang; Lei, Qiong; He, Rui-lin; Zhang, Zhong-feng; Chowdhury, Ahmed Jalal Khan

2015-01-01

In this review, the characteristics and applications of structural laminated veneer lumber made from planted forest wood is introduced, and its preparation is explained, including various tree species and slab qualities, treatments for multiple effects and reinforced composites. The relevant factors in the bonding technology and pressing processes as well as the mechanical properties, research direction and application prospects of structural laminated veneer lumber made from planted forest wood are discussed. PMID:26858559

Cannabis Use Disorder in Adolescence.

PubMed

Simpson, Annabelle K; Magid, Viktoriya

2016-07-01

Cannabis use in the adolescent population poses a significant threat of addiction potential resulting in altered neurodevelopment. There are multiple mechanisms of treatment of cannabis use disorder including behavioral therapy management and emerging data on treatment via pharmacotherapy. Recognizing the diagnostic criteria for cannabis use disorder, cannabis withdrawal syndrome, and mitigating factors that influence adolescent engagement in cannabis use allows for comprehensive assessment and management in the adolescent population. Copyright © 2016 Elsevier Inc. All rights reserved.

Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites.

PubMed

Kaczanowski, Szymon; Sajid, Mohammed; Reece, Sarah E

2011-03-25

Apoptosis-like programmed cell death (PCD) has recently been described in multiple taxa of unicellular protists, including the protozoan parasites Plasmodium, Trypanosoma and Leishmania. Apoptosis-like PCD in protozoan parasites shares a number of morphological features with programmed cell death in multicellular organisms. However, both the evolutionary explanations and mechanisms involved in parasite PCD are poorly understood. Explaining why unicellular organisms appear to undergo 'suicide' is a challenge for evolutionary biology and uncovering death executors and pathways is a challenge for molecular and cell biology. Bioinformatics has the potential to integrate these approaches by revealing homologies in the PCD machinery of diverse taxa and evaluating their evolutionary trajectories. As the molecular mechanisms of apoptosis in model organisms are well characterised, and recent data suggest similar mechanisms operate in protozoan parasites, key questions can now be addressed. These questions include: which elements of apoptosis machinery appear to be shared between protozoan parasites and multicellular taxa and, have these mechanisms arisen through convergent or divergent evolution? We use bioinformatics to address these questions and our analyses suggest that apoptosis mechanisms in protozoan parasites and other taxa have diverged during their evolution, that some apoptosis factors are shared across taxa whilst others have been replaced by proteins with similar biochemical activities.

Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites

PubMed Central

2011-01-01

Apoptosis-like programmed cell death (PCD) has recently been described in multiple taxa of unicellular protists, including the protozoan parasites Plasmodium, Trypanosoma and Leishmania. Apoptosis-like PCD in protozoan parasites shares a number of morphological features with programmed cell death in multicellular organisms. However, both the evolutionary explanations and mechanisms involved in parasite PCD are poorly understood. Explaining why unicellular organisms appear to undergo 'suicide' is a challenge for evolutionary biology and uncovering death executors and pathways is a challenge for molecular and cell biology. Bioinformatics has the potential to integrate these approaches by revealing homologies in the PCD machinery of diverse taxa and evaluating their evolutionary trajectories. As the molecular mechanisms of apoptosis in model organisms are well characterised, and recent data suggest similar mechanisms operate in protozoan parasites, key questions can now be addressed. These questions include: which elements of apoptosis machinery appear to be shared between protozoan parasites and multicellular taxa and, have these mechanisms arisen through convergent or divergent evolution? We use bioinformatics to address these questions and our analyses suggest that apoptosis mechanisms in protozoan parasites and other taxa have diverged during their evolution, that some apoptosis factors are shared across taxa whilst others have been replaced by proteins with similar biochemical activities. PMID:21439063

BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine.

PubMed

Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu

2016-02-16

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM's diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients' target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ's cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the "multi-component, multi-target and multi-pathway" combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM's molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.

A multiscale quantum mechanics/electromagnetics method for device simulations.

PubMed

Yam, ChiYung; Meng, Lingyi; Zhang, Yu; Chen, GuanHua

2015-04-07

Multiscale modeling has become a popular tool for research applying to different areas including materials science, microelectronics, biology, chemistry, etc. In this tutorial review, we describe a newly developed multiscale computational method, incorporating quantum mechanics into electronic device modeling with the electromagnetic environment included through classical electrodynamics. In the quantum mechanics/electromagnetics (QM/EM) method, the regions of the system where active electron scattering processes take place are treated quantum mechanically, while the surroundings are described by Maxwell's equations and a semiclassical drift-diffusion model. The QM model and the EM model are solved, respectively, in different regions of the system in a self-consistent manner. Potential distributions and current densities at the interface between QM and EM regions are employed as the boundary conditions for the quantum mechanical and electromagnetic simulations, respectively. The method is illustrated in the simulation of several realistic systems. In the case of junctionless field-effect transistors, transfer characteristics are obtained and a good agreement between experiments and simulations is achieved. Optical properties of a tandem photovoltaic cell are studied and the simulations demonstrate that multiple QM regions are coupled through the classical EM model. Finally, the study of a carbon nanotube-based molecular device shows the accuracy and efficiency of the QM/EM method.

An Updated Meta-Analysis of Risk of Multiple Sclerosis following Infectious Mononucleosis

PubMed Central

Handel, Adam E.; Williamson, Alexander J.; Disanto, Giulio; Handunnetthi, Lahiru; Giovannoni, Gavin; Ramagopalan, Sreeram V.

2010-01-01

Background Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published. Methods/Principal Findings We performed a Medline search to identify articles published since the original meta-analysis investigating MS risk following IM. A total of 18 articles were included in this study, including 19390 MS patients and 16007 controls. We calculated the relative risk of MS following IM using a generic inverse variance with random effects model. This showed that the risk of MS was strongly associated with IM (relative risk (RR) 2.17; 95% confidence interval 1.97–2.39; p<10−54). Discussion Our results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis. Future work should focus on the mechanism of this association and interaction with other risk factors. PMID:20824132

Analytical model for investigation of interior noise characteristics in aircraft with multiple propellers including synchrophasing

NASA Technical Reports Server (NTRS)

Fuller, C. R.

1986-01-01

A simplified analytical model of transmission of noise into the interior of propeller-driven aircraft has been developed. The analysis includes directivity and relative phase effects of the propeller noise sources, and leads to a closed form solution for the coupled motion between the interior and exterior fields via the shell (fuselage) vibrational response. Various situations commonly encountered in considering sound transmission into aircraft fuselages are investigated analytically and the results obtained are compared to measurements in real aircraft. In general the model has proved successful in identifying basic mechanisms behind noise transmission phenomena.

Large space deployable antenna systems

NASA Technical Reports Server (NTRS)

1978-01-01

The design technology is described for manufacturing a 20 m or larger space erectable antenna with high thermal stability, high dynamic stiffness, and minimum stowed size. The selected approach includes a wrap rib design with a cantilever beam basic element and graphite-epoxy composite lenticular cross section ribs. The rib configuration and powered type operated deploying mechanism are described and illustrated. Other features of the parabolic reflector discussed include weight and stowed diameter characteristics, structural dynamics characteristics, orbit thermal aperture limitations, and equivalent element and secondary (on axis) patterns. A block diagram of the multiple beam pattern is also presented.

Breast cancer - one term, many entities?

PubMed

Bertos, Nicholas R; Park, Morag

2011-10-01

Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups. Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables. A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.

Properties of Refractory Concrete in Tension and Compression

NASA Technical Reports Server (NTRS)

Sampson, Jeffrey

2009-01-01

Refractory concrete on the LC-39A Flame Deflector has been damaged during multiple Space Shuttle launches (e.g. STS-124, STS-126, STS-119, and STS-125, STS-127). These events have prompted a better understanding of the system via an analytical model of the Flame Deflector assembly to include the Fondu Fyre refractory concrete. This model requires test data inputs of the refractory concrete's mechanical properties, which include stress versus strain curves in tension and compression, modulus of elasticity, and Poisson's ratio. Sections of Fondu Fyre refractory concrete removed from the LC-39A Flame Deflector were provided for this testing.

Motion analysis report

NASA Technical Reports Server (NTRS)

Badler, N. I.

1985-01-01

Human motion analysis is the task of converting actual human movements into computer readable data. Such movement information may be obtained though active or passive sensing methods. Active methods include physical measuring devices such as goniometers on joints of the body, force plates, and manually operated sensors such as a Cybex dynamometer. Passive sensing de-couples the position measuring device from actual human contact. Passive sensors include Selspot scanning systems (since there is no mechanical connection between the subject's attached LEDs and the infrared sensing cameras), sonic (spark-based) three-dimensional digitizers, Polhemus six-dimensional tracking systems, and image processing systems based on multiple views and photogrammetric calculations.

Cellular mechanisms of noise-induced hearing loss.

PubMed

Kurabi, Arwa; Keithley, Elizabeth M; Housley, Gary D; Ryan, Allen F; Wong, Ann C-Y

2017-06-01

Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation. Published by Elsevier B.V.

Cited1 Deficiency Suppresses Intestinal Tumorigenesis

PubMed Central

Young, Madeleine; Poetz, Oliver; Parry, Lee; Jenkins, John R.; Williams, Geraint T.; Dunwoodie, Sally L.; Watson, Alastair; Clarke, Alan R.

2013-01-01

Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with ApcMin/+ and AhCre+Apcfl/fl mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in ApcMin/+ mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in ApcMin/+ mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1. PMID:23935526

Renoprotection and the Bardoxolone Methyl Story - Is This the Right Way Forward? A Novel View of Renoprotection in CKD Trials: A New Classification Scheme for Renoprotective Agents.

PubMed

Onuigbo, Macaulay

2013-01-01

In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m(2) of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non-diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple-pathway blocker, is on the horizon. This calls for more research efforts from all.

Renoprotection and the Bardoxolone Methyl Story – Is This the Right Way Forward? A Novel View of Renoprotection in CKD Trials: A New Classification Scheme for Renoprotective Agents

PubMed Central

Onuigbo, Macaulay

2013-01-01

In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m2 of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non-diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple-pathway blocker, is on the horizon. This calls for more research efforts from all. PMID:23687511

Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis.

PubMed

Thomas, Katja; Proschmann, Undine; Ziemssen, Tjalf

2017-10-01

Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with fingolimod use in clinical practice, but also next-generation sphingosin-1-receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis.

Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

PubMed Central

Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

2013-01-01

Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

Dissecting the mechanisms responsible for the multiple insecticide resistance phenotype in Anopheles gambiae s.s., M form, from Vallée du Kou, Burkina Faso

PubMed Central

Kwiatkowska, Rachel M.; Platt, Naomi; Poupardin, Rodolphe; Irving, Helen; Dabire, Roch K.; Mitchell, Sara; Jones, Christopher M.; Diabaté, Abdoulaye; Ranson, Hilary; Wondji, Charles S.

2013-01-01

With the exception of target site mutations, insecticide resistance mechanisms in the principle malaria vector Anopheles gambiae, remains largely uncharacterized in Burkina Faso. Here we detected high prevalence of resistance in Vallée du Kou (VK) to pyrethroids, DDT and dieldrin, moderate level for carbamates and full susceptibility to organophosphates. High frequencies of L1014F kdr (75%) and Rdl (87%) mutations were observed showing strong correlation with pyrethroids/DDT and dieldrin resistance. The frequency of ace1R mutation was low even in carbamate resistant mosquitoes. Microarray analysis identified genes significantly over-transcribed in VK. These include the cytochrome P450 genes, CYP6P3 and CYP6Z2, previously associated with pyrethroid resistance. Gene Ontology (GO) enrichment analysis suggested that elevated neurotransmitter activity is associated with resistance, with the over-transcription of target site resistance genes such as acetylcholinesterase and the GABA receptor. A rhodopsin receptor gene previously associated with pyrethroid resistance in Culex pipiens pallens was also over-transcribed in VK. This study highlights the complex network of mechanisms conferring multiple resistance in malaria vectors and such information should be taken into account when designing and implementing resistance control strategies. PMID:23380570

Excitatory, inhibitory and facilitatory frequency response areas in the inferior colliculus of hearing impaired mice.

PubMed

Felix, Richard A; Portfors, Christine V

2007-06-01

Individuals with age-related hearing loss often have difficulty understanding complex sounds such as basic speech. The C57BL/6 mouse suffers from progressive sensorineural hearing loss and thus is an effective tool for dissecting the neural mechanisms underlying changes in complex sound processing observed in humans. Neural mechanisms important for processing complex sounds include multiple tuning and combination sensitivity, and these responses are common in the inferior colliculus (IC) of normal hearing mice. We examined neural responses in the IC of C57Bl/6 mice to single and combinations of tones to examine the extent of spectral integration in the IC after age-related high frequency hearing loss. Ten percent of the neurons were tuned to multiple frequency bands and an additional 10% displayed non-linear facilitation to the combination of two different tones (combination sensitivity). No combination-sensitive inhibition was observed. By comparing these findings to spectral integration properties in the IC of normal hearing CBA/CaJ mice, we suggest that high frequency hearing loss affects some of the neural mechanisms in the IC that underlie the processing of complex sounds. The loss of spectral integration properties in the IC during aging likely impairs the central auditory system's ability to process complex sounds such as speech.

Combination therapy for treatment or prevention of atherosclerosis: Focus on the lipid-RAAS interaction☆

PubMed Central

Koh, Kwang Kon; Han, Seung Hwan; Oh, Pyung Chun; Shin, Eak Kyun; Quon, Michael J.

2010-01-01

Large clinical trials demonstrate that control of blood pressure or hyperlipidemia reduces risk for cardiovascular events by ~30%. Factors that may further reduce remaining risk are not definitively established. One potential target is atherosclerosis, a crucial feature in the pathogenesis of cardiovascular diseases whose development is determined by multiple mechanism including complex interactions between endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance as well as cross-talk between hyperlipidemia and the rennin–angiotensin–aldosterone system may contribute to development of atherosclerosis. Therefore, one appealing strategy for prevention or treatment of atherosclerosis may be to simultaneously address several risk factors with combination therapies that target multiple pathogenic mechanisms. Combination therapy with statins, peroxisome proliferators-activated receptor agonists, and rennin–angiotensin–aldosterone system blockers demonstrate additive beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapies in patients with cardiovascular risk factors. Additive beneficial effects of combined therapy are mediated by both distinct and interrelated mechanisms, consistent with both pre-clinical and clinical investigations. Thus, combination therapy may be an important concept in developing more effective strategies to treat and prevent atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and insulin resistance. PMID:19800624

Repeated Origin and Loss of Adhesive Toepads in Geckos

PubMed Central

Gamble, Tony; Greenbaum, Eli; Jackman, Todd R.; Russell, Anthony P.; Bauer, Aaron M.

2012-01-01

Geckos are well known for their extraordinary clinging abilities and many species easily scale vertical or even inverted surfaces. This ability is enabled by a complex digital adhesive mechanism (adhesive toepads) that employs van der Waals based adhesion, augmented by frictional forces. Numerous morphological traits and behaviors have evolved to facilitate deployment of the adhesive mechanism, maximize adhesive force and enable release from the substrate. The complex digital morphologies that result allow geckos to interact with their environment in a novel fashion quite differently from most other lizards. Details of toepad morphology suggest multiple gains and losses of the adhesive mechanism, but lack of a comprehensive phylogeny has hindered efforts to determine how frequently adhesive toepads have been gained and lost. Here we present a multigene phylogeny of geckos, including 107 of 118 recognized genera, and determine that adhesive toepads have been gained and lost multiple times, and remarkably, with approximately equal frequency. The most likely hypothesis suggests that adhesive toepads evolved 11 times and were lost nine times. The overall external morphology of the toepad is strikingly similar in many lineages in which it is independently derived, but lineage-specific differences are evident, particularly regarding internal anatomy, with unique morphological patterns defining each independent derivation. PMID:22761794

Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer.

PubMed

Asghari, Mohammad Hossein; Moloudizargari, Milad; Ghobadi, Emad; Fallah, Marjan; Abdollahi, Mohammad

2017-09-15

Gastric cancer (GC) is a predominant malignancy with a high mortality rate affecting a large population worldwide. The etiology of GC is multifactorial spanning from various genetic determinants to different environmental causes. Current tretaments of GC are not efficient enough and require improvements to minimize the adverse effects. Melatonin, a naturally occurring compound with known potent inhibitory effects on cancer cells is one of the major candidates which can be recruited herein. Here we reviewed the articles conducted on the therapeutic effects of melatonin in gastric cancer in various models. The results are classified according to different aspects of cancer pathogenesis and the molecular mechanisms by which melatonin exerts its effects. Melatonin could be used to combat GC exploiting its effects on multiple aspects of its pathogenesis, including formation of cancer cells, tumor growth and angiogenesis, differentiation and metastasis as well as enhancing the anti-tumor immunity. Melatonin is a pleiotropic anti-cancer molecule that affects malignant cells via multiple mechanisms. It has been shown to benefit cancer patients indirectly by reducing side effects of current therapies which have been discussed in this review. This field of research is still underdeveloped and may serve as an interesting subject for further studies aiming at the molecular mechanisms of melatonin and novel treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

Do sleep problems mediate the link between adverse childhood experiences and delinquency in preadolescent children in foster care?

PubMed

Hambrick, Erin P; Rubens, Sonia L; Brawner, Thomas W; Taussig, Heather N

2018-02-01

Adverse childhood experiences (ACEs) are associated with multiple mental and physical health problems. Yet, mechanisms by which ACEs confer risk for specific problems are largely unknown. Children in foster care typically have multiple ACEs and high rates of negative sequelae, including delinquent behaviors. Mechanisms explaining this link have not been explored in this population. Impaired sleep has been identified as a potential mechanism by which ACEs lead to delinquency in adolescents, because inadequate sleep may lead to poor executive function and cognitive control - known risk factors for delinquency. Interviews were conducted with 516 maltreated children in foster care, ages 9-11 years, and their caregivers regarding child exposure to ACEs, sleep problems, engagement in delinquent acts, symptoms of posttraumatic stress disorder, and current psychotropic medication use. ACEs data were also obtained from child welfare case records. After controlling for age, gender, race/ethnicity, placement type (residential, kin, foster), length of time in placement, posttraumatic stress symptoms, and current psychotropic medication use, sleep partially mediated the association between ACEs and delinquency. Although delinquency is likely multiply determined in this population, improving sleep may be one important strategy to reduce delinquency. © 2017 Association for Child and Adolescent Mental Health.

Robo-AO M Dwarf Multiplicity Survey

NASA Astrophysics Data System (ADS)

Lamman, Claire; Baranec, Christoph; Berta-Thompson, Zachory K.; Law, Nicholas M.; Ziegler, Carl; Schonhut-Stasik, Jessica

2018-06-01

We analyzed close to 7,000 observations from Robo-AO’s field M dwarf survey taken on the 2.1m Kitt Peak telescope. Results will help determine the total multiplicity fraction and multiplicity functions of M dwarfs, which are crucial steps towards understanding their evolution and formation mechanics. Through its robotic, laser-guided, and automated system, the Robo-AO instrument has yielded the largest adaptive-optics M dwarf survey to date. I developed a graphical user interface to quickly analyze this data. Initial data analysis included assessing data quality, checking the result from Robo-AO’s automatic reduction pipeline, and determining existence as well as the relative position of companions through a visual inspection. This program can be applied to other datasets and was successfully tested by re-analyzing observations from a separate Robo-AO survey. After a conservative initial cut for quality, over 350 companions were found within 4” of a primary star out of 2,746 high quality Robo-AO M dwarf observations, including four triple systems. Further observations were done with the Keck II telescope by using its NIRC2 imager to follow up on ten select targets for the existence and physical association of companions. Future research will yield insights into low-mass stellar formation and provide a database of nearby M dwarf multiples that will potentially assist ongoing and future surveys for planets around these stars, such as the NASA TESS mission.

Stroke in Primary Hyperoxaluria Type I

PubMed Central

Rao, Neal M.; Yallapragada, Anil; Winden, Kellen D.; Saver, Jeffrey; Liebeskind, David S.

2014-01-01

We report the case of a 27-year-old man with a history of previously undiagnosed renal disease that presented with multiple cerebrovascular infarctions. Workup for traditional causes of cerebrovascular infarction including cardiac telemetry, multiple echocardiograms, and hypercoagulative workup was negative. However, a transcranial Doppler detected circulating microemboli at the rate of 14 per hour. A serum oxalate level greater than the supersaturation point of calcium oxalate was detected, providing a potential source of the microemboli. Furthermore, serial imaging recorded rapid mineralization of the infarcted territories. In the absence of any proximal vessel irregularities, atherosclerosis, valvular abnormalities, arrhythmias, or systemic shunt as potential stroke etiology in this patient, we propose that circulating oxalate precipitate may be a potential mechanism for stroke in patients with primary oxalosis. PMID:23551880

A Meinardus Theorem with Multiple Singularities

NASA Astrophysics Data System (ADS)

Granovsky, Boris L.; Stark, Dudley

2012-09-01

Meinardus proved a general theorem about the asymptotics of the number of weighted partitions, when the Dirichlet generating function for weights has a single pole on the positive real axis. Continuing (Granovsky et al., Adv. Appl. Math. 41:307-328, 2008), we derive asymptotics for the numbers of three basic types of decomposable combinatorial structures (or, equivalently, ideal gas models in statistical mechanics) of size n, when their Dirichlet generating functions have multiple simple poles on the positive real axis. Examples to which our theorem applies include ones related to vector partitions and quantum field theory. Our asymptotic formula for the number of weighted partitions disproves the belief accepted in the physics literature that the main term in the asymptotics is determined by the rightmost pole.

A case of gabapentin-induced rhabdomyolysis requiring renal replacement therapy.

PubMed

Choi, Min Seok; Jeon, Howook; Kim, Hyo Suk; Jang, Bo Hyun; Lee, Yoon Hee; Park, Hoon Suk; Kim, HyungWook; Jin, Dong Chan

2017-01-01

Gabapentin is commonly used for controlling convulsions, restless pain syndrome, and pain in diabetic neuropathy. Common side effects include dizziness, somnolence, ataxia, peripheral edema, and confusion; gabapentin-induced rhabdomyolysis is rarely reported. To date, the reported cases of gabapentin-induced rhabdomyolysis have been associated with patients with multiple underlying diseases and assuming multiple medicines for various reasons. In this report, we describe a case of gabapentin-induced rhabdomyolysis in a 32-year-old woman with no medical history. We also review related literature and discuss the possible mechanism and the association with other factors. This case shows that gabapentin can induce rhabdomyolysis in healthy patients and that clinicians must consider the possible association between gabapentin and rhabdomyolysis. © 2016 International Society for Hemodialysis.

Rendezvous Integration Complexities of NASA Human Flight Vehicles

NASA Technical Reports Server (NTRS)

Brazzel, Jack P.; Goodman, John L.

2009-01-01

Propellant-optimal trajectories, relative sensors and navigation, and docking/capture mechanisms are rendezvous disciplines that receive much attention in the technical literature. However, other areas must be considered. These include absolute navigation, maneuver targeting, attitude control, power generation, software development and verification, redundancy management, thermal control, avionics integration, robotics, communications, lighting, human factors, crew timeline, procedure development, orbital debris risk mitigation, structures, plume impingement, logistics, and in some cases extravehicular activity. While current and future spaceflight programs will introduce new technologies and operations concepts, the complexity of integrating multiple systems on multiple spacecraft will remain. The systems integration task may become more difficult as increasingly complex software is used to meet current and future automation, autonomy, and robotic operation requirements.

The phenoptosis problem: what is causing the death of an organism? Lessons from acute kidney injury.

PubMed

Zorov, D B; Plotnikov, E Y; Jankauskas, S S; Isaev, N K; Silachev, D N; Zorova, L D; Pevzner, I B; Pulkova, N V; Zorov, S D; Morosanova, M A

2012-07-01

Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death.

Multi-band asymmetric acoustic transmission in a bended waveguide with multiple mechanisms

NASA Astrophysics Data System (ADS)

Huang, Yu-lei; Sun, Hong-xiang; Xia, Jian-ping; Yuan, Shou-qi; Ding, Xin-lei

2016-07-01

We report the realization of a multi-band device of the asymmetric acoustic transmission by placing a phononic crystal inside a bended waveguide immersed in water, as determined both experimentally and numerically. The asymmetric acoustic transmission exists in three frequency bands below 500 kHz induced by multiple mechanisms. Besides the band gap of the phononic crystal, we also introduce the deaf mode and interaction between the phononic crystal and waveguide. More importantly, this asymmetric transmission can be systematically controlled by mechanically rotating the square rods of the phononic crystal. The device has the advantages of multiple band, broader bandwidth, and adjustable property, showing promising applications in ultrasonic devices.

Recent Progress on the Stretched Lens Array (SLA)

NASA Technical Reports Server (NTRS)

O'Neill, Markl; McDanal, A. J.; Piszczor, Michael; George, Patrick; Eskenazi, Michael; Botke, Matthew; Edwards, David; Hoppe, David; Brandhorst, Henry

2005-01-01

At the last Space Photovoltaic Research and Technology Conference, SPRAT XVII, held during the fateful week of 9/11/01, our team presented a paper on the early developments related to the new Stretched Lens Array (SLA), including its evolution from the successful SCARLET array on the NASA/JPL Deep Space 1 spacecraft. Within the past two years, the SLA team has made significant progress in the SLA technology, including the successful fabrication and testing of a complete four-panel prototype solar array wing (Fig. 1). The prototype wing verified the mechanical and structural design of the rigid-panel SLA approach, including multiple successful demonstrations of automatic wing deployment. One panel in the prototype wing included four fully functional photovoltaic receivers, employing triple-junction solar cells.

Obesity: Current and potential pharmacotherapeutics and targets.

PubMed

Narayanaswami, Vidya; Dwoskin, Linda P

2017-02-01

Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Obesity: Current and Potential Pharmacotherapeutics and Targets

PubMed Central

Narayanaswami, Vidya; Dwoskin, Linda P.

2016-01-01

Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed. PMID:27773782

Jets and Water Clouds on Jupiter

NASA Astrophysics Data System (ADS)

Lian, Yuan; Showman, A. P.

2012-10-01

Ground-based and spacecraft observations show that Jupiter exhibits multiple banded zonal jet structures. These banded jets correlate with dark and bright clouds, often called "belts" and "zones". The mechanisms that produce these banded zonal jets and clouds are poorly understood. Our previous studies showed that the latent heat released by condensation of water vapor could produce equatorial superrotation along with multiple zonal jets in the mid-to-high latitudes. However, that previous work assumed complete and instant removal of condensate and therefore could not predict the cloud formation. Here we present an improved 3D Jupiter model to investigate some effects of cloud microphysics on large-scale dynamics using a closed water cycle that includes condensation, three-dimensional advection of cloud material by the large-scale circulation, evaporation and sedimentation. We use a dry convective adjustment scheme to adjust the temperature towards a dry adiabat when atmospheric columns become convectively unstable, and the tracers are mixed within the unstable layers accordingly. Other physics parameterizations included in our model are the bottom drag and internal heat flux as well as the choices of either Newtonian heating scheme or gray radiative transfer. Given the poorly understood cloud microphysics, we perform case studies by treating the particle size and condensation/evaporation time scale as free parameters. We find that, in some cases, the active water cycle can produce multiple banded jets and clouds. However, the equatorial jet is generally very weak in all the cases because of insufficient supply of eastward eddy momentum fluxes. These differences may result from differences in the overall vertical stratification, baroclinicity, and moisture distribution in our new models relative to the older ones; we expect to elucidate the dynamical mechanisms in continuing work.

Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

PubMed Central

Cornejo-García, José Antonio; Flores, Carlos; Plaza-Serón, María C.; Acosta-Herrera, Marialbert; Blanca-López, Natalia; Doña, Inmaculada; Torres, María J.; Mayorga, Cristobalina; Guéant-Rodríguez, Rosa M.; Ayuso, Pedro; Fernández, Javier; Laguna, José J.; Agúndez, José A. G.; García-Martín, Elena; Guéant, Jean-Louis; Canto, Gabriela; Blanca, Miguel

2014-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13×10−6), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs. PMID:24618698

Disease-specific molecular events in cortical multiple sclerosis lesions

PubMed Central

Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

2013-01-01

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

[Study on correction of data bias caused by different missing mechanisms in survey of medical expenditure among students enrolling in Urban Resident Basic Medical Insurance].

PubMed

Zhang, Haixia; Zhao, Junkang; Gu, Caijiao; Cui, Yan; Rong, Huiying; Meng, Fanlong; Wang, Tong

2015-05-01

The study of the medical expenditure and its influencing factors among the students enrolling in Urban Resident Basic Medical Insurance (URBMI) in Taiyuan indicated that non response bias and selection bias coexist in dependent variable of the survey data. Unlike previous studies only focused on one missing mechanism, a two-stage method to deal with two missing mechanisms simultaneously was suggested in this study, combining multiple imputation with sample selection model. A total of 1 190 questionnaires were returned by the students (or their parents) selected in child care settings, schools and universities in Taiyuan by stratified cluster random sampling in 2012. In the returned questionnaires, 2.52% existed not missing at random (NMAR) of dependent variable and 7.14% existed missing at random (MAR) of dependent variable. First, multiple imputation was conducted for MAR by using completed data, then sample selection model was used to correct NMAR in multiple imputation, and a multi influencing factor analysis model was established. Based on 1 000 times resampling, the best scheme of filling the random missing values is the predictive mean matching (PMM) method under the missing proportion. With this optimal scheme, a two stage survey was conducted. Finally, it was found that the influencing factors on annual medical expenditure among the students enrolling in URBMI in Taiyuan included population group, annual household gross income, affordability of medical insurance expenditure, chronic disease, seeking medical care in hospital, seeking medical care in community health center or private clinic, hospitalization, hospitalization canceled due to certain reason, self medication and acceptable proportion of self-paid medical expenditure. The two-stage method combining multiple imputation with sample selection model can deal with non response bias and selection bias effectively in dependent variable of the survey data.

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

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

Wang, Jun; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan; Cao, Hui

Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effectivemore » than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.« less

Language experience differentiates prefrontal and subcortical activation of the cognitive control network in novel word learning

PubMed Central

King, Kelly E.; Hernandez, Arturo E.

2012-01-01

The purpose of this study was to examine the cognitive control mechanisms in adult English speaking monolinguals compared to early sequential Spanish-English bilinguals during the initial stages of novel word learning. Functional magnetic resonance imaging during a lexico-semantic task after only two hours of exposure to novel German vocabulary flashcards showed that monolinguals activated a broader set of cortical control regions associated with higher-level cognitive processes, including the supplementary motor area (SMA), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC), as well as the caudate, implicated in cognitive control of language. However, bilinguals recruited a more localized subcortical network that included the putamen, associated more with motor control of language. These results suggest that experience managing multiple languages may differentiate the learning strategy and subsequent neural mechanisms of cognitive control used by bilinguals compared to monolinguals in the early stages of novel word learning. PMID:23194816

Mechanisms of collective cell movement lacking a leading or free front edge in vivo.

PubMed

Uechi, Hiroyuki; Kuranaga, Erina

2017-08-01

Collective cell movement is one of the strategies for achieving the complex shapes of tissues and organs. In this process, multiple cells within a group held together by cell-cell adhesion acquire mobility and move together in the same direction. In some well-studied models of collective cell movement, the mobility depends strongly on traction generated at the leading edge by cells located at the front. However, recent advances in live-imaging techniques have led to the discovery of other types of collective cell movement lacking a leading edge or even a free edge at the front, in a diverse array of morphological events, including tubule elongation, epithelial sheet extension, and tissue rotation. We herein review some of the developmental events that are organized by collective cell movement and attempt to elucidate the underlying cellular and molecular mechanisms, which include membrane protrusions, guidance cues, cell intercalation, and planer cell polarity, or chirality pathways.

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

PubMed

Tremblay-LeMay, Rosemarie; Rastgoo, Nasrin; Chang, Hong

2018-03-27

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

Single-molecule chemo-mechanical unfolding reveals multiple transition state barriers in a small single-domain protein

NASA Astrophysics Data System (ADS)

Guinn, Emily J.; Jagannathan, Bharat; Marqusee, Susan

2015-04-01

A fundamental question in protein folding is whether proteins fold through one or multiple trajectories. While most experiments indicate a single pathway, simulations suggest proteins can fold through many parallel pathways. Here, we use a combination of chemical denaturant, mechanical force and site-directed mutations to demonstrate the presence of multiple unfolding pathways in a simple, two-state folding protein. We show that these multiple pathways have structurally different transition states, and that seemingly small changes in protein sequence and environment can strongly modulate the flux between the pathways. These results suggest that in vivo, the crowded cellular environment could strongly influence the mechanisms of protein folding and unfolding. Our study resolves the apparent dichotomy between experimental and theoretical studies, and highlights the advantage of using a multipronged approach to reveal the complexities of a protein's free-energy landscape.

Computational study of 3-D hot-spot initiation in shocked insensitive high-explosive

NASA Astrophysics Data System (ADS)

Najjar, F. M.; Howard, W. M.; Fried, L. E.; Manaa, M. R.; Nichols, A., III; Levesque, G.

2012-03-01

High-explosive (HE) material consists of large-sized grains with micron-sized embedded impurities and pores. Under various mechanical/thermal insults, these pores collapse generating hightemperature regions leading to ignition. A hydrodynamic study has been performed to investigate the mechanisms of pore collapse and hot spot initiation in TATB crystals, employing a multiphysics code, ALE3D, coupled to the chemistry module, Cheetah. This computational study includes reactive dynamics. Two-dimensional high-resolution large-scale meso-scale simulations have been performed. The parameter space is systematically studied by considering various shock strengths, pore diameters and multiple pore configurations. Preliminary 3-D simulations are undertaken to quantify the 3-D dynamics.

Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer

PubMed Central

Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang

2015-01-01

Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment. PMID:26544935

Meiosis completion and various sperm responses lead to unisexual and sexual reproduction modes in one clone of polyploid Carassius gibelio.

PubMed

Zhang, Jun; Sun, Min; Zhou, Li; Li, Zhi; Liu, Zhen; Li, Xi-Yin; Liu, Xiao-Li; Liu, Wei; Gui, Jian-Fang

2015-06-04

Unisexual polyploid vertebrates are commonly known to reproduce by gynogenesis, parthenogenesis, or hybridogenesis. One clone of polyploid Carassius gibelio has been revealed to possess multiple modes of unisexual gynogenesis and sexual reproduction, but the cytological and developmental mechanisms have remained unknown. In this study, normal meiosis completion was firstly confirmed by spindle co-localization of β-tubulin and Spindlin. Moreover, three types of various nuclear events and development behaviors were revealed by DAPI staining and BrdU-incorporated immunofluorescence detection during the first mitosis in the fertilized eggs by three kinds of different sperms. They include normal sexual reproduction in response to sperm from the same clone male, typical unisexual gynogenesis in response to sperm from the male of another species Cyprinus carpio, and an unusual hybrid-similar development mode in response to sperm from another different clone male. Based on these findings, we have discussed cytological and developmental mechanisms on multiple reproduction modes in the polyploid fish, and highlighted evolutionary significance of meiosis completion and evolutionary consequences of reproduction mode diversity in polyploid vertebrates.

Conformal mapping for multiple terminals

PubMed Central

Wang, Weimin; Ma, Wenying; Wang, Qiang; Ren, Hao

2016-01-01

Conformal mapping is an important mathematical tool that can be used to solve various physical and engineering problems in many fields, including electrostatics, fluid mechanics, classical mechanics, and transformation optics. It is an accurate and convenient way to solve problems involving two terminals. However, when faced with problems involving three or more terminals, which are more common in practical applications, existing conformal mapping methods apply assumptions or approximations. A general exact method does not exist for a structure with an arbitrary number of terminals. This study presents a conformal mapping method for multiple terminals. Through an accurate analysis of boundary conditions, additional terminals or boundaries are folded into the inner part of a mapped region. The method is applied to several typical situations, and the calculation process is described for two examples of an electrostatic actuator with three electrodes and of a light beam splitter with three ports. Compared with previously reported results, the solutions for the two examples based on our method are more precise and general. The proposed method is helpful in promoting the application of conformal mapping in analysis of practical problems. PMID:27830746

Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells.

PubMed

Sala-Rabanal, Monica; Yurtsever, Zeynep; Nichols, Colin G; Brett, Tom J

2015-03-17

Calcium-activated chloride channel regulator 1 (CLCA1) activates calcium-dependent chloride currents; neither the target, nor mechanism, is known. We demonstrate that secreted CLCA1 activates calcium-dependent chloride currents in HEK293T cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents. Exposure to exogenous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells. Altogether, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calcium-dependent chloride currents. Our results identify the first Cl(-) channel target of the CLCA family of proteins and establish CLCA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to increase currents. These results suggest cooperative roles for CLCA and TMEM16 proteins in influencing the physiology of multiple tissues, and the pathology of multiple diseases, including asthma, COPD, cystic fibrosis, and certain cancers.

A Novel Method for Reconstructing Broken Contour Lines Extracted from Scanned Topographic Maps

NASA Astrophysics Data System (ADS)

Wang, Feng; Liu, Pingzhi; Yang, Yun; Wei, Haiping; An, Xiaoya

2018-05-01

It is known that after segmentation and morphological operations on scanned topographic maps, gaps occur in contour lines. It is also well known that filling these gaps and reconstruction of contour lines with high accuracy and completeness is not an easy problem. In this paper, a novel method is proposed dedicated in automatic or semiautomatic filling up caps and reconstructing broken contour lines in binary images. The key part of end points' auto-matching and reconnecting is deeply discussed after introducing the procedure of reconstruction, in which some key algorithms and mechanisms are presented and realized, including multiple incremental backing trace to get weighted average direction angle of end points, the max constraint angle control mechanism based on the multiple gradient ranks, combination of weighted Euclidean distance and deviation angle to determine the optimum matching end point, bidirectional parabola control, etc. Lastly, experimental comparisons based on typically samples are complemented between proposed method and the other representative method, the results indicate that the former holds higher accuracy and completeness, better stability and applicability.

N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities

PubMed Central

Bavarsad Shahripour, Reza; Harrigan, Mark R; Alexandrov, Andrei V

2014-01-01

Background There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways. Aim and discussion Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Conclusion Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage. PMID:24683506

Meiosis completion and various sperm responses lead to unisexual and sexual reproduction modes in one clone of polyploid Carassius gibelio

PubMed Central

Zhang, Jun; Sun, Min; Zhou, Li; Li, Zhi; Liu, Zhen; Li, Xi-Yin; Liu, Xiao-Li; Liu, Wei; Gui, Jian-Fang

2015-01-01

Unisexual polyploid vertebrates are commonly known to reproduce by gynogenesis, parthenogenesis, or hybridogenesis. One clone of polyploid Carassius gibelio has been revealed to possess multiple modes of unisexual gynogenesis and sexual reproduction, but the cytological and developmental mechanisms have remained unknown. In this study, normal meiosis completion was firstly confirmed by spindle co-localization of β-tubulin and Spindlin. Moreover, three types of various nuclear events and development behaviors were revealed by DAPI staining and BrdU-incorporated immunofluorescence detection during the first mitosis in the fertilized eggs by three kinds of different sperms. They include normal sexual reproduction in response to sperm from the same clone male, typical unisexual gynogenesis in response to sperm from the male of another species Cyprinus carpio, and an unusual hybrid-similar development mode in response to sperm from another different clone male. Based on these findings, we have discussed cytological and developmental mechanisms on multiple reproduction modes in the polyploid fish, and highlighted evolutionary significance of meiosis completion and evolutionary consequences of reproduction mode diversity in polyploid vertebrates. PMID:26042995

Recent Progress on Integrated Energy Conversion and Storage Systems.

PubMed

Luo, Bin; Ye, Delai; Wang, Lianzhou

2017-09-01

Over the last few decades, there has been increasing interest in the design and construction of integrated energy conversion and storage systems (IECSSs) that can simultaneously capture and store various forms of energies from nature. A large number of IECSSs have been developed with different combination of energy conversion technologies such as solar cells, mechanical generators and thermoelectric generators and energy storage devices such as rechargeable batteries and supercapacitors. This review summarizes the recent advancements to date of IECSSs based on different energy sources including solar, mechanical, thermal as well as multiple types of energies, with a special focus on the system configuration and working mechanism. With the rapid development of new energy conversion and storage technologies, innovative high performance IECSSs are of high expectation to be realised for diverse practical applications in the near future.

Recent Progress on Integrated Energy Conversion and Storage Systems

PubMed Central

Luo, Bin; Ye, Delai

2017-01-01

Over the last few decades, there has been increasing interest in the design and construction of integrated energy conversion and storage systems (IECSSs) that can simultaneously capture and store various forms of energies from nature. A large number of IECSSs have been developed with different combination of energy conversion technologies such as solar cells, mechanical generators and thermoelectric generators and energy storage devices such as rechargeable batteries and supercapacitors. This review summarizes the recent advancements to date of IECSSs based on different energy sources including solar, mechanical, thermal as well as multiple types of energies, with a special focus on the system configuration and working mechanism. With the rapid development of new energy conversion and storage technologies, innovative high performance IECSSs are of high expectation to be realised for diverse practical applications in the near future. PMID:28932673

Study the Expression of marA Gene in Ciprofloxacin and Tetracycline Resistant Mutants of Esherichia coli

PubMed Central

Pourahmad Jaktaji, Razieh; Ebadi, Rayhaneh

2013-01-01

MarA activates two membrane dependent mechanisms of resistance to different antibiotics, such as ciprofloxacin and tetracycline, including promotion of outflux and inhibition of influx of antibiotics. Thus, MarA causes multiple antibiotic resistance phenotype. The activation of these mechanisms needs overexpression of marA. This could happen through mutation in marR. Thus, the aim of this study was to measure marA expression in ciprofloxacin resistant E. coli gyrA mutants and clones with or without marR mutation. For this purpose, real time PCR was used to measure relative expression of marA in above mutants and clones. Results showed that two clones, C14 and C17 overexpressed marA. It is concluded that the level of marA expression is important for activation of above mechanisms. PMID:24523773

Study the Expression of marA Gene in Ciprofloxacin and Tetracycline Resistant Mutants of Esherichia coli.

PubMed

Pourahmad Jaktaji, Razieh; Ebadi, Rayhaneh

2013-01-01

MarA activates two membrane dependent mechanisms of resistance to different antibiotics, such as ciprofloxacin and tetracycline, including promotion of outflux and inhibition of influx of antibiotics. Thus, MarA causes multiple antibiotic resistance phenotype. The activation of these mechanisms needs overexpression of marA. This could happen through mutation in marR. Thus, the aim of this study was to measure marA expression in ciprofloxacin resistant E. coli gyrA mutants and clones with or without marR mutation. For this purpose, real time PCR was used to measure relative expression of marA in above mutants and clones. Results showed that two clones, C14 and C17 overexpressed marA. It is concluded that the level of marA expression is important for activation of above mechanisms.

Propensity score analysis with partially observed covariates: How should multiple imputation be used?

PubMed

Leyrat, Clémence; Seaman, Shaun R; White, Ian R; Douglas, Ian; Smeeth, Liam; Kim, Joseph; Resche-Rigon, Matthieu; Carpenter, James R; Williamson, Elizabeth J

2017-01-01

Inverse probability of treatment weighting is a popular propensity score-based approach to estimate marginal treatment effects in observational studies at risk of confounding bias. A major issue when estimating the propensity score is the presence of partially observed covariates. Multiple imputation is a natural approach to handle missing data on covariates: covariates are imputed and a propensity score analysis is performed in each imputed dataset to estimate the treatment effect. The treatment effect estimates from each imputed dataset are then combined to obtain an overall estimate. We call this method MIte. However, an alternative approach has been proposed, in which the propensity scores are combined across the imputed datasets (MIps). Therefore, there are remaining uncertainties about how to implement multiple imputation for propensity score analysis: (a) should we apply Rubin's rules to the inverse probability of treatment weighting treatment effect estimates or to the propensity score estimates themselves? (b) does the outcome have to be included in the imputation model? (c) how should we estimate the variance of the inverse probability of treatment weighting estimator after multiple imputation? We studied the consistency and balancing properties of the MIte and MIps estimators and performed a simulation study to empirically assess their performance for the analysis of a binary outcome. We also compared the performance of these methods to complete case analysis and the missingness pattern approach, which uses a different propensity score model for each pattern of missingness, and a third multiple imputation approach in which the propensity score parameters are combined rather than the propensity scores themselves (MIpar). Under a missing at random mechanism, complete case and missingness pattern analyses were biased in most cases for estimating the marginal treatment effect, whereas multiple imputation approaches were approximately unbiased as long as the outcome was included in the imputation model. Only MIte was unbiased in all the studied scenarios and Rubin's rules provided good variance estimates for MIte. The propensity score estimated in the MIte approach showed good balancing properties. In conclusion, when using multiple imputation in the inverse probability of treatment weighting context, MIte with the outcome included in the imputation model is the preferred approach.

Experimental evaluation of multiscale tendon mechanics.

PubMed

Fang, Fei; Lake, Spencer P

2017-07-01

Tendon's primary function is a mechanical link between muscle and bone. The hierarchical structure of tendon and specific compositional constituents are believed to be critical for proper mechanical function. With increased appreciation for tendon importance and the development of various technological advances, this review paper summarizes recent experimental approaches that have been used to study multiscale tendon mechanics, includes an overview of studies that have evaluated the role of specific tissue constituents, and also proposes challenges/opportunities facing tendon study. Tendon has been demonstrated to have specific structural characteristics (e.g., multi-level hierarchy, crimp pattern, helix) and complex mechanical properties (e.g., non-linearity, anisotropy, viscoelasticity). Physical mechanisms including uncrimping, fiber sliding, and collagen reorganization have been shown to govern tendon mechanical responses under both static and dynamic loading. Several tendon constituents with relatively small quantities have been suggested to play a role in its mechanics, although some results are conflicting. Further research should be performed to understand the interplay and communication of tendon mechanical properties across levels of the hierarchical structure, and further show how each of these components contribute to tendon mechanics. The studies summarized and discussed in this review have helped elucidate important aspects of multiscale tendon mechanics, which is a prerequisite for analyzing stress/strain transfer between multiple scales and identifying key principles of mechanotransduction. This information could further facilitate interpreting the functional diversity of tendons from different species, different locations, and even different developmental stages, and then better understand and identify fundamental concepts related to tendon degeneration, disease, and healing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1353-1365, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Protecting muscle ATP: positive roles for peripheral defense mechanisms-introduction.

PubMed

Myburgh, Kathryn H

2004-01-01

Skeletal muscle has evolved an impressive array of mechanisms for peripherally mediated control of ATP homeostasis. Some of these mechanisms are intracellular, and others are extracellular and include influences on the cross-bridge cycle itself and substrate supply. This paper introduces three distinctly different topics that nevertheless all have ATP defense in common. The role of ADP in fatigue is controversial but has recently been more clearly delineated so that an effect on alleviating force declines during extreme fatigue is plausible. AMP plays its role by activating the protein-kinase, AMPK, which is a key sensor of cellular energy stress. AMPK has different isoforms, is not uniformly distributed in the cell, and its activation is carefully controlled. It has multiple effects including improvements in substrate supply for the metabolic pathways producing ATP and inhibition of anabolic processes to further spare ATP. Red blood cells have the capacity to sense hypoxia and to release vasodilators where there is a locally increased demand for blood supply. The papers in this series emphasize the important positive roles of metabolites and sensors of fatigue in the balance between ATP supply and demand.

Epigenetic mechanisms in cerebral ischemia

PubMed Central

Schweizer, Sophie; Meisel, Andreas; Märschenz, Stefanie

2013-01-01

Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration. PMID:23756691

Thalidomide‐induced teratogenesis: History and mechanisms

PubMed Central

2015-01-01

Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. PMID:26043938

An Efficient Modelling Approach for Prediction of Porosity Severity in Composite Structures

NASA Technical Reports Server (NTRS)

Bedayat, Houman; Forghani, Alireza; Hickmott, Curtis; Roy, Martin; Palmieri, Frank; Grimsley, Brian; Coxon, Brian; Fernlund, Goran

2017-01-01

Porosity, as a manufacturing process-induced defect, highly affects the mechanical properties of cured composites. Multiple phenomena affect the formation of porosity during the cure process. Porosity sources include entrapped air, volatiles and off-gassing as well as bag and tool leaks. Porosity sinks are the mechanisms that contribute to reducing porosity, including gas transport, void shrinkage and collapse as well as resin flow into void space. Despite the significant progress in porosity research, the fundamentals of porosity in composites are not yet fully understood. The highly coupled multi-physics and multi-scale nature of porosity make it a complicated problem to predict. Experimental evidence shows that resin pressure history throughout the cure cycle plays an important role in the porosity of the cured part. Maintaining high resin pressure results in void shrinkage and collapse keeps volatiles in solution thus preventing off-gassing and bubble formation. This study summarizes the latest development of an efficient FE modeling framework to simulate the gas and resin transport mechanisms that are among the major phenomena contributing to porosity.

Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes.

PubMed

Bramlett, Helen M; Dietrich, W Dalton

2015-12-01

Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated to the clinic. Increased importance on the progressive, long-term consequences of TBI have been emphasized, both in the experimental and clinical literature. Thus, there is a need for a better understanding of the chronic consequences of TBI, with the ultimate goal of developing novel therapeutic interventions to treat the devastating consequences of brain injury. In models of mild, moderate, and severe TBI, histopathological and behavioral studies have emphasized the progressive nature of the initial traumatic insult and the involvement of multiple pathophysiological mechanisms, including sustained injury cascades leading to prolonged motor and cognitive deficits. Recently, the increased incidence in age-dependent neurodegenerative diseases in this patient population has also been emphasized. Pathomechanisms felt to be active in the acute and long-term consequences of TBI include excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, as well as decreased neurogenesis. The current article will review many of these pathophysiological mechanisms that may be important targets for limiting the chronic consequences of TBI.

Profiles of Cognitive Appraisals and Triangulation into Interparental Conflict: Implications for Adolescent Adjustment

PubMed Central

Fosco, Gregory M.; Bray, Bethany C.

2016-01-01

Youth appraisals and triangulation into conflicts are key mechanisms by which interparental conflict places youth at risk for psychological maladjustment. Although evidence suggests that there are multiple mechanisms at work (e.g., Fosco & Feinberg, 2015; Grych, Harold, & Miles, 2003), this body of work has relied on variable-centered analyses that are limited to the unique contributions of each process to the variance in outcomes. In reality, it is possible that different combinations of these risk mechanisms may account for multifinality in risk outcomes. Using latent profile analysis (LPA) we examined profiles of threat appraisals, self-blaming attributions, and triangulation in relation to internalizing and externalizing problems in a sample of 285, ethnically diverse high school students. The current analyses revealed five distinct profiles of appraisals and triangulation, including an overall low-risk group and a global high-risk group, in which all three processes were below average or above average, respectively. Additional profiles included combinations of threat and blame, threat and triangulation, and blame and triangulation. Links between these profiles and emotional distress, problem behavior, and academic outcomes are discussed. PMID:26963695

Multiple slope failures shaped the lower continental slope offshore NW Svalbard in the Fram Strait

NASA Astrophysics Data System (ADS)

Osti, Giacomo; Mienert, Jürgen; Forwick, Matthias; Sverre Laberg, Jan

2016-04-01

Bathymetry data show that the lower slope (between 1300 m and 3000 m water depth) of the NW-Svalbard passive margin has been affected by multiple slope failure events. The single events differ in terms of extension, volume of mobilized sediments, morphology of the slide scar, run-out distance and age. As for several mega-scale and minor Arctic slides, the trigger mechanism is still speculative and may include high sedimentation rates, dissociation of gas hydrates, excess pore pressure, or earthquakes caused by isostatic rebound. In this study, we discuss the potential trigger mechanisms that have led to the multiple slope failure events within what we suggest to be named the Fram Strait Slide Complex. The slide complex lies in proximity to the tectonically active Spitsbergen Fracture Zone where earthquakes events, occurrences of potential weak layers in the sediment column, low sedimentation rates, and extended gas hydrate-bearing sediments may all have contributed to the causes leading to multiple slope failures. Preliminary results obtained from 14C dating on N. pachyderma sin. from sediment cores from the Spitsbergen Fracture Zone slides (SFZS 1 and 2), coupled with sub-bottom profiler data (frequency 9 to 15 KHz) show that the two shallowest glide planes within one of the observed slide scars failed ~100,000 and ~115,000 yr BP. Whilst SFZS 1 affected an area of 750 km2 mobilizing a total sediment volume of 40 km3, SFZS 2 moved an area of 230 km2 with a sediment volume of 4.5 km3.

Multiple coloured ornaments in male common kestrels: different mechanisms to convey quality

NASA Astrophysics Data System (ADS)

Vergara, Pablo; Fargallo, Juan A.

2011-04-01

The simultaneous exhibition of more than one secondary sexual trait is a widespread phenomenon in nature, though it has rarely been explored. It has been proposed that different ornaments may convey complementary or back-up information about a single aspect of individual quality (redundancy hypothesis) or that each ornament may convey unique information (multiple-messages hypothesis). During a 5-year period, we measured several carotenoid-based (eye ring, bill cere and tarsi skin) and melanin-based (head, back, rump and tail feathers) potential ornamental colours in male common kestrels. We analysed whether multiple ornaments can convey different or related information about individual quality. We explored whether different ornaments can express different information depending on the pigment (carotenoids or melanins), the time-scale over which the ornament can change (dynamic vs. static) and the season of the year when the ornament is formed. We found that both melanin- and carotenoid- based traits correlated with indexes of quality, including body condition, body condition of their partners and laying date. However, not all ornaments correlated with the same measures of quality. In addition, some ornaments were intercorrelated within the same individuals while others were not. These results suggest that different ornaments can convey information about different qualities, as predicted by the multiple-messages hypothesis. In addition, this study suggests that the predominant pigment (e.g. carotenoid vs. melanin, eumelanin vs. pheomelanin), the time-scale over which the trait is developed (static feathers vs. dynamic skin) and the season of the year at which the ornament is produced can be potential mechanisms to convey different messages in male common kestrels.

Constraining the Mechanism of D" Anisotropy: Diversity of Observation Types Required

NASA Astrophysics Data System (ADS)

Creasy, N.; Pisconti, A.; Long, M. D.; Thomas, C.

2017-12-01

A variety of different mechanisms have been proposed as explanations for seismic anisotropy at the base of the mantle, including crystallographic preferred orientation of various minerals (bridgmanite, post-perovskite, and ferropericlase) and shape preferred orientation of elastically distinct materials such as partial melt. Investigations of the mechanism for D" anisotropy are usually ambiguous, as seismic observations rarely (if ever) uniquely constrain a mechanism. Observations of shear wave splitting and polarities of SdS and PdP reflections off the D" discontinuity are among our best tools for probing D" anisotropy; however, typical data sets cannot constrain a unique scenario suggested by the mineral physics literature. In this work, we determine what types of body wave observations are required to uniquely constrain a mechanism for D" anisotropy. We test multiple possible models based on both single-crystal and poly-phase elastic tensors provided by mineral physics studies. We predict shear wave splitting parameters for SKS, SKKS, and ScS phases and reflection polarities off the D" interface for a range of possible propagation directions. We run a series of tests that create synthetic data sets by random selection over multiple iterations, controlling the total number of measurements, the azimuthal distribution, and the type of phases. We treat each randomly drawn synthetic dataset with the same methodology as in Ford et al. (2015) to determine the possible mechanism(s), carrying out a grid search over all possible elastic tensors and orientations to determine which are consistent with the synthetic data. We find is it difficult to uniquely constrain the starting model with a realistic number of seismic anisotropy measurements with only one measurement technique or phase type. However, having a mix of SKS, SKKS, and ScS measurements, or a mix of shear wave splitting and reflection polarity measurements, dramatically increases the probability of uniquely constraining the starting model. We also explore what types of datasets are needed to uniquely constrain the orientation(s) of anisotropic symmetry if the mechanism is assumed.

Linkage mechanisms in the vertebrate skull: Structure and function of three-dimensional, parallel transmission systems.

PubMed

Olsen, Aaron M; Westneat, Mark W

2016-12-01

Many musculoskeletal systems, including the skulls of birds, fishes, and some lizards consist of interconnected chains of mobile skeletal elements, analogous to linkage mechanisms used in engineering. Biomechanical studies have applied linkage models to a diversity of musculoskeletal systems, with previous applications primarily focusing on two-dimensional linkage geometries, bilaterally symmetrical pairs of planar linkages, or single four-bar linkages. Here, we present new, three-dimensional (3D), parallel linkage models of the skulls of birds and fishes and use these models (available as free kinematic simulation software), to investigate structure-function relationships in these systems. This new computational framework provides an accessible and integrated workflow for exploring the evolution of structure and function in complex musculoskeletal systems. Linkage simulations show that kinematic transmission, although a suitable functional metric for linkages with single rotating input and output links, can give misleading results when applied to linkages with substantial translational components or multiple output links. To take into account both linear and rotational displacement we define force mechanical advantage for a linkage (analogous to lever mechanical advantage) and apply this metric to measure transmission efficiency in the bird cranial mechanism. For linkages with multiple, expanding output points we propose a new functional metric, expansion advantage, to measure expansion amplification and apply this metric to the buccal expansion mechanism in fishes. Using the bird cranial linkage model, we quantify the inaccuracies that result from simplifying a 3D geometry into two dimensions. We also show that by combining single-chain linkages into parallel linkages, more links can be simulated while decreasing or maintaining the same number of input parameters. This generalized framework for linkage simulation and analysis can accommodate linkages of differing geometries and configurations, enabling novel interpretations of the mechanics of force transmission across a diversity of vertebrate feeding mechanisms and enhancing our understanding of musculoskeletal function and evolution. J. Morphol. 277:1570-1583, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Metabolite Profiling of Whole Murine Embryos Reveals Metabolic Perturbations Associated with Maternal Valproate-Induced Neural Tube Closure Defects

PubMed Central

Akimova, Darya; Wlodarczyk, Bogdan J.; Lin, Ying; Ross, M. Elizabeth; Finnell, Richard H.; Chen, Qiuying; Gross, Steven S.

2016-01-01

Background Valproic Acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid, a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure stage mouse embryos. Methods Pregnant SWV dams on either a 2ppm or 10ppm folic acid (FA) supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for neural tube closure status. LC/MS metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos to profiles from embryos that underwent normal neural tube closure from control dams. Results NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary folic acid supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared to the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines. Conclusions Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high folic acid diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. PMID:27860192

Multiple imputation methods for bivariate outcomes in cluster randomised trials.

PubMed

DiazOrdaz, K; Kenward, M G; Gomes, M; Grieve, R

2016-09-10

Missing observations are common in cluster randomised trials. The problem is exacerbated when modelling bivariate outcomes jointly, as the proportion of complete cases is often considerably smaller than the proportion having either of the outcomes fully observed. Approaches taken to handling such missing data include the following: complete case analysis, single-level multiple imputation that ignores the clustering, multiple imputation with a fixed effect for each cluster and multilevel multiple imputation. We contrasted the alternative approaches to handling missing data in a cost-effectiveness analysis that uses data from a cluster randomised trial to evaluate an exercise intervention for care home residents. We then conducted a simulation study to assess the performance of these approaches on bivariate continuous outcomes, in terms of confidence interval coverage and empirical bias in the estimated treatment effects. Missing-at-random clustered data scenarios were simulated following a full-factorial design. Across all the missing data mechanisms considered, the multiple imputation methods provided estimators with negligible bias, while complete case analysis resulted in biased treatment effect estimates in scenarios where the randomised treatment arm was associated with missingness. Confidence interval coverage was generally in excess of nominal levels (up to 99.8%) following fixed-effects multiple imputation and too low following single-level multiple imputation. Multilevel multiple imputation led to coverage levels of approximately 95% throughout. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Characterization Methods of Encapsulates

NASA Astrophysics Data System (ADS)

Zhang, Zhibing; Law, Daniel; Lian, Guoping

Food active ingredients can be encapsulated by different processes, including spray drying, spray cooling, spray chilling, spinning disc and centrifugal co-extrusion, extrusion, fluidized bed coating and coacervation (see Chap. 2 of this book). The purpose of encapsulation is often to stabilize an active ingredient, control its release rate and/or convert a liquid formulation into a solid which is easier to handle. A range of edible materials can be used as shell materials of encapsulates, including polysaccharides, fats, waxes and proteins (see Chap. 3 of this book). Encapsulates for typical industrial applications can vary from several microns to several millimetres in diameter although there is an increasing interest in preparing nano-encapsulates. Encapsulates are basically particles with a core-shell structure, but some of them can have a more complex structure, e.g. in a form of multiple cores embedded in a matrix. Particles have physical, mechanical and structural properties, including particle size, size distribution, morphology, surface charge, wall thickness, mechanical strength, glass transition temperature, degree of crystallinity, flowability and permeability. Information about the properties of encapsulates is very important to understanding their behaviours in different environments, including their manufacturing processes and end-user applications. E.g. encapsulates for most industrial applications should have desirable mechanical strength, which should be strong enough to withstand various mechanical forces generated in manufacturing processes, such as mixing, pumping, extrusion, etc., and may be required to be weak enough in order to release the encapsulated active ingredients by mechanical forces at their end-user applications, such as release rate of flavour by chewing. The mechanical strength of encapsulates and release rate of their food actives are related to their size, morphology, wall thickness, chemical composition, structure etc. Hence, reliable methods which can be used to characterize these properties of encapsulates are vital. In this chapter, the state-of-art of these methods, their principles and applications, and release mechanisms are described as follows.

Synergistic activation of NF-{kappa}B by nontypeable H. influenzae and S. pneumoniae is mediated by CK2, IKK{beta}-I{kappa}B{alpha}, and p38 MAPK

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

Kweon, Soo-Mi; Wang, Beinan; Rixter, Davida

2006-12-15

In review of the past studies on NF-{kappa}B regulation, most of them have focused on investigating how NF-{kappa}B is activated by a single inducer at a time. Given the fact that, in mixed bacterial infections in vivo, multiple inflammation inducers, including both nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae, are present simultaneously, a key issue that has yet to be addressed is whether NTHi and S. pneumoniae simultaneously activate NF-{kappa}B and the subsequent inflammatory response in a synergistic manner. Here, we show that NTHi and S. pneumoniae synergistically induce NF-{kappa}B-dependent inflammatory response via activation of multiple signaling pathways in vitromore » and in vivo. The classical IKK{beta}-I{kappa}B{alpha} and p38 MAPK pathways are involved in synergistic activation of NF-{kappa}B via two distinct mechanisms, p65 nuclear translocation-dependent and -independent mechanisms. Moreover, casein kinase 2 (CK2) is involved in synergistic induction of NF-{kappa}B via a mechanism dependent on phosphorylation of p65 at both Ser536 and Ser276 sites. These studies bring new insights into the molecular mechanisms underlying the NF-{kappa}B-dependent inflammatory response in polymicrobial infections and may lead to development of novel therapeutic strategies for modulating inflammation in mixed infections for patients with otitis media and chronic obstructive pulmonary diseases.« less

Steering liquid metal flow in microchannels using low voltages.

PubMed

Tang, Shi-Yang; Lin, Yiliang; Joshipura, Ishan D; Khoshmanesh, Khashayar; Dickey, Michael D

2015-10-07

Liquid metals based on gallium, such as eutectic gallium indium (EGaIn) and Galinstan, have been integrated as static components in microfluidic systems for a wide range of applications including soft electrodes, pumps, and stretchable electronics. However, there is also a possibility to continuously pump liquid metal into microchannels to create shape reconfigurable metallic structures. Enabling this concept necessitates a simple method to control dynamically the path the metal takes through branched microchannels with multiple outlets. This paper demonstrates a novel method for controlling the directional flow of EGaIn liquid metal in complex microfluidic networks by simply applying a low voltage to the metal. According to the polarity of the voltage applied between the inlet and an outlet, two distinct mechanisms can occur. The voltage can lower the interfacial tension of the metal via electrocapillarity to facilitate the flow of the metal towards outlets containing counter electrodes. Alternatively, the voltage can drive surface oxidation of the metal to form a mechanical impediment that redirects the movement of the metal towards alternative pathways. Thus, the method can be employed like a 'valve' to direct the pathway chosen by the metal without mechanical moving parts. The paper elucidates the operating mechanisms of this valving system and demonstrates proof-of-concept control over the flow of liquid metal towards single or multiple directions simultaneously. This method provides a simple route to direct the flow of liquid metal for applications in microfluidics, optics, electronics, and microelectromechanical systems.

Natural variation in germination responses of Arabidopsis to seasonal cues and their associated physiological mechanisms

PubMed Central

Barua, Deepak; Butler, Colleen; Tisdale, Tracy E.; Donohue, Kathleen

2012-01-01

Background and Aims Despite the intense interest in phenological adaptation to environmental change, the fundamental character of natural variation in germination is almost entirely unknown. Specifically, it is not known whether different genotypes within a species are germination specialists to particular conditions, nor is it known what physiological mechanisms of germination regulation vary in natural populations and how they are associated with responses to particular environmental factors. Methods We used a set of recombinant inbred genotypes of Arabidopsis thaliana, in which linkage disequilibrium has been disrupted over seven generations, to test for genetic variation and covariation in germination responses to distinct environmental factors. We then examined physiological mechanisms associated with those responses, including seed-coat permeability and sensitivity to the phytohormones gibberellic acid (GA) and abscisic acid (ABA). Key Results Genetic variation for germination was environment-dependent, but no evidence for specialization of germination to different conditions was found. Hormonal sensitivities also exhibited significant genetic variation, but seed-coat properties did not. GA sensitivity was associated with germination responses to multiple environmental factors, but seed-coat permeability and ABA sensitivity were associated with specific germination responses, suggesting that an evolutionary change in GA sensitivity could affect germination in multiple environments, but that of ABA sensitivity may affect germination under more restricted conditions. Conclusions The physiological mechanisms of germination responses to specific environmental factors therefore can influence the ability to adapt to diverse seasonal environments encountered during colonization of new habitats or with future predicted climate change. PMID:22012958

Non-coding RNAs and Berberine: A new mechanism of its anti-diabetic activities.

PubMed

Chang, Wenguang

2017-01-15

Type 2 Diabetes (T2D) is a metabolic disease with high mortality and morbidity. Non-coding RNAs, including small and long non-coding RNAs, are a novel class of functional RNA molecules that regulate multiple biological functions through diverse mechanisms. Studies in the last decade have demonstrated that non-coding RNAs may represent compelling therapeutic targets and play important roles in regulating the course of insulin resistance and T2D. Berberine, a plant-based alkaloid, has shown promise as an anti-hyperglycaemic, anti-hyperlipidaemic agent against T2D. Previous studies have primarily focused on a diverse array of efficacy end points of berberine in the pathogenesis of metabolic syndromes and inflammation or oxidative stress. Currently, an increasing number of studies have revealed the importance of non-coding RNAs as regulators of the anti-diabetic effects of berberine. The regulation of non-coding RNAs has been associated with several therapeutic actions of berberine in T2D progression. Thus, this review summarizes the anti-diabetic mechanisms of berberine by focusing on its role in regulating non-coding RNA, thus demonstrating that berberine exerts global anti-diabetic effects by targeting non-coding RNAs and that these effects involve several miRNAs, lncRNAs and multiple signal pathways, which may enhance the current understanding of the anti-diabetic mechanism actions of berberine and provide new pathological targets for the development of berberine-related drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Multiple Mechanisms Are Involved in 6-Gingerol-Induced Cell Growth Arrest and Apoptosis in Human Colorectal Cancer Cells

PubMed Central

Lee, Seong-Ho; Cekanova, Maria; Baek, Seung Joon

2008-01-01

6-Gingerol, a natural product of ginger, has been known to possess anti-tumorigenic and pro-apoptotic activities. However, the mechanisms by which it prevents cancer are not well understood in human colorectal cancer. Cyclin D1 is a proto-oncogene that is overexpressed in many cancers and plays a role in cell proliferation through activation by β-catenin signaling. Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and anti-tumorigenic properties. In the present study, we examined whether 6-gingerol influences cyclin D1 and NAG-1 expression and determined the mechanisms by which 6-gingerol affects the growth of human colorectal cancer cells in vitro. 6-Gingerol treatment suppressed cell proliferation and induced apoptosis and G1 cell cycle arrest. Subsequently, 6-gingerol suppressed cyclin D1 expression and induced NAG-1 expression. Cyclin D1 suppression was related to inhibition of β-catenin translocation and cyclin D1 proteolysis. Furthermore, experiments using inhibitors and siRNA transfection confirm the involvement of the PKCε and glycogen synthase kinase (GSK)-3β pathways in 6-gingerol-induced NAG-1 expression. The results suggest that 6-gingerol stimulates apoptosis through upregulation of NAG-1 and G1 cell cycle arrest through downregulation of cyclin D1. Multiple mechanisms appear to be involved in 6-gingerol action, including protein degradation as well as β-catenin, PKCε, and GSK-3β pathways. PMID:18058799

Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment

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

Wilson, Vickie S., E-mail: wilson.vickie@epa.gov; Keshava, Nagalakshmi; Hester, Susan

2013-09-15

The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanismmore » or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment.« less

AE Recorder Characteristics and Development.

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

Partridge, Michael E.; Curtis, Shane Keawe; McGrogan, David Paul

2016-11-01

The Anomalous Environment Recorder (AE Recorder) provides a robust data recording capability for multiple high-shock applications including earth penetrators. The AE Recorder, packaged as a 2.4" di ameter cylinder 3" tall, acquires 12 accelerometer, 2 auxiliary, and 6 discrete signal channels at 250k samples / second. Recording depth is 213 seconds plus 75ms of pre-trigger data. The mechanical, electrical, and firmware are described as well as support electro nics designed for the first use of the recorder.

McStas event logger: Definition and applications

NASA Astrophysics Data System (ADS)

Bergbäck Knudsen, Erik; Bryndt Klinkby, Esben; Kjær Willendrup, Peter

2014-02-01

Functionality is added to the McStas neutron ray-tracing code, which allows individual neutron states before and after a scattering to be temporarily stored, and analysed. This logging mechanism has multiple uses, including studies of longitudinal intensity loss in neutron guides and guide coating design optimisations. Furthermore, the logging method enables the cold/thermal neutron induced gamma background along the guide to be calculated from the un-reflected neutron, using a recently developed MCNPX-McStas interface.

Community hoarding task forces: a comparative case study of five task forces in the United States.

PubMed

Bratiotis, Christiana

2013-05-01

During the past decade, many community task forces have formed to address hoarding problems that come to public attention. Such task forces provide a societal-level intervention to assist people with the most severe cases of hoarding, who do not voluntarily seek or want help for their hoarding behaviour. This qualitative study of five U.S. hoarding task forces included sites selected for their diversity of purpose, approaches to hoarding intervention and community geography, composition and resources. Data were collected during the period of September 2007-March 2008. The case study methodology used multiple forms of data, including semi-structured interviews, analysis of documents, small group interviews and investigator observation. This study captured the perspectives of public and private sector service providers such as mental health, housing, social service, public health agencies and community enforcement organisations (fire, police, legal, animal control) to examine how task forces organise and operate and the emerging practice and policy changes. Study findings suggest that structural factors (e.g. leadership, purpose, funding and membership) impact hoarding task force viability, that participation on a task force influences practice and policy decisions about hoarding, and that social work can expand its role in task force leadership. Task forces may be a mechanism for improving community policies about hoarding and mechanisms for addressing other social problems across multiple sectors. © 2012 Blackwell Publishing Ltd.

Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages.

PubMed

Ma, Tong-Cui; Zhou, Run-Hong; Wang, Xu; Li, Jie-Liang; Sang, Ming; Zhou, Li; Zhuang, Ke; Hou, Wei; Guo, De-Yin; Ho, Wen-Zhe

2016-10-13

The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2',5'-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.

PubMed

Reynolds, Jacob D; Case, Laure K; Krementsov, Dimitry N; Raza, Abbas; Bartiss, Rose; Teuscher, Cory

2017-06-01

Month-season of birth (M-SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M-SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M-SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M-SOB with the lowest birth rate were less susceptible to EAE than mice born during the M-SOB with the highest birth rate. We also show that the M-SOB effect on EAE susceptibility is associated with differential production of multiple cytokines/chemokines by neuroantigen-specific T cells that are known to play a role in EAE pathogenesis. Taken together, these results support the existence of an M-SOB effect that may reflect seasonally dependent developmental differences in adaptive immune responses to self-antigens independent of external stimuli, including exposure to sunlight and vitamin D. Moreover, our documentation of an M-SOB effect on EAE susceptibility in mice allows for modeling and detailed analysis of mechanisms that underlie the M-SOB effect in not only MS but in numerous other diseases in which M-SOB impacts susceptibility.-Reynolds, J. D., Case, L. K., Krementsov, D. N., Raza, A., Bartiss, R., Teuscher, C. Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis. © FASEB.

Immune Tolerance in Multiple Sclerosis

PubMed Central

Goverman, Joan M.

2011-01-01

Summary Multiple sclerosis is believed to be mediated by T cells specific for myelin antigens that circulate harmlessly in the periphery of healthy individuals until they are erroneously by an environmental stimulus. Upon activation, the T cells enter the central nervous system and orchestrate an immune response against myelin. To understand the initial steps in the pathogenesis of multiple sclerosis, it is important to identify the mechanisms that maintain T-cell tolerance to myelin antigens and to understand how some myelin-specific T cells escape tolerance and what conditions lead to their activation. Central tolerance strongly shapes the peripheral repertoire of myelin-specific T cells, as most myelin-specific T cells are eliminated by clonal deletion in the thymus. Self-reactive T cells that escape central tolerance are generally capable only of low-avidity interactions with antigen-presenting cells. Despite the low avidity of these interactions, peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms for myelin-specific T cells have been indentified, the most important of which appears to be regulatory T cells. While most studies have focused on CD4+ myelin-specific T cells, interesting differences in tolerance mechanisms and the conditions that abrogate these mechanisms have recently been described for CD8+ myelin-specific T cells. PMID:21488900

Curcumin therapeutic promises and bioavailability in colorectal cancer.

PubMed

Shehzad, A; Khan, S; Shehzad, O; Lee, Y S

2010-07-01

Curcumin, a polyphenol and derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Several research studies have provided interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancers, including colorectal cancer. Curcumin has the ability to inhibit carcinogenic promotion of colorectal cancer through the modulation of multiple molecular targets such as transcription factors, enzymes, cell cycle proteins, cell surface adhesion proteins, survival pathways and cytokines. A number of clinical trials dealing with curcumin's efficacy and safety revealed poor absorption and low bioavailability. Different factors contributing to the low bioavailability include low plasma level, tissue distribution, rapid metabolism and elimination from the body. Although, curcumin poor absorption and low systemic bioavailability limit its translation into clinics, some of the methods for its use can be approached to enhance the absorption and achieve a therapeutic level of curcumin. Recent clinical trials suggest a potential role for curcumin in regards to colorectal cancer therapy.

Development, Prevention, and Treatment of Alcohol-Induced Organ Injury: The Role of Nutrition

PubMed Central

Barve, Shirish; Chen, Shao-Yu; Kirpich, Irina; Watson, Walter H.; McClain, Craig

2017-01-01

Alcohol and nutrition have the potential to interact at multiple levels. For example, heavy alcohol consumption can interfere with normal nutrition, resulting in overall malnutrition or in deficiencies of important micronutrients, such as zinc, by reducing their absorption or increasing their loss. Interactions between alcohol consumption and nutrition also can affect epigenetic regulation of gene expression by influencing multiple regulatory mechanisms, including methylation and acetylation of histone proteins and DNA. These effects may contribute to alcohol-related organ or tissue injury. The impact of alcohol–nutrition interactions has been assessed for several organs and tissues, including the intestine, where heavy alcohol use can increase intestinal permeability, and the liver, where the degree of malnutrition can be associated with the severity of liver injury and liver disease. Alcohol–nutrition interactions also play a role in alcohol-related lung injury, brain injury, and immune dysfunction. Therefore, treatment involving nutrient supplementation (e.g., with zinc or S-adenosylmethionine) may help prevent or attenuate some types of alcohol-induced organ damage. PMID:28988580

The promise of N-acetylcysteine in neuropsychiatry.

PubMed

Berk, Michael; Malhi, Gin S; Gray, Laura J; Dean, Olivia M

2013-03-01

N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate. Copyright © 2013 Elsevier Ltd. All rights reserved.

Quality measurement and improvement in liver transplantation.

PubMed

Mathur, Amit K; Talwalkar, Jayant

2018-06-01

There is growing interest in the quality of health care delivery in liver transplantation. Multiple stakeholders, including patients, transplant providers and their hospitals, payers, and regulatory bodies have an interest in measuring and monitoring quality in the liver transplant process, and understanding differences in quality across centres. This article aims to provide an overview of quality measurement and regulatory issues in liver transplantation performed within the United States. We review how broader definitions of health care quality should be applied to liver transplant care models. We outline the status quo including the current regulatory agencies, public reporting mechanisms, and requirements around quality assurance and performance improvement (QAPI) activities. Additionally, we further discuss unintended consequences and opportunities for growth in quality measurement. Quality measurement and the integration of quality improvement strategies into liver transplant programmes hold significant promise, but multiple challenges to successful implementation must be addressed to optimise value. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The retrovirus RNA trafficking granule: from birth to maturity

PubMed Central

Cochrane, Alan W; McNally, Mark T; Mouland, Andrew J

2006-01-01

Post-transcriptional events in the life of an RNA including RNA processing, transport, translation and metabolism are characterized by the regulated assembly of multiple ribonucleoprotein (RNP) complexes. At each of these steps, there is the engagement and disengagement of RNA-binding proteins until the RNA reaches its final destination. For retroviral genomic RNA, the final destination is the capsid. Numerous studies have provided crucial information about these processes and serve as the basis for studies on the intracellular fate of retroviral RNA. Retroviral RNAs are like cellular mRNAs but their processing is more tightly regulated by multiple cis-acting sequences and the activities of many trans-acting proteins. This review describes the viral and cellular partners that retroviral RNA encounters during its maturation that begins in the nucleus, focusing on important events including splicing, 3' end-processing, RNA trafficking from the nucleus to the cytoplasm and finally, mechanisms that lead to its compartmentalization into progeny virions. PMID:16545126

Shape Transformations of Epithelial Shells

PubMed Central

Misra, Mahim; Audoly, Basile; Kevrekidis, Ioannis G.; Shvartsman, Stanislav Y.

2016-01-01

Regulated deformations of epithelial sheets are frequently foreshadowed by patterning of their mechanical properties. The connection between patterns of cell properties and the emerging tissue deformations is studied in multiple experimental systems, but the general principles remain poorly understood. For instance, it is in general unclear what determines the direction in which the patterned sheet is going to bend and whether the resulting shape transformation will be discontinuous or smooth. Here these questions are explored computationally, using vertex models of epithelial shells assembled from prismlike cells. In response to rings and patches of apical cell contractility, model epithelia smoothly deform into invaginated or evaginated shapes similar to those observed in embryos and tissue organoids. Most of the observed effects can be captured by a simpler model with polygonal cells, modified to include the effects of the apicobasal polarity and natural curvature of epithelia. Our models can be readily extended to include the effects of multiple constraints and used to describe a wide range of morphogenetic processes. PMID:27074691

Fluorescence-based detection and quantification of features of cellular senescence.

PubMed

Cho, Sohee; Hwang, Eun Seong

2011-01-01

Cellular senescence is a spontaneous organismal defense mechanism against tumor progression which is raised upon the activation of oncoproteins or other cellular environmental stresses that must be circumvented for tumorigenesis to occur. It involves growth-arrest state of normal cells after a number of active divisions. There are multiple experimental routes that can drive cells into a state of senescence. Normal somatic cells and cancer cells enter a state of senescence upon overexpression of oncogenic Ras or Raf protein or by imposing certain kinds of stress such as cellular tumor suppressor function. Both flow cytometry and confocal imaging analysis techniques are very useful in quantitative analysis of cellular senescence phenomenon. They allow quantitative estimates of multiple different phenotypes expressed in multiple cell populations simultaneously. Here we review the various types of fluorescence methodologies including confocal imaging and flow cytometry that are frequently utilized to study a variety of senescence. First, we discuss key cell biological changes occurring during senescence and review the current understanding on the mechanisms of these changes with the goal of improving existing protocols and further developing new ones. Next, we list specific senescence phenotypes associated with each cellular trait along with the principles of their assay methods and the significance of the assay outcomes. We conclude by selecting appropriate references that demonstrate a typical example of each method. Copyright © 2011 Elsevier Inc. All rights reserved.

Modeling the Development of Audiovisual Cue Integration in Speech Perception

PubMed Central

Getz, Laura M.; Nordeen, Elke R.; Vrabic, Sarah C.; Toscano, Joseph C.

2017-01-01

Adult speech perception is generally enhanced when information is provided from multiple modalities. In contrast, infants do not appear to benefit from combining auditory and visual speech information early in development. This is true despite the fact that both modalities are important to speech comprehension even at early stages of language acquisition. How then do listeners learn how to process auditory and visual information as part of a unified signal? In the auditory domain, statistical learning processes provide an excellent mechanism for acquiring phonological categories. Is this also true for the more complex problem of acquiring audiovisual correspondences, which require the learner to integrate information from multiple modalities? In this paper, we present simulations using Gaussian mixture models (GMMs) that learn cue weights and combine cues on the basis of their distributional statistics. First, we simulate the developmental process of acquiring phonological categories from auditory and visual cues, asking whether simple statistical learning approaches are sufficient for learning multi-modal representations. Second, we use this time course information to explain audiovisual speech perception in adult perceivers, including cases where auditory and visual input are mismatched. Overall, we find that domain-general statistical learning techniques allow us to model the developmental trajectory of audiovisual cue integration in speech, and in turn, allow us to better understand the mechanisms that give rise to unified percepts based on multiple cues. PMID:28335558

Modeling the Development of Audiovisual Cue Integration in Speech Perception.

PubMed

Getz, Laura M; Nordeen, Elke R; Vrabic, Sarah C; Toscano, Joseph C

2017-03-21

Adult speech perception is generally enhanced when information is provided from multiple modalities. In contrast, infants do not appear to benefit from combining auditory and visual speech information early in development. This is true despite the fact that both modalities are important to speech comprehension even at early stages of language acquisition. How then do listeners learn how to process auditory and visual information as part of a unified signal? In the auditory domain, statistical learning processes provide an excellent mechanism for acquiring phonological categories. Is this also true for the more complex problem of acquiring audiovisual correspondences, which require the learner to integrate information from multiple modalities? In this paper, we present simulations using Gaussian mixture models (GMMs) that learn cue weights and combine cues on the basis of their distributional statistics. First, we simulate the developmental process of acquiring phonological categories from auditory and visual cues, asking whether simple statistical learning approaches are sufficient for learning multi-modal representations. Second, we use this time course information to explain audiovisual speech perception in adult perceivers, including cases where auditory and visual input are mismatched. Overall, we find that domain-general statistical learning techniques allow us to model the developmental trajectory of audiovisual cue integration in speech, and in turn, allow us to better understand the mechanisms that give rise to unified percepts based on multiple cues.

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects.

PubMed

Bekerman, Elena; Neveu, Gregory; Shulla, Ana; Brannan, Jennifer; Pu, Szu-Yuan; Wang, Stanley; Xiao, Fei; Barouch-Bentov, Rina; Bakken, Russell R; Mateo, Roberto; Govero, Jennifer; Nagamine, Claude M; Diamond, Michael S; De Jonghe, Steven; Herdewijn, Piet; Dye, John M; Randall, Glenn; Einav, Shirit

2017-04-03

Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infection, sunitinib/erlotinib combination protected against morbidity and mortality. We validated sunitinib- and erlotinib-mediated inhibition of AAK1 and GAK activity as an important mechanism of antiviral action. Additionally, we revealed potential roles for additional kinase targets. These findings advance our understanding of virus-host interactions and establish a proof of principle for a repurposed, host-targeted approach to combat emerging viruses.

Etiology in psychiatry: embracing the reality of poly‐gene‐environmental causation of mental illness

PubMed Central

Uher, Rudolf; Zwicker, Alyson

2017-01-01

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in gene‐environment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment‐environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi‐factorial gene‐environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene‐environment studies. Future research may cut across psychiatric disorders and address poly‐causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly‐causation including gene‐environment and environment‐environment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools. PMID:28498595