Are You Trapped In a Cycle of Mindless Munching? 5 Common Signs

Cancer.gov

Have you ever sat down to watch TV only to notice a few minutes later that the bag of chips or pint of ice cream was completely empty? If so, then it’s likely you’ve experienced “mindless munching!”

21 CFR 520.1640 - Oxibendazole suspension.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... westeri). (3) Limitations. Administer by stomach tube in 3 to 4 pints of warm water, or by top dressing or... re-treated in 6 to 8 weeks. Not for use in horses intended for human consumption. Federal law...

27 CFR 7.28 - General requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... on a contrasting background. (b) Size of type—(1) Containers of more than one-half pint. Except for..., type, or printing not smaller than 2 millimeters. If contained among other descriptive or explanatory information, the script, type, or printing of all mandatory information shall be of a size substantially more...

Gas Velocities Reveal Newly Born Planets in a Disk

NASA Astrophysics Data System (ADS)

Kohler, Susanna

2018-06-01

Occasionally, science comes together beautifully for a discovery and sometimes this happens for more than one team at once! Today we explore how two independent collaborations of scientists simultaneously found the very first kinematic evidence for young planets forming in a protoplanetary disk. Though they explored the same disk, the two teams in fact discovered different planets.Evidence for PlanetsALMAs view of the dust in the protoplanetary disk surrounding the young star HD 163296. Todays studies explore not the dust, but the gas of this disk. [ALMA (ESO/NAOJ/NRAO); A. Isella; B. Saxton (NRAO/AUI/NSF)]Over the past three decades, weve detected around 4,000 fully formed exoplanets. Much more elusive, however, are the young planets still in the early stages of formation; only a handful of these have been discovered. More observations of early-stage exoplanets are needed in order to understand how these worlds are born in dusty protoplanetary-disk environments, how they grow their atmospheres, and how they evolve.Recent observations by the Atacama Large Millimeter/submillimeter Array (ALMA) have produced stunning images of protoplanetary disks. The unprecedented resolution of these images reveals substructure in the form of gaps and rings, hinting at the presence of planets that orbit within the disk and clear out their paths as they move. But there are also non-planet mechanisms that could produce such substructure, like grain growth around ice lines, or hydrodynamic instabilities in the disk.How can we definitively determine whether there are nascent planets embedded in these disks? Direct direction of a point source in a dust gap would be a strong confirmation, but now we have the next best thing: kinematic evidence for planets, from the motion of a disks gas.Observations of carbon monoxide line emission at +1km/s from the systemic velocity (left) vs. the outcome of a computer simulation (right) in the Pinte et al. study. A visible kink occurs in the flow, which can be reproduced by the presence of a 2-Jupiter-mass planet at 260 AU. [Pinte et al. 2018]Watching Gas MoveIn two papers published today in ApJL one led by Richard Teague (University of Michigan) and the other led by Christophe Pinte (Monash University in Australia and Grenoble Alpes University in France) astronomers have announced the detection of distinctive signs of planets in the gas motion of the disk surrounding HD 163296. This young star, located about 330 light-years away, is only 4 million years old.Unlike studies that hinge on observations of a disks dust which only makes up 1% of the disks mass! both studies here took a new approach: they used detailed ALMA observations revealing the dynamics of the disks carbon monoxide gas. By studying the gass motion, the teams found deviations from the Keplerian velocity that would be expected if there were no planets present. The authors then ran simulations to demonstrate that the deviations are consistent with local pressure perturbations caused by the passage of giant planets.Rotational velocity deviations due to changes in the local pressure, caused in this simulation by the presence of planets. [Teague et al. 2018]Giants FoundWhat did they find? Teague and collaborators, whose technique to identify velocity variations is best suited to explore the inner regions of the disk, discovered evidence for two separate Jupiter-mass planets orbiting at distances of 83 AU and 137 AU in the disk. Pinte and collaborators, whose velocity-measurement technique better explores the outer regions of the disk, found evidence for a two-Jupiter-mass planet orbiting at 260 AU.These results will rely on additional imaging in the coming years to confirm the presence of these newly born planets and a detection of point sources at these radii remains a hopeful goal for the future. Nonetheless, the new techniques explored here by Teague, Pinte, and collaborators are a promising route for young exoplanet discovery and characterization in other disks imaged by ALMA and future instruments.CitationRichard Teague et al 2018 ApJL 860 L12. doi:10.3847/2041-8213/aac6d7C. Pinte et al 2018 ApJL 860 L13. doi:10.3847/2041-8213/aac6dc

21 CFR 520.2380f - Thiabendazole, piperazine phosphate powder.

Code of Federal Regulations, 2013 CFR

2013-04-01

....2380f Thiabendazole, piperazine phosphate powder. (a) Specifications. Each ounce of water dispersible... oral dose. Administer as a drench or by stomach tube suspended in 1 pint of warm water; by dose syringe suspended in 1/2 ounce of water for each 100 pounds of body weight; or sprinkled over a small amount of...

21 CFR 520.2380f - Thiabendazole, piperazine phosphate powder.

Code of Federal Regulations, 2011 CFR

2011-04-01

....2380f Thiabendazole, piperazine phosphate powder. (a) Specifications. Each ounce of water dispersible... oral dose. Administer as a drench or by stomach tube suspended in 1 pint of warm water; by dose syringe suspended in 1/2 ounce of water for each 100 pounds of body weight; or sprinkled over a small amount of...

21 CFR 520.2380f - Thiabendazole, piperazine phosphate powder.

Code of Federal Regulations, 2010 CFR

2010-04-01

....2380f Thiabendazole, piperazine phosphate powder. (a) Specifications. Each ounce of water dispersible... oral dose. Administer as a drench or by stomach tube suspended in 1 pint of warm water; by dose syringe suspended in 1/2 ounce of water for each 100 pounds of body weight; or sprinkled over a small amount of...

42 CFR 489.31 - Allowable charges: Blood.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Allowable charges: Blood. 489.31 Section 489.31... Allowable charges: Blood. (a) Limitations on charges. (1) A provider may charge the beneficiary (or other person on his or her behalf) only for the first three pints of blood or units of packed red cells...

42 CFR 489.31 - Allowable charges: Blood.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 5 2011-10-01 2011-10-01 false Allowable charges: Blood. 489.31 Section 489.31... Allowable charges: Blood. (a) Limitations on charges. (1) A provider may charge the beneficiary (or other person on his or her behalf) only for the first three pints of blood or units of packed red cells...

42 CFR 489.31 - Allowable charges: Blood.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 5 2012-10-01 2012-10-01 false Allowable charges: Blood. 489.31 Section 489.31... Allowable charges: Blood. (a) Limitations on charges. (1) A provider may charge the beneficiary (or other person on his or her behalf) only for the first three pints of blood or units of packed red cells...

42 CFR 489.31 - Allowable charges: Blood.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 5 2014-10-01 2014-10-01 false Allowable charges: Blood. 489.31 Section 489.31... Allowable charges: Blood. (a) Limitations on charges. (1) A provider may charge the beneficiary (or other person on his or her behalf) only for the first three pints of blood or units of packed red cells...

42 CFR 489.31 - Allowable charges: Blood.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 5 2013-10-01 2013-10-01 false Allowable charges: Blood. 489.31 Section 489.31... Allowable charges: Blood. (a) Limitations on charges. (1) A provider may charge the beneficiary (or other person on his or her behalf) only for the first three pints of blood or units of packed red cells...

This Specialty Line of Clothing Really Is the "Bee's Knees"

ERIC Educational Resources Information Center

Hollingsworth, Jan Carter

2009-01-01

This article features "Bee's Knees," a specialty line of clothing. While not the typical product one would think of when considering mobility equipment, this line of clothing certainly does aid in helping those with disabilities access their world more safely and comfortably. "Bee's Knees" offers pint-sized pants made of kid-friendly, durable…

Reading Aloud: Spelling-Sound Translation Uses Central Attention

ERIC Educational Resources Information Center

O'Malley, Shannon; Reynolds, Michael G.; Stolz, Jennifer A.; Besner, Derek

2008-01-01

Contrary to the received view that reading aloud reflects processes that are "automatic," recent evidence suggests that some of these processes require a form of attention. This issue was investigated further by examining the effect of a prior presentation of exception words (words whose spelling-sound translation are atypical, such as pint as…

The effect of glass shape on alcohol consumption in a naturalistic setting: a feasibility study.

PubMed

Troy, David M; Maynard, Olivia M; Hickman, Matthew; Attwood, Angela S; Munafò, Marcus R

2015-12-01

Alcohol-related harms are a major public health concern, and population-level interventions are needed to reduce excessive alcohol consumption. Glass shape is an easily modifiable target for public health intervention. Laboratory findings show beer is consumed slower from a straight glass compared to a curved glass, but these findings have not been replicated in a naturalistic setting. The purpose of this study is to investigate the feasibility of conducting a randomised controlled trial investigating the effect of glass shape on alcohol consumption in public houses. Straight and curved half-pint and pint glasses were delivered to three public houses over two weekends. Glass type was counterbalanced over the two weekends and between the public houses. Monetary takings were recorded as an indirect measure of consumption. Replacing stocks of glassware in public houses was feasible and can be enacted in a short space of time. One landlord found the study too disruptive, possibly due to a laborious exchange of glassware and complaints about the new glassware from some customers. One public house's dishwasher could not accommodate the supplied curved full-pint glasses. Obtaining monetary takings from public house staff was a feasible and efficient way of measuring consumption, although reporting absolute amounts may be commercially sensitive. Monetary takings were reduced by 24 % (95 % confidence interval 77 % reduction to 29 % increase) when straight glasses were used compared to curved glasses. This study shows that it is feasible to carry out a trial investigating glass shape in a naturalistic environment, although a number of challenges were encountered. Brewery owners and landlords are willing to engage with public health research in settings where alcohol is consumed, such as public houses. Good communication with stakeholders was vital to acquire good data, and highlighting the potential commercial benefits of participating was vital to the study's success. A full scale evaluation of the effects of glass shape on alcohol consumption could inform local and national policy.

Pint-Sized Public Relations: The Development of Reputation Management.

PubMed

Silver, Ike M; Shaw, Alex

2018-04-01

Until recently, many psychologists were skeptical that young children cared about reputation. New evidence suggests that by age five, children begin to understand the broad importance of reputation and to engage in surprisingly sophisticated impression management. These findings prompt exciting new questions about the development of a fundamental social competency. Copyright © 2018 Elsevier Ltd. All rights reserved.

Boundary pint corrections for variable radius plots - simulation results

Treesearch

Margaret Penner; Sam Otukol

2000-01-01

The boundary plot problem is encountered when a forest inventory plot includes two or more forest conditions. Depending on the correction method used, the resulting estimates can be biased. The various correction alternatives are reviewed. No correction, area correction, half sweep, and toss-back methods are evaluated using simulation on an actual data set. Based on...

Statistical Forecasting of Bankruptcy of Defense Contractors. Problems and Prospects

DTIC Science & Technology

1994-01-01

investors is along the lines of the Capital Asset Pricing Model ( CAPM ). In portfolio theory generally, investors demand an expected-return premium for...Ellen Pint, Rachel Schmidt, and especially Dennis Smallwood of RAND also contributed useful insights and comments. xv Acronyms CAPM Capital Asset ...Bond Yields ............................................. 26 Bond Model Performance ................................. 27 Extensions and Limitations

77 FR 75112 - Agency Information Collection Activities: Existing Collection; Comment Request-Forms FNS-806-A...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

... Reimbursement, Forms FNS-806-A and FNS-806-B, respectively, are used to collect meal and milk data from school... order to determine the amount of reimbursement for meals and milk served, the school food authorities... based on performance that is measured as an assigned rate per meal or half pint of milk served. To...

The Milk in Schools Scheme, 1934-45: "Nationalization" and Resistance

ERIC Educational Resources Information Center

Atkins, Peter

2005-01-01

In October 1934 the National Government took over what had previously been a commercial initiative to encourage milk-drinking in schools. By the outbreak of war the Milk in Schools Scheme had reached 87 per cent of elementary schools in England and Wales and 56 per cent of pupils were drinking one-third of a pint daily. This paper investigates the…

Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards.

PubMed

Murray, John M; McBride, Kristin; Boesecke, Christoph; Bailey, Michelle; Amin, Janaki; Suzuki, Kazuo; Baker, David; Zaunders, John J; Emery, Sean; Cooper, David A; Koelsch, Kersten K; Kelleher, Anthony D

2012-03-13

We investigated the dynamics of HIV RNA and HIV DNA levels after the commencement of raltegravir-based antiretroviral therapy (ART) in primary (PHI) and chronically HIV-infected (CHI) individuals (the PINT study). We recruited 8 PHI and 8 CHI ART-naive individuals who commenced a 1-year combination regimen of Truvada and the integrase inhibitor raltegravir. Nonlinear mixed effects modelling was used to determine multiphasic decay of plasma HIV RNA levels (pVL), as well as dynamics of total, episomal [2-long terminal repeats (LTR)] and integrated HIV DNA in CD4 T cells from peripheral blood. Although pVL decreased faster through first and second phase for PHI individuals there was no difference in the final level reaching a mean of 9 copies/ml by week 16 that was maintained thereafter. Total HIV DNA and integrated HIV DNA levels from CHI patients were significantly higher than from PHI patients. However, at no time did 2-LTR levels differ between groups. Of note, 2-LTR circles exhibited an initial increase peaking at week 3 followed by biphasic decay with a half-life of 29 days. Second phase integrated HIV DNA levels were significantly correlated with duration of infection and consistent with this form of infection occurring at approximately 100 000 integration events per day in the absence of ART, achieving its 50% level 2 years after infection. Integrated HIV DNA levels accumulate with duration of untreated HIV infection. The relatively short half-life and high levels of 2-LTR circles after 1 year support continued HIV transmission during ART.

Portable Chemical Agent Detection System: Differential Reflectometer and Light Scattering Approaches

DTIC Science & Technology

2005-02-15

possible to conduct elemental analysis on modified capillaries because of the polymer coating. Instead, measurements of electroosmotic flow were used...design There are several essential requirements for a sensitive chemiluminescence cell (Figure 1); good reagent/analyte mixing for maximum photon yield...Cutaway of Chemiluminescence cell the cooled pint housing. In our design, the concentric inlets will increase photon collection due to better mixing of

Handbook for the Institutional and Financial Implementation of Water Utilities.

DTIC Science & Technology

1984-05-01

water . From a public health standpoint, water is necessary for drinking and sanitation. While public drinking water use aver- ages approximately 5 pints a... water . Domestic water includes that water furnished to homes, hotels, apartments, etc., for sanitary, drinking , washing, and other purposes. This use...with establishing Primary Drinking Water Standards under the Safe Drinking Water Act of 1974 (Public Law 93-523) for all public

[Script crossing in scanning electron microscopy].

PubMed

Oehmichen, M; von Kortzfleisch, D; Hegner, B

1989-01-01

A case of mixed script in which ball point-pen ink was contaminated with typewriting prompted a survey of the literature and a systematic SEM study of mixed script with various writing instruments or inks. Mixed scripts produced with the following instruments or inks were investigated: pencil, ink/India ink, ball-pint pen, felt-tip pen, copied script and typewriter. This investigation showed SEM to be the method of choice for visualizing overlying scripts produced by different writing instruments or inks.

Cold-Weather Engineering, Chapters 1 to 5

DTIC Science & Technology

1949-01-01

adäquate^, except under- extreme con~ ditiOns. of heat loss.. Milkr-Qrie ’pint or mo:re daily;. Eva-? poiiated or powdered milk is- $xistr äs good...as fi;esh milk . Egga^One or two, per day. Dehydrated ¥ggs are- äs good as- fresh eggs.-. Meat-One serving per day> ._ Äth some fat/ Liver...it.i Material for building, maintaining/ and lubricating the human engine is -obtained’ from proteins’ %ae.at;, fish, - milk ,, eggs), and

A Guide for Emergency Evacuation Management and Operations

DTIC Science & Technology

1981-02-01

such as scrambled eggs (A.M. meal) and hash or stew (P.M. meal). Frequent cold meals are possible. Some relocation guidance indicates that...cheese; and nuts) 4 lbs. with bone Eggs 6 eggs Milk (fresh) 7 pints (If fresh fluid milk is not available, see Exhibit 20.2 for acceptable substitutes...Unit Equivalent Unit Substitute Foods Meat and Meat 1/2 lb. Cereal and cereal products Alternates 1/4 lb. Food fats and oils 12 Eggs 1 lb. boneless 2-3

Direct Numerical Simulations of an Unpremixed Turbulent Jet Flame

DTIC Science & Technology

1988-03-01

shear layer. As the vortices reach the outflow boundary, the zero-gradient condition seems to allow them to travel out of the computational domain...ei Ii-t salp . Thiey- used pint ihe ustial d ependent variales. I1 Imerefre for r’- H(1/2 act1ig flows tile dimniensiomalit v of tilie vystveni call...seems to allow them to travel out of the computational domain. As mentioned in the previous section, the errors associated with this boundary condition

Common Genetic Variants in ARNTL and NPAS2 and at Chromosome 12p13 are Associated with Objectively Measured Sleep Traits in the Elderly

PubMed Central

Evans, Daniel S.; Parimi, Neeta; Nievergelt, Caroline M.; Blackwell, Terri; Redline, Susan; Ancoli-Israel, Sonia; Orwoll, Eric S.; Cummings, Steven R.; Stone, Katie L.; Tranah, Gregory J.

2013-01-01

Study Objectives: To determine the association between common genetic variation in the clock gene pathway and objectively measured acti-graphic sleep and activity rhythm traits. Design: Genetic association study in two population-based cohorts of elderly participants: the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men (MrOS) study. Setting: Population-based. Participants: SOF participants (n = 1,407, 100% female, mean age 84 years) and MrOS participants (n = 2,527, 100% male, mean age 77 years) with actigraphy and genotype data. Interventions: N/A. Measurements and Results: Common genetic variation in 30 candidate genes was captured using 529 single nucleotide polymorphisms (SNPs). Sleep and activity rhythm traits were objectively measured using wrist actigraphy. In a region of high linkage disequilibrium on chromosome 12p13 containing the candidate gene GNB3, the rs1047776 A allele and the rs2238114 C allele were significantly associated with higher wake after sleep onset (meta-analysis: rs1047776 PADD = 2 × 10-5, rs2238114 PADD = 5 × 10-5) and lower LRRC23 gene expression (rs1047776: ρ = -0.22, P = 0.02; rs2238114: ρ = -0.50, P = 5 × 10-8). In MrOS participants, SNPs in ARNTL and NPAS2, genes coding for binding partners, were associated with later sleep and wake onset time (sleep onset time: ARNTL rs3816358 P2DF = 1 × 10-4, NPAS2 rs3768984 P2DF = 5 × 10-5; wake onset time: rs3816358 P2DF = 3 × 10-3, rs3768984 P2DF = 2 × 10-4) and the SNP interaction was significant (sleep onset time PINT = 0.003, wake onset time PINT = 0.001). A SNP association in the CLOCK gene replicated in the MrOS cohort, and rs3768984 was associated with sleep duration in a previously reported study. Cluster analysis identified four clusters of genetic associations. Conclusions: These findings support a role for common genetic variation in clock genes in the regulation of inter-related sleep traits in the elderly. Citation: Evans DS; Parimi N; Nievergelt CM; Blackwell T; Redline S; Ancoli-Israel S; Orwoll ES; Cummings SR; Stone KL; Tranah GJ. Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. SLEEP 2013;36(3):431-446. PMID:23449886

Psychosocial Work Factors and Musculoskeletal Pain: A Cross-Sectional Study among Swedish Flight Baggage Handlers

PubMed Central

Mathiassen, S. E.; Vingård, E.

2015-01-01

Objective. Flight baggage handlers sort and load luggage to airplanes. This study aimed at investigating associations between psychosocial exposures and low back and shoulder musculoskeletal disorders (MSDs) among Swedish flight baggage handlers. Methods. A questionnaire addressing MSDs (Standardized Nordic Questionnaire) and psychosocial factors (Copenhagen Psychosocial Questionnaire, COPSOQ) was answered by 525 baggage handlers in six Swedish airports. Results. Low back (LBP) and shoulder pain (SP) were reported by 70% and 60%, respectively. Pain was reported to interfere with work (PIW) by 30% (low back) and 18% (shoulders), and intense pain (PINT) occurred in 34% and 28% of the population. Quality of leadership was the most dissatisfying psychosocial factor, while the most positive was social community at work. Low ratings in the combined domain Work organization and job content were significantly associated with PIW in both low back and shoulders (Adjusted Hazard Ratios 3.65 (95% CI 1.67–7.99) and 2.68 (1.09–6.61)) while lower ratings in the domain Interpersonal relations and leadership were associated with PIW LBP (HR 2.18 (1.06–4.49)) and PINT LBP and SP (HRs 1.95 (1.05–3.65) and 2.11 (1.08–4.12)). Conclusion. Severity of pain among flight baggage handlers was associated with psychosocial factors at work, suggesting that they may be a relevant target for intervention in this occupation. PMID:26558282

Ambient air pollution and adverse birth outcomes: Differences by maternal comorbidities.

PubMed

Lavigne, Eric; Yasseen, Abdool S; Stieb, David M; Hystad, Perry; van Donkelaar, Aaron; Martin, Randall V; Brook, Jeffrey R; Crouse, Daniel L; Burnett, Richard T; Chen, Hong; Weichenthal, Scott; Johnson, Markey; Villeneuve, Paul J; Walker, Mark

2016-07-01

Prenatal exposure to ambient air pollution has been associated with adverse birth outcomes, but the potential modifying effect of maternal comorbidities remains understudied. Our objective was to investigate whether associations between prenatal air pollution exposures and birth outcomes differ by maternal comorbidities. A total of 818,400 singleton live births were identified in the province of Ontario, Canada from 2005 to 2012. We assigned exposures to fine particulate matter (PM2.5), nitrogen dioxide (NO2) and ozone (O3) to maternal residences during pregnancy. We evaluated potential effect modification by maternal comorbidities (i.e. asthma, hypertension, pre-existing diabetes mellitus, heart disease, gestational diabetes and preeclampsia) on the associations between prenatal air pollution and preterm birth, term low birth weight and small for gestational age. Interquartile range (IQR) increases in PM2.5 (2μg/m(3)), NO2 (9ppb) and O3 (5ppb) over the entire pregnancy were associated with a 4% (95% CI: 2.4-5.6%), 8.4% (95% CI: 5.5-10.3%) and 2% (95% CI: 0.5-4.1%) increase in the odds of preterm birth, respectively. Increases of 10.6% (95% CI: 0.2-2.1%) and 23.8% (95% CI: 5.5-44.8%) in the odds of preterm birth were observed among women with pre-existing diabetes while the increases were of 3.8% (95% CI: 2.2-5.4%) and 6.5% (95% CI: 3.7-8.4%) among women without this condition for pregnancy exposure to PM2.5 and NO2, respectively (Pint<0.01). The increase in the odds of preterm birth for exposure to PM2.5 during pregnancy was higher among women with preeclampsia (8.3%, 95% CI: 0.8-16.4%) than among women without (3.6%, 95% CI: 1.8-5.3%) (Pint=0.04). A stronger increase in the odds of preterm birth was found for exposure to O3 during pregnancy among asthmatic women (12.0%, 95% CI: 3.5-21.1%) compared to non-asthmatic women (2.0%, 95% CI: 0.1-3.5%) (Pint<0.01). We did not find statistically significant effect modification for the other outcomes investigated. Findings of this study suggest that associations of ambient air pollution with preterm birth are stronger among women with pre-existing diabetes, asthma, and preeclampsia. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Credit WCT. Original 2Y4" x 2Y4" color negative is housed ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Credit WCT. Original 2-Y4" x 2-Y4" color negative is housed in the JPL Photography Laboratory, Pasadena, California. JPL staff members Harold Anderson and John Morrow cast grain from the 1-gallon BakerPerkins model 4-PU mixer. A 1-pint Baker-Perkins model 2-PX mixer stands to the left in this view (JPL negative no. JPL-10295BC, 27 January 1989) - Jet Propulsion Laboratory Edwards Facility, Mixer & Casting Building, Edwards Air Force Base, Boron, Kern County, CA

The Diagnostic Rhyme Test (DRT): An Air Force Implementation

DTIC Science & Technology

1978-05-01

I Deputy for Electronic Technology (RADC/E-. I May 07 8____ Is MONSI0RIN,. ACENCY NAME A ADONESS,, dilletiot from, Cont-l,’t. oil ".) i Sf1ý.ujlT...page reader and extracts the following information: 1. Svste mn 11). 2. Listener ID. 3. Word List ID. 4. Speaker ID. 5. Page number. 6. The responses...Bome GNAW BOCK ROss No" sNOES OOZE POO" THOUGH CHOOSE THOSE POo COUGH CHEEP SINS THEE OIL ? KEEP THING ZEE JILT DANK NET FAD PINT BANK MET THAO TENT DOT

Failure Modes, Effects and Criticality Analysis (FMECA) of Type AN/GRN-27 (V) Instrument Landing System with Traveling-Wave Localizer Antenna.

DTIC Science & Technology

1983-02-01

reference glideslope). three an- common to tennas. both trans- ,11 =. 635 nitters), an side band immediate ref.) shutdown after an automatic IlA transfer will...CONDITION PRESENT: PINT CL 5.n8X 10-. BI8 HR)2 + (1.14O X10-6 .168 HR) _ 1.g2X10-4 PCF =___ - 4X XX10- 44.1J2 + 13 ~C (~j7X10-2 4 4 8 PCLVA )(1.92 X 10

Saugus River and Tributaries, Lynn Malden, Revere and Saugus, Massachusetts. Flood Damage Reduction. Volume 6. Appendix I. Planning Correspondence: Lynn, Malden, Revere, Saugus, Interest Groups, and News Articles

DTIC Science & Technology

1989-06-01

Development Representative Alfred 9. Saggesse Mabel Voodcock Robert Fox Fred Milton G73 PINES RIVERSIDE ASSOCIATION REVERE, MASSACHUSETTS 02151 April...28 Rice Ave. Revere, Massachusetts 02151 Dear Mr. Piccinni: I appreciate your willingness to sit on the Citizens’ Steering Comittee for the Saugus...Pint t/ nej sack 6 I 9nc. 2S RICE AVENUE, REVERE, MASS. 02151 Telephone 284-9717 Mr. Joseph L. Ignazio March 30, 1987 Chief, Planning Division New

Developmental changes in brain regions involved in phonological and orthographic processing during spoken language processing

PubMed Central

Cone, Nadia E.; Burman, Douglas D.; Bitan, Tali; Bolger, Donald J.; Booth, James R.

2008-01-01

Developmental differences in brain activation of 9- to 15-year-old children were examined during an auditory rhyme decision task to spoken words using functional magnetic resonance imaging (fMRI). As a group, children showed activation in left superior/middle temporal gyri (BA 22, 21), right middle temporal gyrus (BA 21), dorsal (BA 45, pars opercularis) and ventral (BA 46, pars triangularis) aspects of left inferior frontal gyrus, and left fusiform gyrus (BA 37). There was a developmental increase in activation in left middle temporal gyrus (BA 22) across all lexical conditions, suggesting that automatic semantic processing increases with age regardless of task demands. Activation in left dorsal inferior frontal gyrus also showed developmental increases for the conflicting (e.g. PINT-MINT) compared to the non-conflicting (e.g. PRESS-LIST) non-rhyming conditions, indicating that this area becomes increasingly involved in strategic phonological processing in the face of conflicting orthographic and phonological representations. Left inferior temporal/fusiform gyrus (BA 37) activation was also greater for the conflicting (e.g. PINT-MINT) condition, and a developmental increase was found in the positive relationship between individuals' reaction time and activation in left lingual/fusiform gyrus (BA 18) in this condition, indicating an age-related increase in the association between longer reaction times and greater visual-orthographic processing in this conflicting condition. These results suggest that orthographic processing is automatically engaged by children in a task that does not require access to orthographic information for correct performance, especially when orthographic and phonological representations conflict, and especially for longer response latencies in older children. PMID:18413290

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin--Insights From the ENGAGE AF-TIMI 48 Trial.

PubMed

Shimada, Yuichi J; Yamashita, Takeshi; Koretsune, Yukihiro; Kimura, Tetsuya; Abe, Kenji; Sasaki, Shunichi; Mercuri, Michele; Ruff, Christian T; Giugliano, Robert P

2015-01-01

In 21,105 patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial, edoxaban was non-inferior to warfarin in preventing thromboembolic events while reducing bleeding. We compared results in Japan with the rest of East Asia (EA), including China, Korea, and Taiwan. We compared baseline characteristics, time-in-therapeutic range (TTR) for warfarin, and outcomes (efficacy: stroke or systemic embolic events [SEE], safety: major bleeding). Interaction P values were used to assess for effect modification of treatment (higher-dose edoxaban [HDE, 60 mg/30 mg] vs. warfarin; lower-dose edoxaban [LDE, 30 mg/15 mg] vs. warfarin) by region with adjustments for baseline characteristics. Fewer patients in Japan (n=1,010) were female, taking aspirin or amiodarone, naïve to warfarin (P<0.001 for each), had a history of stroke or transient ischemic attack (P=0.02), and more patients needed dose reduction (P<0.001) compared with EA (n=933). The mean TTR was higher in Japan (70% vs. 56%, P<0.001). Evidence for statistical interactions was observed for HDE vs. warfarin by region for stroke/SEE (adjusted P-int=0.052) and major bleeding (adjusted P-int=0.048) with greater relative efficacy and safety with HDE in EA compared with Japan. No interactions were observed for LDE vs. warfarin after adjustment. HDE had a greater relative efficacy and safety in EA compared with Japan that was only partially explained by differences in baseline characteristics and TTR.

The role of alcohol in forging and maintaining friendships amongst Scottish men in midlife.

PubMed

Emslie, Carol; Hunt, Kate; Lyons, Antonia

2013-01-01

Men drink more heavily and are more likely to die from alcohol-related causes than women. Most alcohol research focuses on young drinkers. We describe the context of men's drinking in midlife and explore how alcohol is associated with the construction of masculinities. Qualitative research was used to examine the social context of drinking alcohol. We conducted 15 focus groups (single and mixed sex) with respondents in the west of Scotland, United Kingdom. Here we focus on the findings from 22 men aged 28 to 52 years. Men regarded drinking pints of beer in the pub together as an "act of friendship" and this functioned as a hegemonically appropriate way to communicate with and support each other. However, male friends also constructed some nonhegemonic behaviors as forgivable-and indeed acceptable-while drinking alcohol together. This included practices such as the explicit discussion of emotions and mental health and the consumption of "feminine" drinks under certain circumstances (e.g., in private, with close friends). This exploration of drinking reveals the fluidity of gender constructions-and the strategic ways in which men take up positions around hegemonic masculinity-in midlife. The close interweaving of drinking pints in the pub with notions of male friendship could lead to both health-damaging (excessive drinking) and potentially health-promoting (social support) behaviors. Health promotion experts need to be sensitive to cultural constructions of gender to address the high rates of drinking in this age group. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Multivariate Lipschitz optimization: Survey and computational comparison

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

Hansen, P.; Gourdin, E.; Jaumard, B.

1994-12-31

Many methods have been proposed to minimize a multivariate Lipschitz function on a box. They pertain the three approaches: (i) reduction to the univariate case by projection (Pijavskii) or by using a space-filling curve (Strongin); (ii) construction and refinement of a single upper bounding function (Pijavskii, Mladineo, Mayne and Polak, Jaumard Hermann and Ribault, Wood...); (iii) branch and bound with local upper bounding functions (Galperin, Pint{acute e}r, Meewella and Mayne, the present authors). A survey is made, stressing similarities of algorithms, expressed when possible within a unified framework. Moreover, an extensive computational comparison is reported on.

Sinking bubbles in stout beers

NASA Astrophysics Data System (ADS)

Lee, W. T.; Kaar, S.; O'Brien, S. B. G.

2018-04-01

A surprising phenomenon witnessed by many is the sinking bubbles seen in a settling pint of stout beer. Bubbles are less dense than the surrounding fluid so how does this happen? Previous work has shown that the explanation lies in a circulation of fluid promoted by the tilted sides of the glass. However, this work has relied heavily on computational fluid dynamics (CFD) simulations. Here, we show that the phenomenon of sinking bubbles can be predicted using a simple analytic model. To make the model analytically tractable, we work in the limit of small bubbles and consider a simplified geometry. The model confirms both the existence of sinking bubbles and the previously proposed mechanism.

Conference Proceedings of International High Speed Networks for Scientific and Technical Information, Held at Ottawa, Canada on 6-7 October 1993 (Les Reseaux Internationaux Rapides D’Echange D’Information Scientifique et Technique)

DTIC Science & Technology

1994-02-01

examined issues, such asstandards, security, management , property rihts/copyright, etc., ftom the pint of view of the end user, the information provider...de lIST sur l’afrospatiale, Is difense et sur d’autres domaines. Toutefois, l’imergence de ces r6scaux laisse poindre certaines preoccupations et...questions. Cette riunion de spdcialistes des pays de I’OTAN a permis de faire It survol de Ia situation, d’evaluer le potentiel d’avenir et d’examiner

Initial steps toward automation of a propellant processor

NASA Technical Reports Server (NTRS)

Schallhorn, Paul; Ramohalli, Kumar

1990-01-01

This paper presents the results from an experimental study aimed at ultimately automating the mixing of propellants in order to minimize unintended variations usually attributed to human error. The water heater and delivery system of a one-pint Baker-Perkins (APV) vertical mixer are automated with computer control. Various innovations are employed to introduce economy and low thermal inertia. Some of these include twin heaters/reservoirs instead of one large reservoir, a compact water mixer for achieving the desired temperature quickly, and thorough insulation of the entire water system. The completed system is tested during two propellant mixes. The temperature uniformly is proven through careful measurements employing several local thermocouples.

Floral pathway integrator gene expression mediates gradual transmission of environmental and endogenous cues to flowering time.

PubMed

van Dijk, Aalt D J; Molenaar, Jaap

2017-01-01

The appropriate timing of flowering is crucial for the reproductive success of plants. Hence, intricate genetic networks integrate various environmental and endogenous cues such as temperature or hormonal statues. These signals integrate into a network of floral pathway integrator genes. At a quantitative level, it is currently unclear how the impact of genetic variation in signaling pathways on flowering time is mediated by floral pathway integrator genes. Here, using datasets available from literature, we connect Arabidopsis thaliana flowering time in genetic backgrounds varying in upstream signalling components with the expression levels of floral pathway integrator genes in these genetic backgrounds. Our modelling results indicate that flowering time depends in a quite linear way on expression levels of floral pathway integrator genes. This gradual, proportional response of flowering time to upstream changes enables a gradual adaptation to changing environmental factors such as temperature and light.

Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study

PubMed Central

Rudolph, Anja; Hein, Rebecca; Lindström, Sara; Beckmann, Lars; Behrens, Sabine; Liu, Jianjun; Aschard, Hugues; Bolla, Manjeet K.; Wang, Jean; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; Brüning, Thomas; Harth, Volker; Severi, Gianluca; Baglietto, Laura; Southey, Melissa; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Eriksson, Mikael; Humpreys, Keith; Darabi, Hatef; Olson, Janet E.; Stevens, Kristen N.; Vachon, Celine M.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Webb, Penny M.; Guénel, Pascal; Brauch, Hiltrud; Giles, Graham; García-Closas, Montserrat; Czene, Kamila; Chenevix-Trench, Georgia; Couch, Fergus J.; Andrulis, Irene L.; Swerdlow, Anthony; Hunter, David J.; Flesch-Janys, Dieter; Easton, Douglas F.; Hall, Per; Nevanlinna, Heli; Kraft, Peter; Chang-Claude, Jenny

2013-01-01

Women using menopausal hormone therapy (MHT) are at increased risk to develop breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in eleven case-control studies. We used a case-only design to assess interactions between single nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2,920 cases (541 lobular) from four genome-wide association studies. The top 1,391 SNPs showing P-values for interaction (Pint) <3.0×10−03 were selected for replication using pooled case-control data from eleven studies of the Breast Cancer Association Consortium, including 7,689 cases (676 lobular) and 9,266 controls. Fixed effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9×10−06), two SNPs in SLC25A21 (combined Pint≤4.8×10−05), and three SNPs in PLCG2 (combined Pint≤4.5×10−05). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7×10−05), one SNP in CD80 (combined Pint≤8.2×10−06), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10−06), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6×10−05). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies. PMID:24080446

Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort.

PubMed

Abbas, Sascha; Ihle, Peter; Harder, Sebastian; Schubert, Ingrid

2014-05-05

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenprocoumon users ≥ 18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20-2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84-2.38 and OR 1.34, 95% CI 1.03-1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62-3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08-4.84) and fluorquinolones (OR 3.13, 95% CI 2.74-3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01-8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics - particularly quinolones and cotrimoxazole - should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.

Pathview: an R/Bioconductor package for pathway-based data integration and visualization.

PubMed

Luo, Weijun; Brouwer, Cory

2013-07-15

Pathview is a novel tool set for pathway-based data integration and visualization. It maps and renders user data on relevant pathway graphs. Users only need to supply their data and specify the target pathway. Pathview automatically downloads the pathway graph data, parses the data file, maps and integrates user data onto the pathway and renders pathway graphs with the mapped data. Although built as a stand-alone program, Pathview may seamlessly integrate with pathway and functional analysis tools for large-scale and fully automated analysis pipelines. The package is freely available under the GPLv3 license through Bioconductor and R-Forge. It is available at http://bioconductor.org/packages/release/bioc/html/pathview.html and at http://Pathview.r-forge.r-project.org/. luo_weijun@yahoo.com Supplementary data are available at Bioinformatics online.

Pathview Web: user friendly pathway visualization and data integration

PubMed Central

Pant, Gaurav; Bhavnasi, Yeshvant K.; Blanchard, Steven G.; Brouwer, Cory

2017-01-01

Abstract Pathway analysis is widely used in omics studies. Pathway-based data integration and visualization is a critical component of the analysis. To address this need, we recently developed a novel R package called Pathview. Pathview maps, integrates and renders a large variety of biological data onto molecular pathway graphs. Here we developed the Pathview Web server, as to make pathway visualization and data integration accessible to all scientists, including those without the special computing skills or resources. Pathview Web features an intuitive graphical web interface and a user centered design. The server not only expands the core functions of Pathview, but also provides many useful features not available in the offline R package. Importantly, the server presents a comprehensive workflow for both regular and integrated pathway analysis of multiple omics data. In addition, the server also provides a RESTful API for programmatic access and conveniently integration in third-party software or workflows. Pathview Web is openly and freely accessible at https://pathview.uncc.edu/. PMID:28482075

Mining and integration of pathway diagrams from imaging data.

PubMed

Kozhenkov, Sergey; Baitaluk, Michael

2012-03-01

Pathway diagrams from PubMed and World Wide Web (WWW) contain valuable highly curated information difficult to reach without tools specifically designed and customized for the biological semantics and high-content density of the images. There is currently no search engine or tool that can analyze pathway images, extract their pathway components (molecules, genes, proteins, organelles, cells, organs, etc.) and indicate their relationships. Here, we describe a resource of pathway diagrams retrieved from article and web-page images through optical character recognition, in conjunction with data mining and data integration methods. The recognized pathways are integrated into the BiologicalNetworks research environment linking them to a wealth of data available in the BiologicalNetworks' knowledgebase, which integrates data from >100 public data sources and the biomedical literature. Multiple search and analytical tools are available that allow the recognized cellular pathways, molecular networks and cell/tissue/organ diagrams to be studied in the context of integrated knowledge, experimental data and the literature. BiologicalNetworks software and the pathway repository are freely available at www.biologicalnetworks.org. Supplementary data are available at Bioinformatics online.

[Challenges in geriatric rehabilitation: the development of an integrated care pathway].

PubMed

Everink, Irma Helga Johanna; van Haastregt, Jolanda C M; Kempen, Gertrudis I J M; Dielis, Leen M J; Maessen, José M C; Schols, Jos M G A

2015-04-01

Coordination and continuity of care within geriatric rehabilitation is challenging. To tackle these challenges, an integrated care pathway within geriatric rehabilitation care (hospital, geriatric rehabilitation and follow-up care in the home situation) has been developed. The aim of this article is to expound the process of developing the integrated care pathway, and to describe and discuss the results of this process (which is the integrated care pathway). Developing the integrated care pathway was done by the guidance of the first four steps of the theoretical framework for implementation of change from Grol and Wensing: (1) development of a specific proposal for change in practice; (2) analysis of current care practice; (3) analysis of the target group and setting; and (4) development and selection of interventions/strategies for change. The organizations involved in geriatric rehabilitation argued that the integrated care pathway should focus on improving the process of care, including transfer of patients, handovers and communication between care organizations. Current practice, barriers and incentives for change were analyzed through literature research, expert consultation, and interviews with the involved caregivers and by establishing working groups of health care professionals, patients and informal caregivers. This resulted in valuable proposals for improvement of the care process, which were gathered and combined in the integrated care pathway. The integrated care pathway entails agreements on (a) the triage process in the hospital; (b) active engagement of patients and informal caregivers in the care process; (c) timely and high quality handovers; and (d) improved communication between caregivers.

Using the Semantic Web for Rapid Integration of WikiPathways with Other Biological Online Data Resources

PubMed Central

Waagmeester, Andra; Pico, Alexander R.

2016-01-01

The diversity of online resources storing biological data in different formats provides a challenge for bioinformaticians to integrate and analyse their biological data. The semantic web provides a standard to facilitate knowledge integration using statements built as triples describing a relation between two objects. WikiPathways, an online collaborative pathway resource, is now available in the semantic web through a SPARQL endpoint at http://sparql.wikipathways.org. Having biological pathways in the semantic web allows rapid integration with data from other resources that contain information about elements present in pathways using SPARQL queries. In order to convert WikiPathways content into meaningful triples we developed two new vocabularies that capture the graphical representation and the pathway logic, respectively. Each gene, protein, and metabolite in a given pathway is defined with a standard set of identifiers to support linking to several other biological resources in the semantic web. WikiPathways triples were loaded into the Open PHACTS discovery platform and are available through its Web API (https://dev.openphacts.org/docs) to be used in various tools for drug development. We combined various semantic web resources with the newly converted WikiPathways content using a variety of SPARQL query types and third-party resources, such as the Open PHACTS API. The ability to use pathway information to form new links across diverse biological data highlights the utility of integrating WikiPathways in the semantic web. PMID:27336457

Using the Semantic Web for Rapid Integration of WikiPathways with Other Biological Online Data Resources.

PubMed

Waagmeester, Andra; Kutmon, Martina; Riutta, Anders; Miller, Ryan; Willighagen, Egon L; Evelo, Chris T; Pico, Alexander R

2016-06-01

The diversity of online resources storing biological data in different formats provides a challenge for bioinformaticians to integrate and analyse their biological data. The semantic web provides a standard to facilitate knowledge integration using statements built as triples describing a relation between two objects. WikiPathways, an online collaborative pathway resource, is now available in the semantic web through a SPARQL endpoint at http://sparql.wikipathways.org. Having biological pathways in the semantic web allows rapid integration with data from other resources that contain information about elements present in pathways using SPARQL queries. In order to convert WikiPathways content into meaningful triples we developed two new vocabularies that capture the graphical representation and the pathway logic, respectively. Each gene, protein, and metabolite in a given pathway is defined with a standard set of identifiers to support linking to several other biological resources in the semantic web. WikiPathways triples were loaded into the Open PHACTS discovery platform and are available through its Web API (https://dev.openphacts.org/docs) to be used in various tools for drug development. We combined various semantic web resources with the newly converted WikiPathways content using a variety of SPARQL query types and third-party resources, such as the Open PHACTS API. The ability to use pathway information to form new links across diverse biological data highlights the utility of integrating WikiPathways in the semantic web.

Pathview Web: user friendly pathway visualization and data integration.

PubMed

Luo, Weijun; Pant, Gaurav; Bhavnasi, Yeshvant K; Blanchard, Steven G; Brouwer, Cory

2017-07-03

Pathway analysis is widely used in omics studies. Pathway-based data integration and visualization is a critical component of the analysis. To address this need, we recently developed a novel R package called Pathview. Pathview maps, integrates and renders a large variety of biological data onto molecular pathway graphs. Here we developed the Pathview Web server, as to make pathway visualization and data integration accessible to all scientists, including those without the special computing skills or resources. Pathview Web features an intuitive graphical web interface and a user centered design. The server not only expands the core functions of Pathview, but also provides many useful features not available in the offline R package. Importantly, the server presents a comprehensive workflow for both regular and integrated pathway analysis of multiple omics data. In addition, the server also provides a RESTful API for programmatic access and conveniently integration in third-party software or workflows. Pathview Web is openly and freely accessible at https://pathview.uncc.edu/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

PathJam: a new service for integrating biological pathway information.

PubMed

Glez-Peña, Daniel; Reboiro-Jato, Miguel; Domínguez, Rubén; Gómez-López, Gonzalo; Pisano, David G; Fdez-Riverola, Florentino

2010-10-28

Biological pathways are crucial to much of the scientific research today including the study of specific biological processes related with human diseases. PathJam is a new comprehensive and freely accessible web-server application integrating scattered human pathway annotation from several public sources. The tool has been designed for both (i) being intuitive for wet-lab users providing statistical enrichment analysis of pathway annotations and (ii) giving support to the development of new integrative pathway applications. PathJam’s unique features and advantages include interactive graphs linking pathways and genes of interest, downloadable results in fully compatible formats, GSEA compatible output files and a standardized RESTful API.

Dissecting Cell-Fate Determination Through Integrated Mathematical Modeling of the ERK/MAPK Signaling Pathway.

PubMed

Shin, Sung-Young; Nguyen, Lan K

2017-01-01

The past three decades have witnessed an enormous progress in the elucidation of the ERK/MAPK signaling pathway and its involvement in various cellular processes. Because of its importance and complex wiring, the ERK pathway has been an intensive subject for mathematical modeling, which facilitates the unraveling of key dynamic properties and behaviors of the pathway. Recently, however, it became evident that the pathway does not act in isolation but closely interacts with many other pathways to coordinate various cellular outcomes under different pathophysiological contexts. This has led to an increasing number of integrated, large-scale models that link the ERK pathway to other functionally important pathways. In this chapter, we first discuss the essential steps in model development and notable models of the ERK pathway. We then use three examples of integrated, multipathway models to investigate how crosstalk of ERK signaling with other pathways regulates cell-fate decision-making in various physiological and disease contexts. Specifically, we focus on ERK interactions with the phosphoinositide-3 kinase (PI3K), c-Jun N-terminal kinase (JNK), and β-adrenergic receptor (β-AR) signaling pathways. We conclude that integrated modeling in combination with wet-lab experimentation have been and will be instrumental in gaining an in-depth understanding of ERK signaling in multiple biological contexts.

Systematic analysis of signaling pathways using an integrative environment.

PubMed

Visvanathan, Mahesh; Breit, Marc; Pfeifer, Bernhard; Baumgartner, Christian; Modre-Osprian, Robert; Tilg, Bernhard

2007-01-01

Understanding the biological processes of signaling pathways as a whole system requires an integrative software environment that has comprehensive capabilities. The environment should include tools for pathway design, visualization, simulation and a knowledge base concerning signaling pathways as one. In this paper we introduce a new integrative environment for the systematic analysis of signaling pathways. This system includes environments for pathway design, visualization, simulation and a knowledge base that combines biological and modeling information concerning signaling pathways that provides the basic understanding of the biological system, its structure and functioning. The system is designed with a client-server architecture. It contains a pathway designing environment and a simulation environment as upper layers with a relational knowledge base as the underlying layer. The TNFa-mediated NF-kB signal trans-duction pathway model was designed and tested using our integrative framework. It was also useful to define the structure of the knowledge base. Sensitivity analysis of this specific pathway was performed providing simulation data. Then the model was extended showing promising initial results. The proposed system offers a holistic view of pathways containing biological and modeling data. It will help us to perform biological interpretation of the simulation results and thus contribute to a better understanding of the biological system for drug identification.

Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.

PubMed

Cavill, Rachel; Kamburov, Atanas; Ellis, James K; Athersuch, Toby J; Blagrove, Marcus S C; Herwig, Ralf; Ebbels, Timothy M D; Keun, Hector C

2011-03-01

Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.

An ontology-driven semantic mash-up of gene and biological pathway information: Application to the domain of nicotine dependence

PubMed Central

Sahoo, Satya S.; Bodenreider, Olivier; Rutter, Joni L.; Skinner, Karen J.; Sheth, Amit P.

2008-01-01

Objectives This paper illustrates how Semantic Web technologies (especially RDF, OWL, and SPARQL) can support information integration and make it easy to create semantic mashups (semantically integrated resources). In the context of understanding the genetic basis of nicotine dependence, we integrate gene and pathway information and show how three complex biological queries can be answered by the integrated knowledge base. Methods We use an ontology-driven approach to integrate two gene resources (Entrez Gene and HomoloGene) and three pathway resources (KEGG, Reactome and BioCyc), for five organisms, including humans. We created the Entrez Knowledge Model (EKoM), an information model in OWL for the gene resources, and integrated it with the extant BioPAX ontology designed for pathway resources. The integrated schema is populated with data from the pathway resources, publicly available in BioPAX-compatible format, and gene resources for which a population procedure was created. The SPARQL query language is used to formulate queries over the integrated knowledge base to answer the three biological queries. Results Simple SPARQL queries could easily identify hub genes, i.e., those genes whose gene products participate in many pathways or interact with many other gene products. The identification of the genes expressed in the brain turned out to be more difficult, due to the lack of a common identification scheme for proteins. Conclusion Semantic Web technologies provide a valid framework for information integration in the life sciences. Ontology-driven integration represents a flexible, sustainable and extensible solution to the integration of large volumes of information. Additional resources, which enable the creation of mappings between information sources, are required to compensate for heterogeneity across namespaces. Resource page http://knoesis.wright.edu/research/lifesci/integration/structured_data/JBI-2008/ PMID:18395495

An ontology-driven semantic mashup of gene and biological pathway information: application to the domain of nicotine dependence.

PubMed

Sahoo, Satya S; Bodenreider, Olivier; Rutter, Joni L; Skinner, Karen J; Sheth, Amit P

2008-10-01

This paper illustrates how Semantic Web technologies (especially RDF, OWL, and SPARQL) can support information integration and make it easy to create semantic mashups (semantically integrated resources). In the context of understanding the genetic basis of nicotine dependence, we integrate gene and pathway information and show how three complex biological queries can be answered by the integrated knowledge base. We use an ontology-driven approach to integrate two gene resources (Entrez Gene and HomoloGene) and three pathway resources (KEGG, Reactome and BioCyc), for five organisms, including humans. We created the Entrez Knowledge Model (EKoM), an information model in OWL for the gene resources, and integrated it with the extant BioPAX ontology designed for pathway resources. The integrated schema is populated with data from the pathway resources, publicly available in BioPAX-compatible format, and gene resources for which a population procedure was created. The SPARQL query language is used to formulate queries over the integrated knowledge base to answer the three biological queries. Simple SPARQL queries could easily identify hub genes, i.e., those genes whose gene products participate in many pathways or interact with many other gene products. The identification of the genes expressed in the brain turned out to be more difficult, due to the lack of a common identification scheme for proteins. Semantic Web technologies provide a valid framework for information integration in the life sciences. Ontology-driven integration represents a flexible, sustainable and extensible solution to the integration of large volumes of information. Additional resources, which enable the creation of mappings between information sources, are required to compensate for heterogeneity across namespaces. RESOURCE PAGE: http://knoesis.wright.edu/research/lifesci/integration/structured_data/JBI-2008/

Toward industrial production of isoprenoids in Escherichia coli: Lessons learned from CRISPR-Cas9 based optimization of a chromosomally integrated mevalonate pathway.

PubMed

Alonso-Gutierrez, Jorge; Koma, Daisuke; Hu, Qijun; Yang, Yuchen; Chan, Leanne J G; Petzold, Christopher J; Adams, Paul D; Vickers, Claudia E; Nielsen, Lars K; Keasling, Jay D; Lee, Taek S

2018-04-01

Escherichia coli has been the organism of choice for the production of different chemicals by engineering native and heterologous pathways. In the present study, we simultaneously address some of the main issues associated with E. coli as an industrial platform for isoprenoids, including an inability to grow on sucrose, a lack of endogenous control over toxic mevalonate (MVA) pathway intermediates, and the limited pathway engineering into the chromosome. As a proof of concept, we generated an E. coli DH1 strain able to produce the isoprenoid bisabolene from sucrose by integrating the cscAKB operon into the chromosome and by expressing a heterologous MVA pathway under stress-responsive control. Production levels dropped dramatically relative to plasmid-mediated expression when the entire pathway was integrated into the chromosome. In order to optimize the chromosomally integrated MVA pathway, we established a CRISPR-Cas9 system to rapidly and systematically replace promoter sequences. This strategy led to higher pathway expression and a fivefold improvement in bisabolene production. More interestingly, we analyzed proteomics data sets to understand and address some of the challenges associated with metabolic engineering of the chromosomally integrated pathway. This report shows that integrating plasmid-optimized operons into the genome and making them work optimally is not a straightforward task and any poor engineering choices on the chromosome may lead to cell death rather than just resulting in low titers. Based on these results, we also propose directions for chromosomal metabolic engineering. © 2017 Wiley Periodicals, Inc.

Prediction of enzymatic pathways by integrative pathway mapping

PubMed Central

Wichelecki, Daniel J; San Francisco, Brian; Zhao, Suwen; Rodionov, Dmitry A; Vetting, Matthew W; Al-Obaidi, Nawar F; Lin, Henry; O'Meara, Matthew J; Scott, David A; Morris, John H; Russel, Daniel; Almo, Steven C; Osterman, Andrei L

2018-01-01

The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology. PMID:29377793

Application of the critical pathway and integrated case teaching method to nursing orientation.

PubMed

Goodman, D

1997-01-01

Nursing staff development programs must be responsive to current changes in healthcare. New nursing staff must be prepared to manage continuous change and to function competently in clinical practice. The orientation pathway, based on a case management model, is used as a structure for the orientation phase of staff development. The integrated case is incorporated as a teaching strategy in orientation. The integrated case method is based on discussion and analysis of patient situations with emphasis on role modeling and integration of theory and skill. The orientation pathway and integrated case teaching method provide a useful framework for orientation of new staff. Educators, preceptors and orientees find the structure provided by the orientation pathway very useful. Orientation that is developed, implemented and evaluated based on a case management model with the use of an orientation pathway and incorporation of an integrated case teaching method provides a standardized structure for orientation of new staff. This approach is designed for the adult learner, promotes conceptual reasoning, and encourages the social and contextual basis for continued learning.

Audio-visual integration through the parallel visual pathways.

PubMed

Kaposvári, Péter; Csete, Gergő; Bognár, Anna; Csibri, Péter; Tóth, Eszter; Szabó, Nikoletta; Vécsei, László; Sáry, Gyula; Tamás Kincses, Zsigmond

2015-10-22

Audio-visual integration has been shown to be present in a wide range of different conditions, some of which are processed through the dorsal, and others through the ventral visual pathway. Whereas neuroimaging studies have revealed integration-related activity in the brain, there has been no imaging study of the possible role of segregated visual streams in audio-visual integration. We set out to determine how the different visual pathways participate in this communication. We investigated how audio-visual integration can be supported through the dorsal and ventral visual pathways during the double flash illusion. Low-contrast and chromatic isoluminant stimuli were used to drive preferably the dorsal and ventral pathways, respectively. In order to identify the anatomical substrates of the audio-visual interaction in the two conditions, the psychophysical results were correlated with the white matter integrity as measured by diffusion tensor imaging.The psychophysiological data revealed a robust double flash illusion in both conditions. A correlation between the psychophysical results and local fractional anisotropy was found in the occipito-parietal white matter in the low-contrast condition, while a similar correlation was found in the infero-temporal white matter in the chromatic isoluminant condition. Our results indicate that both of the parallel visual pathways may play a role in the audio-visual interaction. Copyright © 2015. Published by Elsevier B.V.

Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution

EPA Science Inventory

There are many technological pathways that can lead to reduced carbon dioxide emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessmen...

Integrating disease management and wound care critical pathways in home care.

PubMed

Barr, J E

1999-10-01

This article discusses the need for an integration of the concepts of disease management and critical pathways as a foundation of a healthcare delivery system. The steps in the process for development, implementation, and evaluation of a wound care critical pathway are reviewed and variance classifications are defined. Co-pathways and algorithms are presented as methodologies for dealing with variances. A template of a wound care critical pathway that has been developed for use in the home care setting is included.

Meta-dimensional data integration identifies critical pathways for susceptibility, tumorigenesis and progression of endometrial cancer.

PubMed

Wei, Runmin; De Vivo, Immaculata; Huang, Sijia; Zhu, Xun; Risch, Harvey; Moore, Jason H; Yu, Herbert; Garmire, Lana X

2016-08-23

Endometrial Cancer (EC) is one of the most common female cancers. Genome-wide association studies (GWAS) have been investigated to identify genetic polymorphisms that are predictive of EC risks. Here we utilized a meta-dimensional integrative approach to seek genetically susceptible pathways that may be associated with tumorigenesis and progression of EC. We analyzed GWAS data obtained from Connecticut Endometrial Cancer Study (CECS) and identified the top 20 EC susceptible pathways. To further verify the significance of top 20 EC susceptible pathways, we conducted pathway-level multi-omics analyses using EC exome-Seq, RNA-Seq and survival data, all based on The Cancer Genome Atlas (TCGA) samples. We measured the overall consistent rankings of these pathways in all four data types. Some well-studied pathways, such as p53 signaling and cell cycle pathways, show consistently high rankings across different analyses. Additionally, other cell signaling pathways (e.g. IGF-1/mTOR, rac-1 and IL-5 pathway), genetic information processing pathway (e.g. homologous recombination) and metabolism pathway (e.g. sphingolipid metabolism) are also highly associated with EC risks, diagnosis and prognosis. In conclusion, the meta-dimensional integration of EC cohorts has suggested some common pathways that may be associated from predisposition, tumorigenesis to progression.

R-Based Software for the Integration of Pathway Data into Bioinformatic Algorithms

PubMed Central

Kramer, Frank; Bayerlová, Michaela; Beißbarth, Tim

2014-01-01

Putting new findings into the context of available literature knowledge is one approach to deal with the surge of high-throughput data results. Furthermore, prior knowledge can increase the performance and stability of bioinformatic algorithms, for example, methods for network reconstruction. In this review, we examine software packages for the statistical computing framework R, which enable the integration of pathway data for further bioinformatic analyses. Different approaches to integrate and visualize pathway data are identified and packages are stratified concerning their features according to a number of different aspects: data import strategies, the extent of available data, dependencies on external tools, integration with further analysis steps and visualization options are considered. A total of 12 packages integrating pathway data are reviewed in this manuscript. These are supplemented by five R-specific packages for visualization and six connector packages, which provide access to external tools. PMID:24833336

Bubble clustering in a glass of stout beer

NASA Astrophysics Data System (ADS)

Iwatsubo, Fumiya; Watamura, Tomoaki; Sugiyama, Kazuyasu

2017-11-01

To clarify why the texture in stout beer poured into a pint glass descends, we investigated local time development of the void fraction and velocity of bubbles. The propagation of the number density distribution, i.e. the texture, appearing near the inclined wall is observed. We visualized individual advective bubbles near the inclined wall by microscope and measured the local void fraction using brightness of images while the velocity of bubbles by means of Particle Tracking Velocimetry. As the result of measurements, we found the local void fraction and the bubbles advection velocity increase and decrease repeatedly with a time delay. We conclude the texture pattern is composed of fluid blobs which contain less bubbles; extruding and suction flows respectively toward and from the interior of the container form respectively in front and back of the blobs.

Eye-fixation patterns of high- and low-span young and older adults: down the garden path and back again.

PubMed

Kemper, Susan; Crow, Angela; Kemtes, Karen

2004-03-01

Young and older adults' eye fixations were monitored as they read sentences with temporary ambiguities such as "The experienced soldiers warned about the dangers conducted the midnight raid." Their fixation patterns were similar except that older adults made many regressions. In a 2nd experiment, high- and low-span older adults were compared with high- and low-span young adults. Pint-pass fixations were similar, except low-span readers made many regressions and their total fixation times were longer. High-span readers also used the focus operator "only" (e.g., "Only experienced soldiers warned about the dangers.") to immediately resolve the temporary ambiguities. No age group differences were observed. These results are discussed with reference to theories of the role of working memory in sentence processing.

An integrated pathway system modeling of Saccharomyces cerevisiae HOG pathway: a Petri net based approach.

PubMed

Tomar, Namrata; Choudhury, Olivia; Chakrabarty, Ankush; De, Rajat K

2013-02-01

Biochemical networks comprise many diverse components and interactions between them. It has intracellular signaling, metabolic and gene regulatory pathways which are highly integrated and whose responses are elicited by extracellular actions. Previous modeling techniques mostly consider each pathway independently without focusing on the interrelation of these which actually functions as a single system. In this paper, we propose an approach of modeling an integrated pathway using an event-driven modeling tool, i.e., Petri nets (PNs). PNs have the ability to simulate the dynamics of the system with high levels of accuracy. The integrated set of signaling, regulatory and metabolic reactions involved in Saccharomyces cerevisiae's HOG pathway has been collected from the literature. The kinetic parameter values have been used for transition firings. The dynamics of the system has been simulated and the concentrations of major biological species over time have been observed. The phenotypic characteristics of the integrated system have been investigated under two conditions, viz., under the absence and presence of osmotic pressure. The results have been validated favorably with the existing experimental results. We have also compared our study with the study of idFBA (Lee et al., PLoS Comput Biol 4:e1000-e1086, 2008) and pointed out the differences between both studies. We have simulated and monitored concentrations of multiple biological entities over time and also incorporated feedback inhibition by Ptp2 which has not been included in the idFBA study. We have concluded that our study is the first to the best of our knowledge to model signaling, metabolic and regulatory events in an integrated form through PN model framework. This study is useful in computational simulation of system dynamics for integrated pathways as there are growing evidences that the malfunctioning of the interplay among these pathways is associated with disease.

People Experiencing Chronic Homelessness

MedlinePlus

... Housing Affordable Housing Rapid Re-Housing Supportive Housing Foster Education Connections Build Career Pathways Integrate Health Care ... Housing Affordable Housing Rapid Re-Housing Supportive Housing Foster Education Connections Build Career Pathways Integrate Health Care ...

On the choice of the functional form of the aftershocks decay equation

NASA Astrophysics Data System (ADS)

Gasperini, P.; Lolli, B.

2003-04-01

To infer the optimal form of the rate equation describing the decay of aftershock sequences, we analyzed the correlation among parameter estimates made for New Zealand (Eberhard-Phillips, 1998) and Italy (Lolli and Gasperini, 2003), for the simple model proposed by Reasenberg and Jones (1989) λ(t)=10a+b(Mm-Mmin)over(t+c)^p} We found significant correlations between the sequence productivity parameter a and all other ones (p, c and b) and between p and c. At odd with previous findings (Guo and Ogata, 1995; 1997) we did not find instead correlation between b and p. We verified that the explicit inclusion in the formula of the time decay normalization integral removes the correlation of a with both parameters p and c. We also found, separately for both regions, that assuming the linear coefficient of main shock magnitude M_m about 2/3b makes parameter a also independent of b. The a parameter of the resulting rate equation λ(t)= 10a+2/3bMm-bMmin/ (t+c)^pint_ST(t+c)-pdt being almost independent of the other ones, can be reliably considered the expressions of a peculiar property of the seismogenic process. Thus we can infer that the new equation could be more appropriate than the previous one to predict sequence behavior in different areas. This formulation has also been applied to more sophisticated models of the epidemic type (ETAS), letting the coefficient of the main shock magnitude to vary freely. Some preliminary experiments give estimates close to 1/2b for this parameter.

Improving wood properties for wood utilization through multi-omics integration in lignin biosynthesis

DOE PAGES

Wang, Jack P.; Matthews, Megan L.; Williams, Cranos M.; ...

2018-04-20

A multi-omics quantitative integrative analysis of lignin biosynthesis can advance the strategic engineering of wood for timber, pulp, and biofuels. Lignin is polymerized from three monomers (monolignols) produced by a grid-like pathway. The pathway in wood formation of Populus trichocarpa has at least 21 genes, encoding enzymes that mediate 37 reactions on 24 metabolites, leading to lignin and affecting wood properties. We perturb these 21 pathway genes and integrate transcriptomic, proteomic, fluxomic and phenomic data from 221 lines selected from ~2000 transgenics (6-month-old). The integrative analysis estimates how changing expression of pathway gene or gene combination affects protein abundance, metabolic-flux,more » metabolite concentrations, and 25 wood traits, including lignin, tree-growth, density, strength, and saccharification. The analysis then predicts improvements in any of these 25 traits individually or in combinations, through engineering expression of specific monolignol genes. The analysis may lead to greater understanding of other pathways for improved growth and adaptation.« less

Improving wood properties for wood utilization through multi-omics integration in lignin biosynthesis

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

Wang, Jack P.; Matthews, Megan L.; Williams, Cranos M.

A multi-omics quantitative integrative analysis of lignin biosynthesis can advance the strategic engineering of wood for timber, pulp, and biofuels. Lignin is polymerized from three monomers (monolignols) produced by a grid-like pathway. The pathway in wood formation of Populus trichocarpa has at least 21 genes, encoding enzymes that mediate 37 reactions on 24 metabolites, leading to lignin and affecting wood properties. We perturb these 21 pathway genes and integrate transcriptomic, proteomic, fluxomic and phenomic data from 221 lines selected from ~2000 transgenics (6-month-old). The integrative analysis estimates how changing expression of pathway gene or gene combination affects protein abundance, metabolic-flux,more » metabolite concentrations, and 25 wood traits, including lignin, tree-growth, density, strength, and saccharification. The analysis then predicts improvements in any of these 25 traits individually or in combinations, through engineering expression of specific monolignol genes. The analysis may lead to greater understanding of other pathways for improved growth and adaptation.« less

Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

PubMed Central

Levin, David E.

2011-01-01

The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed. PMID:22174182

Improving wood properties for wood utilization through multi-omics integration in lignin biosynthesis.

PubMed

Wang, Jack P; Matthews, Megan L; Williams, Cranos M; Shi, Rui; Yang, Chenmin; Tunlaya-Anukit, Sermsawat; Chen, Hsi-Chuan; Li, Quanzi; Liu, Jie; Lin, Chien-Yuan; Naik, Punith; Sun, Ying-Hsuan; Loziuk, Philip L; Yeh, Ting-Feng; Kim, Hoon; Gjersing, Erica; Shollenberger, Todd; Shuford, Christopher M; Song, Jina; Miller, Zachary; Huang, Yung-Yun; Edmunds, Charles W; Liu, Baoguang; Sun, Yi; Lin, Ying-Chung Jimmy; Li, Wei; Chen, Hao; Peszlen, Ilona; Ducoste, Joel J; Ralph, John; Chang, Hou-Min; Muddiman, David C; Davis, Mark F; Smith, Chris; Isik, Fikret; Sederoff, Ronald; Chiang, Vincent L

2018-04-20

A multi-omics quantitative integrative analysis of lignin biosynthesis can advance the strategic engineering of wood for timber, pulp, and biofuels. Lignin is polymerized from three monomers (monolignols) produced by a grid-like pathway. The pathway in wood formation of Populus trichocarpa has at least 21 genes, encoding enzymes that mediate 37 reactions on 24 metabolites, leading to lignin and affecting wood properties. We perturb these 21 pathway genes and integrate transcriptomic, proteomic, fluxomic and phenomic data from 221 lines selected from ~2000 transgenics (6-month-old). The integrative analysis estimates how changing expression of pathway gene or gene combination affects protein abundance, metabolic-flux, metabolite concentrations, and 25 wood traits, including lignin, tree-growth, density, strength, and saccharification. The analysis then predicts improvements in any of these 25 traits individually or in combinations, through engineering expression of specific monolignol genes. The analysis may lead to greater understanding of other pathways for improved growth and adaptation.

Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

PubMed

Zhang, Ying-Ying; Li, Hai-Xia; Chen, Yin-Ying; Fang, Hong; Yu, Ya-Nan; Liu, Jun; Jing, Zhi-Wei; Wang, Zhong; Wang, Yong-Yan

2014-03-01

Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations. © 2013 John Wiley & Sons Ltd.

Integrating human health and ecological data into cumulative risk assessment through the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from relevant stressors across different species. Integration is important to provide a more complete assessment of risk, but evaluating endpoints a...

KRE5 Suppression Induces Cell Wall Stress and Alternative ER Stress Response Required for Maintaining Cell Wall Integrity in Candida glabrata

PubMed Central

Sasaki, Masato; Ito, Fumie; Aoyama, Toshio; Sato-Okamoto, Michiyo; Takahashi-Nakaguchi, Azusa; Chibana, Hiroji; Shibata, Nobuyuki

2016-01-01

The maintenance of cell wall integrity in fungi is required for normal cell growth, division, hyphae formation, and antifungal tolerance. We observed that endoplasmic reticulum stress regulated cell wall integrity in Candida glabrata, which possesses uniquely evolved mechanisms for unfolded protein response mechanisms. Tetracycline-mediated suppression of KRE5, which encodes a predicted UDP-glucose:glycoprotein glucosyltransferase localized in the endoplasmic reticulum, significantly increased cell wall chitin content and decreased cell wall β-1,6-glucan content. KRE5 repression induced endoplasmic reticulum stress-related gene expression and MAP kinase pathway activation, including Slt2p and Hog1p phosphorylation, through the cell wall integrity signaling pathway. Moreover, the calcineurin pathway negatively regulated cell wall integrity, but not the reduction of β-1,6-glucan content. These results indicate that KRE5 is required for maintaining both endoplasmic reticulum homeostasis and cell wall integrity, and that the calcineurin pathway acts as a regulator of chitin-glucan balance in the cell wall and as an alternative mediator of endoplasmic reticulum stress in C. glabrata. PMID:27548283

Hippo pathway and protection of genome stability in response to DNA damage.

PubMed

Pefani, Dafni E; O'Neill, Eric

2016-04-01

The integrity of DNA is constantly challenged by exposure to the damaging effects of chemical and physical agents. Elucidating the cellular mechanisms that maintain genomic integrity via DNA repair and cell growth control is vital because errors in these processes lead to genomic damage and the development of cancer. By gaining a deep molecular understanding of the signaling pathways regulating genome integrity it is hoped to uncover new therapeutics and treatment designs to combat cancer. Components of the Hippo pathway, a tumor-suppressor cascade, have recently been defined to limit cancer transformation in response to DNA damage. In this review, we briefly introduce the Hippo signaling cascade in mammals and discuss in detail how the Hippo pathway has been established as part of the DNA damage response, activated by apical signaling kinases that recognize breaks in DNA. We also highlight the significance of the Hippo pathway activator RASSF1A tumor suppressor, a direct target of ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related ATR. Furthermore we discuss how Hippo pathway in response DNA lesions can induce cell death via Yes-associated protein (YAP) (the canonical Hippo pathway effector) or promote maintenance of genome integrity in a YAP-independent manner. © 2015 FEBS.

Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

PubMed

Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

2017-06-01

Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RP<0.01 were defined as critical pathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RP<0.01, and the top 10 pathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

A case study to illustrate the utility of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks for integrating human health and ecological data into cumulative risk assessment

EPA Science Inventory

Cumulative risk assessment (CRA) methods, which evaluate the risk of multiple adverse outcomes (AOs) from multiple chemicals, promote the use of a conceptual site model (CSM) to integrate risk from relevant stressors. The Adverse Outcome Pathway (AOP) framework can inform these r...

Johnston Atoll Plutonium Cleanup Project. Contract bridge report. Technical report, 1 June-5 August 1993

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

Hellier, C.L.; Doane, R.W.

1995-04-01

This report continues the documentation of the operation of TMA/Eberline`s Segmented Gate System technology for removing mixed plutonium and americium contamination at DNA`s Johnston Atoll site. Contaminated feed is conveyed under arrays of radiation detectors coupled with sophisticated computer software developed by Eberline Instrument Corporation. Segmented gates (chutes) on pneumatically-driven pistons move forward when contamination is detected to remove only the contaminated portion from the main flow of feed material. Only about one pint of contaminant is removed during each diversion event. At the JA site, a 98% volume reduction has been achieved, with the remediated soil cleaned to DNA`smore » criteria for release for unrestricted use of 500 Bq/kg total transuranic alpha contamination and no hot particles of greater than 5000 Becquerrels. The low level waste concentrate is expected to be packaged for shipment to an approved defense waste disposal site.« less

The Ventral Anterior Temporal Lobe has a Necessary Role in Exception Word Reading.

PubMed

Ueno, Taiji; Meteyard, Lotte; Hoffman, Paul; Murayama, Kou

2018-06-06

An influential account of reading holds that words with exceptional spelling-to-sound correspondences (e.g., PINT) are read via activation of their lexical-semantic representations, supported by the anterior temporal lobe (ATL). This account has been inconclusive because it is based on neuropsychological evidence, in which lesion-deficit relationships are difficult to localize precisely, and functional neuroimaging data, which is spatially precise but cannot demonstrate whether the ATL activity is necessary for exception word reading. To address these issues, we used a technique with good spatial specificity-repetitive transcranial magnetic stimulation (rTMS)-to demonstrate a necessary role of ATL in exception word reading. Following rTMS to left ventral ATL, healthy Japanese adults made more regularization errors in reading Japanese exception words. We successfully simulated these results in a computational model in which exception word reading was underpinned by semantic activations. The ATL is critically and selectively involved in reading exception words.

Identifying novel glioma associated pathways based on systems biology level meta-analysis.

PubMed

Hu, Yangfan; Li, Jinquan; Yan, Wenying; Chen, Jiajia; Li, Yin; Hu, Guang; Shen, Bairong

2013-01-01

With recent advances in microarray technology, including genomics, proteomics, and metabolomics, it brings a great challenge for integrating this "-omics" data to analysis complex disease. Glioma is an extremely aggressive and lethal form of brain tumor, and thus the study of the molecule mechanism underlying glioma remains very important. To date, most studies focus on detecting the differentially expressed genes in glioma. However, the meta-analysis for pathway analysis based on multiple microarray datasets has not been systematically pursued. In this study, we therefore developed a systems biology based approach by integrating three types of omics data to identify common pathways in glioma. Firstly, the meta-analysis has been performed to study the overlapping of signatures at different levels based on the microarray gene expression data of glioma. Among these gene expression datasets, 12 pathways were found in GeneGO database that shared by four stages. Then, microRNA expression profiles and ChIP-seq data were integrated for the further pathway enrichment analysis. As a result, we suggest 5 of these pathways could be served as putative pathways in glioma. Among them, the pathway of TGF-beta-dependent induction of EMT via SMAD is of particular importance. Our results demonstrate that the meta-analysis based on systems biology level provide a more useful approach to study the molecule mechanism of complex disease. The integration of different types of omics data, including gene expression microarrays, microRNA and ChIP-seq data, suggest some common pathways correlated with glioma. These findings will offer useful potential candidates for targeted therapeutic intervention of glioma.

FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway

PubMed Central

Ali, Abdullah Mahmood; Pradhan, Arun; Singh, Thiyam Ramsingh; Du, Changhu; Li, Jie; Wahengbam, Kebola; Grassman, Elke; Auerbach, Arleen D.; Pang, Qishen

2012-01-01

Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair. This pathway is inactivated in FA, a devastating genetic disease, which leads to hematologic defects and cancer in patients. Here we report the isolation and characterization of a novel 20-kDa FANCA-associated protein (FAAP20). We show that FAAP20 is an integral component of the FA nuclear core complex. We identify a region on FANCA that physically interacts with FAAP20, and show that FANCA regulates stability of this protein. FAAP20 contains a conserved ubiquitin-binding zinc-finger domain (UBZ), and binds K-63–linked ubiquitin chains in vitro. The FAAP20-UBZ domain is not required for interaction with FANCA, but is required for DNA-damage–induced chromatin loading of FANCA and the functional integrity of the FA pathway. These findings reveal critical roles for FAAP20 in the FA-BRCA pathway of DNA damage repair and genome maintenance. PMID:22343915

Integrated analysis of miRNA and mRNA expression data identifies multiple miRNAs regulatory networks for the tumorigenesis of colorectal cancer.

PubMed

Xu, Peng; Wang, Junhua; Sun, Bo; Xiao, Zhongdang

2018-06-15

Investigating the potential biological function of differential changed genes through integrating multiple omics data including miRNA and mRNA expression profiles, is always hot topic. However, how to evaluate the repression effect on target genes integrating miRNA and mRNA expression profiles are not fully solved. In this study, we provide an analyzing method by integrating both miRNAs and mRNAs expression data simultaneously. Difference analysis was adopted based on the repression score, then significantly repressed mRNAs were screened out by DEGseq. Pathway analysis for the significantly repressed mRNAs shows that multiple pathways such as MAPK signaling pathway, TGF-beta signaling pathway and so on, may correlated to the colorectal cancer(CRC). Focusing on the MAPK signaling pathway, a miRNA-mRNA network that centering the cell fate genes was constructed. Finally, the miRNA-mRNAs that potentially important in the CRC carcinogenesis were screened out and scored by impact index. Copyright © 2018 Elsevier B.V. All rights reserved.

Integrative Analysis of Longitudinal Metabolomics Data from a Personal Multi-Omics Profile

PubMed Central

Stanberry, Larissa; Mias, George I.; Haynes, Winston; Higdon, Roger; Snyder, Michael; Kolker, Eugene

2013-01-01

The integrative personal omics profile (iPOP) is a pioneering study that combines genomics, transcriptomics, proteomics, metabolomics and autoantibody profiles from a single individual over a 14-month period. The observation period includes two episodes of viral infection: a human rhinovirus and a respiratory syncytial virus. The profile studies give an informative snapshot into the biological functioning of an organism. We hypothesize that pathway expression levels are associated with disease status. To test this hypothesis, we use biological pathways to integrate metabolomics and proteomics iPOP data. The approach computes the pathways’ differential expression levels at each time point, while taking into account the pathway structure and the longitudinal design. The resulting pathway levels show strong association with the disease status. Further, we identify temporal patterns in metabolite expression levels. The changes in metabolite expression levels also appear to be consistent with the disease status. The results of the integrative analysis suggest that changes in biological pathways may be used to predict and monitor the disease. The iPOP experimental design, data acquisition and analysis issues are discussed within the broader context of personal profiling. PMID:24958148

From generic pathways to ICT-supported horizontally integrated care: the SmartCare approach and convergence with future Internet assembly.

PubMed

Urošević, Vladimir; Mitić, Marko

2014-01-01

Successful service integration in policy and practice requires both technology innovation and service process innovation being pursued and implemented at the same time. The SmartCare project (partially EC-funded under CIP ICT PSP Program) aims to achieve this through development, piloting and evaluation of ICT-based services, horizontally integrating health and social care in ten pilot regions, including Kraljevo region in Serbia. The project has identified and adopted two generic highest-level common thematic pathways in joint consolidation phase - integrated support for long-term care and integrated support after hospital discharge. A common set of standard functional specifications for an open ICT platform enabling the delivery of integrated care is being defined, around the challenges of data sharing, coordination and communication in these two formalized pathways. Implementation and system integration on technology and architecture level are to be based on open standards, multivendor interoperability, and leveraging on the current evolving open specification technology foundations developed in relevant projects across the European Research Area.

Integrating toxicogenomics data into cancer adverse outcome pathways

EPA Science Inventory

Integrating toxicogenomics data into adverse outcome pathways for cancer.J. Christopher CortonNHEERL/ORD, EPA, Research Triangle Park, NCAs the toxicology field continues to move towards a new paradigm in toxicity testing and safety assessment, there is the expectation that model...

e-Science and biological pathway semantics

PubMed Central

Luciano, Joanne S; Stevens, Robert D

2007-01-01

Background The development of e-Science presents a major set of opportunities and challenges for the future progress of biological and life scientific research. Major new tools are required and corresponding demands are placed on the high-throughput data generated and used in these processes. Nowhere is the demand greater than in the semantic integration of these data. Semantic Web tools and technologies afford the chance to achieve this semantic integration. Since pathway knowledge is central to much of the scientific research today it is a good test-bed for semantic integration. Within the context of biological pathways, the BioPAX initiative, part of a broader movement towards the standardization and integration of life science databases, forms a necessary prerequisite for its successful application of e-Science in health care and life science research. This paper examines whether BioPAX, an effort to overcome the barrier of disparate and heterogeneous pathway data sources, addresses the needs of e-Science. Results We demonstrate how BioPAX pathway data can be used to ask and answer some useful biological questions. We find that BioPAX comes close to meeting a broad range of e-Science needs, but certain semantic weaknesses mean that these goals are missed. We make a series of recommendations for re-modeling some aspects of BioPAX to better meet these needs. Conclusion Once these semantic weaknesses are addressed, it will be possible to integrate pathway information in a manner that would be useful in e-Science. PMID:17493286

Techno-economic analysis of biofuel production considering logistic configurations.

PubMed

Li, Qi; Hu, Guiping

2016-04-01

In the study, a techno-economic analysis method considering logistic configurations is proposed. The economic feasibility of a low temperature biomass gasification pathway and an integrated pathway with fast pyrolysis and bio-oil gasification are evaluated and compared with the proposed method in Iowa. The results show that both pathways are profitable, biomass gasification pathway could achieve an Internal Rate of Return (IRR) of 10.00% by building a single biorefinery and integrated bio-oil gasification pathway could achieve an IRR of 3.32% by applying decentralized supply chain structure. A Monte-Carlo simulation considering interactions among parameters is also proposed and conducted, which indicates that both pathways are at high risk currently. Copyright © 2016 Elsevier Ltd. All rights reserved.

Towards an effective record of dipole moment variations since the Precambrian using new reliability criteria and outputs from numerical dynamo simulations

NASA Astrophysics Data System (ADS)

Biggin, A. J.; Suttie, N.; Paterson, G. A.; Aubert, J.; Hurst, E.; Clarke, A.

2013-12-01

On timescales over which mantle convection may be affecting the geodynamo (10-100s of million years), magnetic reversal frequency is the best documented aspect of geomagnetic behaviour. Suitable, continuous recorders of this parameter become very sparse before a few hundreds of millions of years however presenting a major challenge to documenting and understanding geomagnetic variations on the timescale of even the most recent supercontinent cycle. It is hypothetically possible to measure the absolute geomagnetic palaeointensity from any geological material that has cooled from above the Curie Temperature of its constituent magnetic remanence carriers. Since igneous rocks are abundant in the geological record, estimates of dipole moment from these present a vital resource in documenting geomagnetic variations into deep time. In practice, a host of practical problems makes obtaining such measurements reliably from geological materials challenging. Nevertheless, the absolute palaeointensity database PINT, newly linked to the comprehensive Magnetics Information Consortium (MagIC) database, already contains 3,941 published dipole moment estimates from rocks older than 50,000 years ago and continues to grow rapidly. In order that even the existing record may be used to maximum effectiveness in characterising geomagnetic behaviour, two challenges must be met. 1. The variable reliability of individual measurements must be reasonably assessed 2. The impact of the inhomogeneous distribution of dipole moment estimates in space and time must be ascertained. Here, we will report efforts attempting to address these two challenges using novel approaches. A new set of quality criteria for palaeointensity data (QPI) has been developed and tested by application to studies recently incorporated into PINT. To address challenge 1, we propose that every published dipole moment estimate eventually be given a QPI score indicating the number of these criteria fulfilled. To begin to address challenge 2, we take an approach using the outputs of numerical dynamo simulations. This involves subsampling synthetic global time series of full-vector magnetic field data, converting these datasets into virtual (axial) dipole moments, and comparing these to the entire distribution to ascertain how well secular variation is averaged and characterised. Finally, the two approaches will be combined. Datasets of real dipole moment estimates, filtered by QPI, will be compared to the synthetic distributions in order to present more robust characterisations of geomagnetic behaviour in different time intervals than has previously been possible.

Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial

PubMed Central

Schnatz, Peter F.; Jiang, Xuezhi; Aragaki, Aaron K.; Nudy, Matthew; O'Sullivan, David M.; Williams, Mark; LeBlanc, Erin S.; Martin, Lisa W.; Manson, JoAnn E.; Shikany, James M.; Johnson, Karen C.; Stefanick, Marcia L.; Payne, Martha E.; Cauley, Jane A.; Howard, Barbara V.; Robbins, John

2016-01-01

Objective To analyze the treatment effect of calcium + Vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors. Methods We conducted a prospective, randomized, double-blind, placebo controlled trial among Women's Health Initiative participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C). Results Between September 1993 to October 1998, a total of 68,132 women aged 50-79 were recruited and randomized to the WHI-Dietary Modification (WHI-DM) (n=48,835) and WHI-Hormone Therapy (WHI-HT) trials (n=27,347). Subsequently, 36,282 women from WHI-HT (16,089) and WHI-DM (n=25,210) trials were randomized in the WHI-calcium + Vitamin D (WHI-CaD) trial to 1,000 mg of elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the HT and CaD trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared to placebo, was −1.6 ,(95th CI–5.5, 2.2) mg/dL for calcium + Vitamin D-alone, −9.0 (95th CI, −13.0, −5.1) mg/dL for hormone therapy alone, and −13.8 (95th CI,−17.8, −9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium + Vitamin D + hormone therapy on LDL-C (p-value for interaction (p-int) = 0.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (p-int = 0.03). Conclusion Reductions in LDL-C were greater among women randomized to both calcium + Vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium + Vitamin D + hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium + Vitamin D supplementation, current use of hormone therapy should not influence that decision. PMID:27926633

IntPath--an integrated pathway gene relationship database for model organisms and important pathogens.

PubMed

Zhou, Hufeng; Jin, Jingjing; Zhang, Haojun; Yi, Bo; Wozniak, Michal; Wong, Limsoon

2012-01-01

Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors in WikiPathways and relationship errors in KEGG). We turn complicated and incompatible xml data formats and inconsistent gene and gene relationship representations from different source databases into normalized and unified pathway-gene and pathway-gene pair relationships neatly recorded in simple tab-delimited text format and MySQL tables, which facilitates convenient automatic computation and large-scale referencing in many related studies. IntPath data can be downloaded in text format or MySQL dump. IntPath data can also be retrieved and analyzed conveniently through web service by local programs or through web interface by mouse clicks. Several useful analysis tools are also provided in IntPath. We have overcome in IntPath the issues of compatibility, consistency, and comprehensiveness that often hamper effective use of pathway databases. We have included four organisms in the current release of IntPath. Our methodology and programs described in this work can be easily applied to other organisms; and we will include more model organisms and important pathogens in future releases of IntPath. IntPath maintains regular updates and is freely available at http://compbio.ddns.comp.nus.edu.sg:8080/IntPath.

Penalized differential pathway analysis of integrative oncogenomics studies.

PubMed

van Wieringen, Wessel N; van de Wiel, Mark A

2014-04-01

Through integration of genomic data from multiple sources, we may obtain a more accurate and complete picture of the molecular mechanisms underlying tumorigenesis. We discuss the integration of DNA copy number and mRNA gene expression data from an observational integrative genomics study involving cancer patients. The two molecular levels involved are linked through the central dogma of molecular biology. DNA copy number aberrations abound in the cancer cell. Here we investigate how these aberrations affect gene expression levels within a pathway using observational integrative genomics data of cancer patients. In particular, we aim to identify differential edges between regulatory networks of two groups involving these molecular levels. Motivated by the rate equations, the regulatory mechanism between DNA copy number aberrations and gene expression levels within a pathway is modeled by a simultaneous-equations model, for the one- and two-group case. The latter facilitates the identification of differential interactions between the two groups. Model parameters are estimated by penalized least squares using the lasso (L1) penalty to obtain a sparse pathway topology. Simulations show that the inclusion of DNA copy number data benefits the discovery of gene-gene interactions. In addition, the simulations reveal that cis-effects tend to be over-estimated in a univariate (single gene) analysis. In the application to real data from integrative oncogenomic studies we show that inclusion of prior information on the regulatory network architecture benefits the reproducibility of all edges. Furthermore, analyses of the TP53 and TGFb signaling pathways between ER+ and ER- samples from an integrative genomics breast cancer study identify reproducible differential regulatory patterns that corroborate with existing literature.

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

Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.

The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes inmore » the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.« less

An economic evaluation of an integrated care pathway in geriatric rehabilitation for older patients with complex health problems

PubMed Central

van Haastregt, Jolanda C. M.; Evers, Silvia M. A. A.; Kempen, Gertrudis I. J. M.; Schols, Jos M. G. A.

2018-01-01

Background Integrated care pathways which cover multiple care settings are increasingly used as a tool to structure care, enhance coordination and improve transitions between care settings. However, little is known about their economic impact. The objective of this study is to determine the cost-effectiveness and cost-utility of an integrated care pathway designed for patients with complex health problems transferring from the hospital, a geriatric rehabilitation facility and primary care. Methods This economic evaluation was performed from a societal perspective alongside a prospective cohort study with two cohorts of patients. The care as usual cohort was included before implementation of the pathway and the care pathway cohort after implementation of the pathway. Both cohorts were measured over nine months, during which intervention costs, healthcare costs, patient and family costs were identified. The outcome measures were dependence in activities of daily living (measured with the KATZ-15) and quality adjusted life years (EQ-5D-3L). Costs and effects were bootstrapped and various sensitivity analyses were performed to assess robustness of the results. Results After nine months, the average societal costs were significantly lower for patients in the care pathway cohort (€50,791) versus patients in the care as usual cohort (€62,170; CI = -22,090, -988). Patients in the care pathway cohort had better scores on the KATZ-15 (1.04), indicating cost-effectiveness. No significant differences were found between the two groups on QALY scores (0.01). Conclusions The results of this study indicate that the integrated care pathway is a cost-effective intervention. Therefore, dissemination of the integrated care pathway on a wider scale could be considered. This would provide us the opportunity to confirm the findings of our study in larger economic evaluations. When looking at QALYs, no effects were found. Therefore, it is also recommended to explore if therapy in geriatric rehabilitation could also pay attention to other quality of life-related domains, such as mood and social participation. PMID:29489820

White matter integrity deficits in prefrontal-amygdala pathways in Williams syndrome.

PubMed

Avery, Suzanne N; Thornton-Wells, Tricia A; Anderson, Adam W; Blackford, Jennifer Urbano

2012-01-16

Williams syndrome is a neurodevelopmental disorder associated with significant non-social fears. Consistent with this elevated non-social fear, individuals with Williams syndrome have an abnormally elevated amygdala response when viewing threatening non-social stimuli. In typically-developing individuals, amygdala activity is inhibited through dense, reciprocal white matter connections with the prefrontal cortex. Neuroimaging studies suggest a functional uncoupling of normal prefrontal-amygdala inhibition in individuals with Williams syndrome, which might underlie both the extreme amygdala activity and non-social fears. This functional uncoupling might be caused by structural deficits in underlying white matter pathways; however, prefrontal-amygdala white matter deficits have yet to be explored in Williams syndrome. We used diffusion tensor imaging to investigate prefrontal-amygdala white matter integrity differences in individuals with Williams syndrome and typically-developing controls with high levels of non-social fear. White matter pathways between the amygdala and several prefrontal regions were isolated using probabilistic tractography. Within each pathway, we tested for between-group differences in three measures of white matter integrity: fractional anisotropy (FA), radial diffusivity (RD), and parallel diffusivity (λ(1)). Individuals with Williams syndrome had lower FA, compared to controls, in several of the prefrontal-amygdala pathways investigated, indicating a reduction in white matter integrity. Lower FA in Williams syndrome was explained by significantly higher RD, with no differences in λ(1), suggestive of lower fiber density or axon myelination in prefrontal-amygdala pathways. These results suggest that deficits in the structural integrity of prefrontal-amygdala white matter pathways might underlie the increased amygdala activity and extreme non-social fears observed in Williams syndrome. Copyright © 2011 Elsevier Inc. All rights reserved.

Large-scale integrative network-based analysis identifies common pathways disrupted by copy number alterations across cancers

PubMed Central

2013-01-01

Background Many large-scale studies analyzed high-throughput genomic data to identify altered pathways essential to the development and progression of specific types of cancer. However, no previous study has been extended to provide a comprehensive analysis of pathways disrupted by copy number alterations across different human cancers. Towards this goal, we propose a network-based method to integrate copy number alteration data with human protein-protein interaction networks and pathway databases to identify pathways that are commonly disrupted in many different types of cancer. Results We applied our approach to a data set of 2,172 cancer patients across 16 different types of cancers, and discovered a set of commonly disrupted pathways, which are likely essential for tumor formation in majority of the cancers. We also identified pathways that are only disrupted in specific cancer types, providing molecular markers for different human cancers. Analysis with independent microarray gene expression datasets confirms that the commonly disrupted pathways can be used to identify patient subgroups with significantly different survival outcomes. We also provide a network view of disrupted pathways to explain how copy number alterations affect pathways that regulate cell growth, cycle, and differentiation for tumorigenesis. Conclusions In this work, we demonstrated that the network-based integrative analysis can help to identify pathways disrupted by copy number alterations across 16 types of human cancers, which are not readily identifiable by conventional overrepresentation-based and other pathway-based methods. All the results and source code are available at http://compbio.cs.umn.edu/NetPathID/. PMID:23822816

Modeling biochemical pathways in the gene ontology

DOE PAGES

Hill, David P.; D’Eustachio, Peter; Berardini, Tanya Z.; ...

2016-09-01

The concept of a biological pathway, an ordered sequence of molecular transformations, is used to collect and represent molecular knowledge for a broad span of organismal biology. Representations of biomedical pathways typically are rich but idiosyncratic presentations of organized knowledge about individual pathways. Meanwhile, biomedical ontologies and associated annotation files are powerful tools that organize molecular information in a logically rigorous form to support computational analysis. The Gene Ontology (GO), representing Molecular Functions, Biological Processes and Cellular Components, incorporates many aspects of biological pathways within its ontological representations. Here we present a methodology for extending and refining the classes inmore » the GO for more comprehensive, consistent and integrated representation of pathways, leveraging knowledge embedded in current pathway representations such as those in the Reactome Knowledgebase and MetaCyc. With carbohydrate metabolic pathways as a use case, we discuss how our representation supports the integration of variant pathway classes into a unified ontological structure that can be used for data comparison and analysis.« less

Development of a plug-type IMS-MS instrument and its applications in resolving problems existing in in-situ detection of illicit drugs and explosives by IMS.

PubMed

Du, Zhenxia; Sun, Tangqiang; Zhao, Jianan; Wang, Di; Zhang, Zhongxia; Yu, Wenlian

2018-07-01

Ion mobility spectrometry (IMS) which acts as a rapid analysis technique is widely used in the field detection of illicit drugs and explosives. Due to limited separation abilities of the pint-sized IMS challenges and problems still exist regarding high false positive and false negative responses due to the interference of the matrix. In addition, the gas-phase ion chemistry and special phenomena in the IMS spectra, such one substance showing two peaks, were not identified unambiguously. In order to explain or resolve these questions, in this paper, an ion mobility spectrometry was coupled to a mass spectrometry (IMS-MS). A commercial IMS is embedded in a custom-built ion chamber shell was attached to the mass spectrometer. The faraday plate of IMS was fabricated with a hole for the ions to passing through to the mass spectrometer. The ion transmission efficiency of IMS-MS was optimized by optimizing the various parameters, especially the distance between the faraday plate and the cone of mass spectrum. This design keeps the integrity of the two original instruments and the mass spectrometry still works with multimode ionization source (i.e., IMS-MS, ESI-MS, APCI-MS modes). The illicit drugs and explosive samples were analyzed by the IMS-MS with 63 Ni source. The results showed that the IMS-MS is of high sensitivity. The ionization mechanism of the illicit drug and explosive samples with 63 Ni source were systematically studied. In addition, the interferent which interfered the detection of cocaine was identified as dibutyl phthalate (DBP) by this platform. The reason why the acetone solution of amphetamine showed two peaks was explained. Copyright © 2018 Elsevier B.V. All rights reserved.

Introducing a New Interface for the Online MagIC Database by Integrating Data Uploading, Searching, and Visualization

NASA Astrophysics Data System (ADS)

Jarboe, N.; Minnett, R.; Constable, C.; Koppers, A. A.; Tauxe, L.

2013-12-01

The Magnetics Information Consortium (MagIC) is dedicated to supporting the paleomagnetic, geomagnetic, and rock magnetic communities through the development and maintenance of an online database (http://earthref.org/MAGIC/), data upload and quality control, searches, data downloads, and visualization tools. While MagIC has completed importing some of the IAGA paleomagnetic databases (TRANS, PINT, PSVRL, GPMDB) and continues to import others (ARCHEO, MAGST and SECVR), further individual data uploading from the community contributes a wealth of easily-accessible rich datasets. Previously uploading of data to the MagIC database required the use of an Excel spreadsheet using either a Mac or PC. The new method of uploading data utilizes an HTML 5 web interface where the only computer requirement is a modern browser. This web interface will highlight all errors discovered in the dataset at once instead of the iterative error checking process found in the previous Excel spreadsheet data checker. As a web service, the community will always have easy access to the most up-to-date and bug free version of the data upload software. The filtering search mechanism of the MagIC database has been changed to a more intuitive system where the data from each contribution is displayed in tables similar to how the data is uploaded (http://earthref.org/MAGIC/search/). Searches themselves can be saved as a permanent URL, if desired. The saved search URL could then be used as a citation in a publication. When appropriate, plots (equal area, Zijderveld, ARAI, demagnetization, etc.) are associated with the data to give the user a quicker understanding of the underlying dataset. The MagIC database will continue to evolve to meet the needs of the paleomagnetic, geomagnetic, and rock magnetic communities.

Integrating care for neurodevelopmental disorders by unpacking control: A grounded theory study

PubMed Central

Waxegård, Gustaf; Thulesius, Hans

2016-01-01

Background To establish integrated healthcare pathways for patients with neurodevelopmental disorders (ND) such as autism spectrum disorder and attention-deficit hyperactivity disorder is challenging. This study sets out to investigate the main concerns for healthcare professionals when integrating ND care pathways and how they resolve these concerns. Methods Using classic grounded theory (Glaser), we analysed efforts to improve and integrate an ND care pathway for children and youth in a Swedish region over a period of 6 years. Data from 42 individual interviews with a range of ND professionals, nine group interviews with healthcare teams, participant observation, a 2-day dialogue conference, focus group meetings, regional media coverage, and reports from other Swedish regional ND projects were analysed. Results The main concern for participants was to deal with overwhelming ND complexity by unpacking control, which is control over strategies to define patients’ status and needs. Unpacking control is key to the professionals’ strivings to expand constructive life space for patients, to squeeze health care to reach available care goals, to promote professional ideologies, and to uphold workplace integrity. Control-seeking behaviour in relation to ND unpacking is ubiquitous and complicates integration of ND care pathways. Conclusions The Unpacking control theory expands central aspects of professions theory and may help to improve ND care development. PMID:27609793

PATIKA: an integrated visual environment for collaborative construction and analysis of cellular pathways.

PubMed

Demir, E; Babur, O; Dogrusoz, U; Gursoy, A; Nisanci, G; Cetin-Atalay, R; Ozturk, M

2002-07-01

Availability of the sequences of entire genomes shifts the scientific curiosity towards the identification of function of the genomes in large scale as in genome studies. In the near future, data produced about cellular processes at molecular level will accumulate with an accelerating rate as a result of proteomics studies. In this regard, it is essential to develop tools for storing, integrating, accessing, and analyzing this data effectively. We define an ontology for a comprehensive representation of cellular events. The ontology presented here enables integration of fragmented or incomplete pathway information and supports manipulation and incorporation of the stored data, as well as multiple levels of abstraction. Based on this ontology, we present the architecture of an integrated environment named Patika (Pathway Analysis Tool for Integration and Knowledge Acquisition). Patika is composed of a server-side, scalable, object-oriented database and client-side editors to provide an integrated, multi-user environment for visualizing and manipulating network of cellular events. This tool features automated pathway layout, functional computation support, advanced querying and a user-friendly graphical interface. We expect that Patika will be a valuable tool for rapid knowledge acquisition, microarray generated large-scale data interpretation, disease gene identification, and drug development. A prototype of Patika is available upon request from the authors.

Developing an Integrated Treatment Pathway for a Post-Coronary Artery Bypass Grating (CABG) Geriatric Patient with Comorbid Hypertension and Type 1 Diabetes Mellitus for Treating Acute Hypoglycemia and Electrolyte Imbalance.

PubMed

Naqvi, Atta Abbas; Shah, Amna; Ahmad, Rizwan; Ahmad, Niyaz

2017-01-01

The ailments afflicting the elderly population is a well-defined specialty of medicine. It calls for an immaculately designed health-care plan to treat diseases in geriatrics. For chronic illnesses such as diabetes mellitus (DM), coronary heart disease, and hypertension (HTN), they require proper management throughout the rest of patient's life. An integrated treatment pathway helps in treatment decision-making and improving standards of health care for the patient. This case describes an exclusive clinical pharmacist-driven designing of an integrated treatment pathway for a post-coronary artery bypass grafting (CABG) geriatric male patient with DM type I and HTN for the treatment of hypoglycemia and electrolyte imbalance. The treatment begins addressing the chief complaints which were vomiting and unconsciousness. Biochemical screening is essential to establish a diagnosis of electrolyte imbalance along with blood glucose level after which the integrated pathway defines the treatment course. This individualized treatment pathway provides an outline of the course of treatment of acute hypoglycemia, electrolyte imbalance as well as some unconfirmed diagnosis, namely, acute coronary syndrome and respiratory tract infection for a post-CABG geriatric patient with HTN and type 1 DM. The eligibility criterion for patients to be treated according to treatment pathway is to fall in the defined category.

IntPath--an integrated pathway gene relationship database for model organisms and important pathogens

PubMed Central

2012-01-01

Background Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. Results In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors in WikiPathways and relationship errors in KEGG). We turn complicated and incompatible xml data formats and inconsistent gene and gene relationship representations from different source databases into normalized and unified pathway-gene and pathway-gene pair relationships neatly recorded in simple tab-delimited text format and MySQL tables, which facilitates convenient automatic computation and large-scale referencing in many related studies. IntPath data can be downloaded in text format or MySQL dump. IntPath data can also be retrieved and analyzed conveniently through web service by local programs or through web interface by mouse clicks. Several useful analysis tools are also provided in IntPath. Conclusions We have overcome in IntPath the issues of compatibility, consistency, and comprehensiveness that often hamper effective use of pathway databases. We have included four organisms in the current release of IntPath. Our methodology and programs described in this work can be easily applied to other organisms; and we will include more model organisms and important pathogens in future releases of IntPath. IntPath maintains regular updates and is freely available at http://compbio.ddns.comp.nus.edu.sg:8080/IntPath. PMID:23282057

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Gujarat

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Andhra Pradesh is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Tamil Nadu

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Tamil Nadu is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Rajasthan

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Andhra Pradesh is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Andhra Pradesh

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Andhra Pradesh is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Karnataka

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Andhra Pradesh is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Regional Study: Maharashtra

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

Cochran, Jaquelin M; Palchak, Joseph D; Ehlen, Annaliese K

This chapter on Andhra Pradesh is one of six state chapters included in Appendix C of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study). The objective of the state chapters is to provide modeling assumptions, results, and next steps to use and improve the model specific to each state. The model has inherent uncertainties, particularly in how the intrastate transmission network and RE generation projects will develop (e.g., locations, capacities). The model also does not include information on contracts or must-run status of particular plantsmore » for reliability purposes. By providing details on the higher spatial resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.'« less

Operational integration in primary health care: patient encounters and workflows.

PubMed

Sifaki-Pistolla, Dimitra; Chatzea, Vasiliki-Eirini; Markaki, Adelais; Kritikos, Kyriakos; Petelos, Elena; Lionis, Christos

2017-11-29

Despite several countrywide attempts to strengthen and standardise the primary healthcare (PHC) system, Greece is still lacking a sustainable, policy-based model of integrated services. The aim of our study was to identify operational integration levels through existing patient care pathways and to recommend an alternative PHC model for optimum integration. The study was part of a large state-funded project, which included 22 randomly selected PHC units located across two health regions of Greece. Dimensions of operational integration in PHC were selected based on the work of Kringos and colleagues. A five-point Likert-type scale, coupled with an algorithm, was used to capture and transform theoretical framework features into measurable attributes. PHC services were grouped under the main categories of chronic care, urgent/acute care, preventive care, and home care. A web-based platform was used to assess patient pathways, evaluate integration levels and propose improvement actions. Analysis relied on a comparison of actual pathways versus optimal, the latter ones having been identified through literature review. Overall integration varied among units. The majority (57%) of units corresponded to a basic level. Integration by type of PHC service ranged as follows: basic (86%) or poor (14%) for chronic care units, poor (78%) or basic (22%) for urgent/acute care units, basic (50%) for preventive care units, and partial or basic (50%) for home care units. The actual pathways across all four categories of PHC services differed from those captured in the optimum integration model. Certain similarities were observed in the operational flows between chronic care management and urgent/acute care management. Such similarities were present at the highest level of abstraction, but also in common steps along the operational flows. Existing patient care pathways were mapped and analysed, and recommendations for an optimum integration PHC model were made. The developed web platform, based on a strong theoretical framework, can serve as a robust integration evaluation tool. This could be a first step towards restructuring and improving PHC services within a financially restrained environment.

Integrated Analysis of Mutation Data from Various Sources Identifies Key Genes and Signaling Pathways in Hepatocellular Carcinoma

PubMed Central

Wei, Lin; Tang, Ruqi; Lian, Baofeng; Zhao, Yingjun; He, Xianghuo; Xie, Lu

2014-01-01

Background Recently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored. Principal Findings In this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features. Conclusions Our workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers. PMID:24988079

Integrated analysis of mutation data from various sources identifies key genes and signaling pathways in hepatocellular carcinoma.

PubMed

Zhang, Yuannv; Qiu, Zhaoping; Wei, Lin; Tang, Ruqi; Lian, Baofeng; Zhao, Yingjun; He, Xianghuo; Xie, Lu

2014-01-01

Recently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored. In this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features. Our workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers.

PathText: a text mining integrator for biological pathway visualizations

PubMed Central

Kemper, Brian; Matsuzaki, Takuya; Matsuoka, Yukiko; Tsuruoka, Yoshimasa; Kitano, Hiroaki; Ananiadou, Sophia; Tsujii, Jun'ichi

2010-01-01

Motivation: Metabolic and signaling pathways are an increasingly important part of organizing knowledge in systems biology. They serve to integrate collective interpretations of facts scattered throughout literature. Biologists construct a pathway by reading a large number of articles and interpreting them as a consistent network, but most of the models constructed currently lack direct links to those articles. Biologists who want to check the original articles have to spend substantial amounts of time to collect relevant articles and identify the sections relevant to the pathway. Furthermore, with the scientific literature expanding by several thousand papers per week, keeping a model relevant requires a continuous curation effort. In this article, we present a system designed to integrate a pathway visualizer, text mining systems and annotation tools into a seamless environment. This will enable biologists to freely move between parts of a pathway and relevant sections of articles, as well as identify relevant papers from large text bases. The system, PathText, is developed by Systems Biology Institute, Okinawa Institute of Science and Technology, National Centre for Text Mining (University of Manchester) and the University of Tokyo, and is being used by groups of biologists from these locations. Contact: brian@monrovian.com. PMID:20529930

Integrated Interactive Chart as a Tool for Teaching Metabolic Pathways

ERIC Educational Resources Information Center

Kalogiannis, Stavros; Pagkalos, Ioannis; Koufoudakis, Panagiotis; Dashi, Ino; Pontikeri, Kyriaki; Christodoulou, Constantina

2014-01-01

An interactive chart of energy metabolism with didactic function, complementary to the already existing metabolic maps, located at the URL www.metpath.teithe.gr is being presented. The chart illustrates the major catabolic and biosynthetic pathways of glucose, fatty acids, and aminoacids, individually as well as in an integrated view. For every…

Equitable Access by Design. A Conceptual Framework for Integrated Student Supports within Linked Learning Pathways

ERIC Educational Resources Information Center

de Velasco, Jorge Ruiz; Newman, Elizabeth; Borsato, Graciela

2016-01-01

This report proposes a conceptual framework for defining and implementing a system of integrated student supports that provides equitable access to college and career readiness via Linked Learning pathways in high schools. The framework emphasizes the central commitment of the Linked Learning approach to challenge prevailing norms of…

Cross-species integration of human health and ecological endpoints into risk assessment using the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Exposure to environmental contaminants can influence both human health and ecological endpoints. Chemical risk assessments combine exposure and toxicity data to estimate the likelihood of adverse outcomes for these endpoints, but are rarely conducted in a manner that integrates ...

Fostering development of nursing practices to support integrated care when implementing integrated care pathways: what levers to use?

PubMed

Longpré, Caroline; Dubois, Carl-Ardy

2017-11-29

Care integration has been the focus of recent health system reforms. Given their functions at all levels of the care continuum, nurses have a substantial and primordial role to play in such integration processes. The aim of this study was to identify levers and strategies that organizations can use to support the development of a nursing practice aligned with the requirements of care integration in a health and social services centre (HSSC) in Quebec. The research design was a cross-sectional descriptive qualitative study based on a single case study with nested levels of analysis. The case was a public, multi-disciplinary HSSC in a semi-urban region of Quebec. Semi-structured interviews with 37 persons (nurses, professionals, managers, administrators) allowed for data saturation and ensured theoretical representation by covering four care pathways constituting different care integration contexts. Analysis involved four steps: preparing a predetermined list of codes based on the reference framework developed by Minkman (2011); coding transcript content; developing general and summary matrices to group observations for each care pathway; and creating a general model showing the overall results for the four pathways. The organization's capacity for response with regard to developing an integrated system of services resulted in two types of complementary interventions. The first involved investing in key resources and renewing organizational structures; the second involved deploying a series of organizational and clinical-administrative processes. In resource terms, integration efforts resulted in setting up new strategic services, re-arranging physical infrastructures, and deploying new technological resources. Organizational and clinical-administrative processes to promote integration involved renewing governance, improving the flow of care pathways, fostering continuous quality improvement, developing new roles, promoting clinician collaboration, and strengthening care providers' capacities. However, progress in these areas was offset by persistent constraints. The results highlight key levers organizations can use to foster the implementation and institutionalization of integrative nursing practices. They show that progress in this area requires a combination of strategies using multiple complementary levers. They also suggest that such progress calls for rethinking not only the deployment of certain organizational resources and structures, but also a series of organizational and clinical processes.

A peer review process as part of the implementation of clinical pathways in radiation oncology: Does it improve compliance?

PubMed

Gebhardt, Brian J; Heron, Dwight E; Beriwal, Sushil

Clinical pathways are patient management plans that standardize evidence-based practices to ensure high-quality and cost-effective medical care. Implementation of a pathway is a collaborative process in our network, requiring the active involvement of physicians. This approach promotes acceptance of pathway recommendations, although a peer review process is necessary to ensure compliance and to capture and approve off-pathway selections. We investigated the peer review process and factors associated with time to completion of peer review. Our cancer center implemented radiation oncology pathways for every disease site throughout a large, integrated network. Recommendations are written based upon national guidelines, published literature, and institutional experience with evidence evaluated hierarchically in order of efficacy, toxicity, and then cost. Physicians enter decisions into an online, menu-driven decision support tool that integrates with medical records. Data were collected from the support tool and included the rate of on- and off-pathway selections, peer review decisions performed by disease site directors, and time to complete peer review. A total of 6965 treatment decisions were entered in 2015, and 605 (8.7%) were made off-pathway and were subject to peer review. The median time to peer review decision was 2 days (interquartile range, 0.2-6.8). Factors associated with time to peer review decision >48 hours on univariate analysis include disease site (P < .0001) with a trend toward significance (P = .066) for radiation therapy modality. There was no difference between recurrent and non-recurrent disease (P = .267). Multivariable analysis revealed disease site was associated with time to peer review (P < .001), with lymphoma and skin/sarcoma most strongly influencing decision time >48 hours. Clinical pathways are an integral tool for standardizing evidence-based care throughout our large, integrated network, with 91.3% of all treatment decisions being made as per pathway. The peer review process was feasible, with <1% selections ultimately rejected, suggesting that awareness of peer review of treatment decisions encourages compliance with clinical pathway recommendations. Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Associations between Proprioceptive Neural Pathway Structural Connectivity and Balance in People with Multiple Sclerosis

PubMed Central

Fling, Brett W.; Dutta, Geetanjali Gera; Schlueter, Heather; Cameron, Michelle H.; Horak, Fay B.

2014-01-01

Mobility and balance impairments are a hallmark of multiple sclerosis (MS), affecting nearly half of patients at presentation and resulting in decreased activity and participation, falls, injuries, and reduced quality of life. A growing body of work suggests that balance impairments in people with mild MS are primarily the result of deficits in proprioception, the ability to determine body position in space in the absence of vision. A better understanding of the pathophysiology of balance disturbances in MS is needed to develop evidence-based rehabilitation approaches. The purpose of the current study was to (1) map the cortical proprioceptive pathway in vivo using diffusion-weighted imaging and (2) assess associations between proprioceptive pathway white matter microstructural integrity and performance on clinical and behavioral balance tasks. We hypothesized that people with MS (PwMS) would have reduced integrity of cerebral proprioceptive pathways, and that reduced white matter microstructure within these tracts would be strongly related to proprioceptive-based balance deficits. We found poorer balance control on proprioceptive-based tasks and reduced white matter microstructural integrity of the cortical proprioceptive tracts in PwMS compared with age-matched healthy controls (HC). Microstructural integrity of this pathway in the right hemisphere was also strongly associated with proprioceptive-based balance control in PwMS and controls. Conversely, while white matter integrity of the right hemisphere’s proprioceptive pathway was significantly correlated with overall balance performance in HC, there was no such relationship in PwMS. These results augment existing literature suggesting that balance control in PwMS may become more dependent upon (1) cerebellar-regulated proprioceptive control, (2) the vestibular system, and/or (3) the visual system. PMID:25368564

Associations between Proprioceptive Neural Pathway Structural Connectivity and Balance in People with Multiple Sclerosis.

PubMed

Fling, Brett W; Dutta, Geetanjali Gera; Schlueter, Heather; Cameron, Michelle H; Horak, Fay B

2014-01-01

Mobility and balance impairments are a hallmark of multiple sclerosis (MS), affecting nearly half of patients at presentation and resulting in decreased activity and participation, falls, injuries, and reduced quality of life. A growing body of work suggests that balance impairments in people with mild MS are primarily the result of deficits in proprioception, the ability to determine body position in space in the absence of vision. A better understanding of the pathophysiology of balance disturbances in MS is needed to develop evidence-based rehabilitation approaches. The purpose of the current study was to (1) map the cortical proprioceptive pathway in vivo using diffusion-weighted imaging and (2) assess associations between proprioceptive pathway white matter microstructural integrity and performance on clinical and behavioral balance tasks. We hypothesized that people with MS (PwMS) would have reduced integrity of cerebral proprioceptive pathways, and that reduced white matter microstructure within these tracts would be strongly related to proprioceptive-based balance deficits. We found poorer balance control on proprioceptive-based tasks and reduced white matter microstructural integrity of the cortical proprioceptive tracts in PwMS compared with age-matched healthy controls (HC). Microstructural integrity of this pathway in the right hemisphere was also strongly associated with proprioceptive-based balance control in PwMS and controls. Conversely, while white matter integrity of the right hemisphere's proprioceptive pathway was significantly correlated with overall balance performance in HC, there was no such relationship in PwMS. These results augment existing literature suggesting that balance control in PwMS may become more dependent upon (1) cerebellar-regulated proprioceptive control, (2) the vestibular system, and/or (3) the visual system.

NAViGaTing the Micronome – Using Multiple MicroRNA Prediction Databases to Identify Signalling Pathway-Associated MicroRNAs

PubMed Central

Shirdel, Elize A.; Xie, Wing; Mak, Tak W.; Jurisica, Igor

2011-01-01

Background MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome – referred to as the micronome – to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal — mirDIP (http://ophid.utoronto.ca/mirDIP). Results mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05), suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001), to be more studied (p<0.0002), and to have higher degree in the KEGG cancer pathway (p<0.0001), compared to intra-pathway microRNAs. Conclusions Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level. PMID:21364759

Integrative care for the management of low back pain: use of a clinical care pathway.

PubMed

Maiers, Michele J; Westrom, Kristine K; Legendre, Claire G; Bronfort, Gert

2010-10-29

For the treatment of chronic back pain, it has been theorized that integrative care plans can lead to better outcomes than those achieved by monodisciplinary care alone, especially when using a collaborative, interdisciplinary, and non-hierarchical team approach. This paper describes the use of a care pathway designed to guide treatment by an integrative group of providers within a randomized controlled trial. A clinical care pathway was used by a multidisciplinary group of providers, which included acupuncturists, chiropractors, cognitive behavioral therapists, exercise therapists, massage therapists and primary care physicians. Treatment recommendations were based on an evidence-informed practice model, and reached by group consensus. Research study participants were empowered to select one of the treatment recommendations proposed by the integrative group. Common principles and benchmarks were established to guide treatment management throughout the study. Thirteen providers representing 5 healthcare professions collaborated to provide integrative care to study participants. On average, 3 to 4 treatment plans, each consisting of 2 to 3 modalities, were recommended to study participants. Exercise, massage, and acupuncture were both most commonly recommended by the team and selected by study participants. Changes to care commonly incorporated cognitive behavioral therapy into treatment plans. This clinical care pathway was a useful tool for the consistent application of evidence-based care for low back pain in the context of an integrative setting. ClinicalTrials.gov NCT00567333.

Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data.

PubMed

Zhang, Tianyu; Xu, Jielin; Deng, Siyuan; Zhou, Fengqi; Li, Jin; Zhang, Liwei; Li, Lang; Wang, Qi-En; Li, Fuhai

2018-01-01

Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers.

Integrative Approaches to Enhance Understanding of Plant Metabolic Pathway Structure and Regulation1

PubMed Central

Tohge, Takayuki; Scossa, Federico; Fernie, Alisdair R.

2015-01-01

Huge insight into molecular mechanisms and biological network coordination have been achieved following the application of various profiling technologies. Our knowledge of how the different molecular entities of the cell interact with one another suggests that, nevertheless, integration of data from different techniques could drive a more comprehensive understanding of the data emanating from different techniques. Here, we provide an overview of how such data integration is being used to aid the understanding of metabolic pathway structure and regulation. We choose to focus on the pairwise integration of large-scale metabolite data with that of the transcriptomic, proteomics, whole-genome sequence, growth- and yield-associated phenotypes, and archival functional genomic data sets. In doing so, we attempt to provide an update on approaches that integrate data obtained at different levels to reach a better understanding of either single gene function or metabolic pathway structure and regulation within the context of a broader biological process. PMID:26371234

The integrated effect of moderate exercise on coronary heart disease.

PubMed

Mathews, Marc J; Mathews, Edward H; Mathews, George E

Moderate exercise is associated with a lower risk for coronary heart disease (CHD). A suitable integrated model of the CHD pathogenetic pathways relevant to moderate exercise may help to elucidate this association. Such a model is currently not available in the literature. An integrated model of CHD was developed and used to investigate pathogenetic pathways of importance between exercise and CHD. Using biomarker relative-risk data, the pathogenetic effects are representable as measurable effects based on changes in biomarkers. The integrated model provides insight into higherorder interactions underlying the associations between CHD and moderate exercise. A novel 'connection graph' was developed, which simplifies these interactions. It quantitatively illustrates the relationship between moderate exercise and various serological biomarkers of CHD. The connection graph of moderate exercise elucidates all the possible integrated actions through which risk reduction may occur. An integrated model of CHD provides a summary of the effects of moderate exercise on CHD. It also shows the importance of each CHD pathway that moderate exercise influences. The CHD risk-reducing effects of exercise appear to be primarily driven by decreased inflammation and altered metabolism.

Engineering of a Highly Efficient Escherichia coli Strain for Mevalonate Fermentation through Chromosomal Integration

PubMed Central

Wang, Jilong; Niyompanich, Suthamat; Tai, Yi-Shu; Wang, Jingyu; Bai, Wenqin; Mahida, Prithviraj; Gao, Tuo

2016-01-01

ABSTRACT Chromosomal integration of heterologous metabolic pathways is optimal for industrially relevant fermentation, as plasmid-based fermentation causes extra metabolic burden and genetic instabilities. In this work, chromosomal integration was adapted for the production of mevalonate, which can be readily converted into β-methyl-δ-valerolactone, a monomer for the production of mechanically tunable polyesters. The mevalonate pathway, driven by a constitutive promoter, was integrated into the chromosome of Escherichia coli to replace the native fermentation gene adhE or ldhA. The engineered strains (CMEV-1 and CMEV-2) did not require inducer or antibiotic and showed slightly higher maximal productivities (0.38 to ∼0.43 g/liter/h) and yields (67.8 to ∼71.4% of the maximum theoretical yield) than those of the plasmid-based fermentation. Since the glycolysis pathway is the first module for mevalonate synthesis, atpFH deletion was employed to improve the glycolytic rate and the production rate of mevalonate. Shake flask fermentation results showed that the deletion of atpFH in CMEV-1 resulted in a 2.1-fold increase in the maximum productivity. Furthermore, enhancement of the downstream pathway by integrating two copies of the mevalonate pathway genes into the chromosome further improved the mevalonate yield. Finally, our fed-batch fermentation showed that, with deletion of the atpFH and sucA genes and integration of two copies of the mevalonate pathway genes into the chromosome, the engineered strain CMEV-7 exhibited both high maximal productivity (∼1.01 g/liter/h) and high yield (86.1% of the maximum theoretical yield, 30 g/liter mevalonate from 61 g/liter glucose after 48 h in a shake flask). IMPORTANCE Metabolic engineering has succeeded in producing various chemicals. However, few of these chemicals are commercially competitive with the conventional petroleum-derived materials. In this work, chromosomal integration of the heterologous pathway and subsequent optimization strategies ensure stable and efficient (i.e., high-titer, high-yield, and high-productivity) production of mevalonate, which demonstrates the potential for scale-up fermentation. Among the optimization strategies, we demonstrated that enhancement of the glycolytic flux significantly improved the productivity. This result provides an example of how to tune the carbon flux for the optimal production of exogenous chemicals. PMID:27736790

Fusion yield: Guderley model and Tsallis statistics

NASA Astrophysics Data System (ADS)

Haubold, H. J.; Kumar, D.

2011-02-01

The reaction rate probability integral is extended from Maxwell-Boltzmann approach to a more general approach by using the pathway model introduced by Mathai in 2005 (A pathway to matrix-variate gamma and normal densities. Linear Algebr. Appl. 396, 317-328). The extended thermonuclear reaction rate is obtained in the closed form via a Meijer's G-function and the so-obtained G-function is represented as a solution of a homogeneous linear differential equation. A physical model for the hydrodynamical process in a fusion plasma-compressed and laser-driven spherical shock wave is used for evaluating the fusion energy integral by integrating the extended thermonuclear reaction rate integral over the temperature. The result obtained is compared with the standard fusion yield obtained by Haubold and John in 1981 (Analytical representation of the thermonuclear reaction rate and fusion energy production in a spherical plasma shock wave. Plasma Phys. 23, 399-411). An interpretation for the pathway parameter is also given.

Hydrophobically stabilized open state for the lateral gate of the Sec translocon

PubMed Central

Zhang, Bin; Miller, Thomas F.

2010-01-01

The Sec translocon is a central component of cellular pathways for protein translocation and membrane integration. Using both atomistic and coarse-grained molecular simulations, we investigate the conformational landscape of the translocon and explore the role of peptide substrates in the regulation of the translocation and integration pathways. Inclusion of a hydrophobic peptide substrate in the translocon stabilizes the opening of the lateral gate for membrane integration, whereas a hydrophilic peptide substrate favors the closed lateral gate conformation. The relative orientation of the plug moiety and a peptide substrate within the translocon channel is similarly dependent on whether the substrate is hydrophobic or hydrophilic in character, and the energetics of the translocon lateral gate opening in the presence of a peptide substrate is governed by the energetics of the peptide interface with the membrane. Implications of these results for the regulation of Sec-mediated pathways for protein translocation vs. membrane integration are discussed. PMID:20203009

Plant hormone signaling lightens up: integrators of light and hormones.

PubMed

Lau, On Sun; Deng, Xing Wang

2010-10-01

Light is an important environmental signal that regulates diverse growth and developmental processes in plants. In these light-regulated processes, multiple hormonal pathways are often modulated by light to mediate the developmental changes. Conversely, hormone levels in plants also serve as endogenous cues in influencing light responsiveness. Although interactions between light and hormone signaling pathways have long been observed, recent studies have advanced our understanding by identifying signaling integrators that connect the pathways. These integrators, namely PHYTOCHROME-INTERACTING FACTOR 3 (PIF3), PIF4, PIF3-LIKE 5 (PIL5)/PIF1 and LONG HYPOCOTYL 5 (HY5), are key light signaling components and they link light signals to the signaling of phytohormones, such as gibberellin (GA), abscisic acid (ABA), auxin and cytokinin, in regulating seedling photomorphogenesis and seed germination. This review focuses on these integrators in illustrating how light and hormone interact. Copyright © 2010 Elsevier Ltd. All rights reserved.

Re-Structuring Preservice Teacher Education: Introducing the School-Community Integrated Learning (SCIL) Pathway

ERIC Educational Resources Information Center

Hudson, Sue; Hudson, Peter

2013-01-01

Reviews into teacher education call for new models that develop preservice teachers' practical knowledge and skills. The study involved 9 mentor teachers and 14 mentees (final-year preservice teachers) working in a new teacher education model, the School-Community Integrated Learning (SCIL) pathway, and analysed data from a Likert survey with…

The School-Community Integrated Learning Pathway: Exploring a New Way to Prepare and Induct Final-Year Preservice Teachers

ERIC Educational Resources Information Center

Hudson, Suzanne; Hudson, Peter; Adie, Lenore

2015-01-01

Universities and teacher employment bodies seek new, cost-effective ways for graduating classroom-ready teachers. This study involved 32 final-year preservice teachers in an innovative school--university partnership teacher education programme titled, the School-Community Integrated Learning (SCIL) pathway. Data were collected using a five-part…

Tolerant industrial yeast Saccharomyces cerevisiae posses a more robust cell wall integrity signaling pathway against 2-furaldehyde and 5-(hydroxymethyl)-2-furaldehyde

USDA-ARS?s Scientific Manuscript database

Cell wall integrity signaling pathway in Saccharomyces cerevisiae is a conserved function for detecting and responding to cell stress conditions but less understood for industrial yeast. We dissected gene expression dynamics for a tolerant industrial yeast strain NRRL Y-50049 in response to challeng...

Neurological and Biological Foundations of Children's Social and Emotional Development: An Integrated Literature Review

ERIC Educational Resources Information Center

Nelson, Helen Jean; Kendall, Garth Edward; Shields, Linda

2014-01-01

This article provides an integrated review of the expert literature on developmental processes that combine social, biological, and neurological pathways, and the mechanisms through which these pathways may influence school success and health. It begins with a historical overview of the current understanding of how attachment relationships and…

WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data

PubMed Central

Yi, Ming; Horton, Jay D; Cohen, Jonathan C; Hobbs, Helen H; Stephens, Robert M

2006-01-01

Background Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data. Result WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Biocarta, GO (Gene Ontology) terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs). WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery. Conclusion This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at . PMID:16423281

When benefits outweigh costs: reconsidering "automatic" phonological recoding when reading aloud.

PubMed

Robidoux, Serje; Besner, Derek

2011-06-01

Skilled readers are slower to read aloud exception words (e.g., PINT) than regular words (e.g., MINT). In the case of exception words, sublexical knowledge competes with the correct pronunciation driven by lexical knowledge, whereas no such competition occurs for regular words. The dominant view is that the cost of this "regularity" effect is evidence that sublexical spelling-sound conversion is impossible to prevent (i.e., is "automatic"). This view has become so reified that the field rarely questions it. However, the results of simulations from the most successful computational models on the table suggest that the claim of "automatic" sublexical phonological recoding is premature given that there is also a benefit conferred by sublexical processing. Taken together with evidence from skilled readers that sublexical phonological recoding can be stopped, we suggest that the field is too narrowly focused when it asserts that sublexical phonological recoding is "automatic" and that a broader, more nuanced and contextually driven approach provides a more useful framework.

Efficient Process Migration for Parallel Processing on Non-Dedicated Networks of Workstations

NASA Technical Reports Server (NTRS)

Chanchio, Kasidit; Sun, Xian-He

1996-01-01

This paper presents the design and preliminary implementation of MpPVM, a software system that supports process migration for PVM application programs in a non-dedicated heterogeneous computing environment. New concepts of migration point as well as migration point analysis and necessary data analysis are introduced. In MpPVM, process migrations occur only at previously inserted migration points. Migration point analysis determines appropriate locations to insert migration points; whereas, necessary data analysis provides a minimum set of variables to be transferred at each migration pint. A new methodology to perform reliable point-to-point data communications in a migration environment is also discussed. Finally, a preliminary implementation of MpPVM and its experimental results are presented, showing the correctness and promising performance of our process migration mechanism in a scalable non-dedicated heterogeneous computing environment. While MpPVM is developed on top of PVM, the process migration methodology introduced in this study is general and can be applied to any distributed software environment.

Johnston Atoll Plutonium Cleanup Project, plant modification and operation. Volume 1. Annual report option year 2. Technical report, 1 October 1992-24 May 1993

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

Moroney, K.S.; Moroney, J.D.; Johnson, N.R.

1995-04-01

This report continues the documentation of the operation of TMA/Eberline`s Segmented Gate System technology for removing mixed plutonium and americium contamination at DNA`s Johnston Atoll site. Contaminated feed is conveyed under arrays of radiation detectors coupled with sophisticated computer software developed by Eberline Instrument Corporation. Segmented gates (chutes) on pneumatically-driven pistons move forward when contamination is detected to remove only the contaminated portion from the main flow of feed material. Only about one pint of contaminant is removed during each diversion event. At the JA site, a 98% volume reduction has been achieved, with the remediated soil cleaned to DNA`smore » criteria for release for unrestricted use of 500 Bq/kg total tnansuranic alpha contamination and no hot particles of greater than 5000 Becquerrels. The low level waste concentrate is expected to be packaged for shipment to an approved defense waste disposal site.« less

Johnston Atoll Plutonium Cleanup Project. Plant modification and operation. Volume 2. Annual report option year 2. Appendix A. Technical report, 1 October 1992-24 May 1993

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

Moroney, K.S.; Moroney, J.D.; Johnson, N.R.

1995-04-01

This report continues the documentation of the operation of TMA/Eberline`s Segmented Gate System technology for removing mixed plutonium and americium contamination at DNA`s Johnston Atoll site. Contaminated feed is conveyed under arrays of radiation detectors coupled with sophisticated computer software developed by Eberline Instrument Corporation. Segmented gates (chutes) on pneumatically-driven pistons move forward when contamination is detected to remove only the contaminated portion from the main flow of feed material. Only about one pint of contaminant is removed during each diversion event. At the JA site, a 98% volume reduction has been achieved, with the remediated soil cleaned to DNA`smore » criteria for release for unrestricted use of 500 Bq/kg total transuranic alpha contamination and no hot particles of greater than 5000 Becquerrels. The low level waste concentrate is expected to be packaged for shipment to an approved defense waste disposal site.« less

Johnston Atoll Plutonium Cleanup Project, plant modification and operation. Volume 3. Annual report option year 2. Appendices b through h. Technical report, 1 October 1992-24 May 1993

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

Moroney, K.S.; Moroney, J.D.; Johnson, N.R.

1995-04-01

This report continues the documentation of the operation of TMA/Eberline`s Segmented Gate System technology for removing mixed plutonium and americium contamination at DNA`s Johnston Atoll site. Contaminated feed is conveyed under arrays of radiation detectors coupled with sophisticated computer software developed by Eberline Instrument Corporation. Segmented gates (chutes) on pneumatically-driven pistons move forward when contamination is detected to remove only the contaminated portion from the main flow of feed material. Only about one pint of contaminant is removed during each diversion event. At the JA site, a 98% volume reduction has been achieved, with the remediated soil cleaned to DNA`smore » criteria for release for unrestricted use of 500 Bq/kg total transuranic alpha contamination and no hot particles of greater than 5000 Becquerrels. The low level waste concentrate is expected to be packaged for shipment to an approved defense waste disposal site.« less

Application of Monte Carlo cross-validation to identify pathway cross-talk in neonatal sepsis.

PubMed

Zhang, Yuxia; Liu, Cui; Wang, Jingna; Li, Xingxia

2018-03-01

To explore genetic pathway cross-talk in neonates with sepsis, an integrated approach was used in this paper. To explore the potential relationships between differently expressed genes between normal uninfected neonates and neonates with sepsis and pathways, genetic profiling and biologic signaling pathway were first integrated. For different pathways, the score was obtained based upon the genetic expression by quantitatively analyzing the pathway cross-talk. The paired pathways with high cross-talk were identified by random forest classification. The purpose of the work was to find the best pairs of pathways able to discriminate sepsis samples versus normal samples. The results found 10 pairs of pathways, which were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways were identified according to analysis of extensive literature. Impact statement To find the best pairs of pathways able to discriminate sepsis samples versus normal samples, an RF classifier, the DS obtained by DEGs of paired pathways significantly associated, and Monte Carlo cross-validation were applied in this paper. Ten pairs of pathways were probably able to discriminate neonates with sepsis versus normal uninfected neonates. Among them, the best two paired pathways ((7) IL-6 Signaling and Phospholipase C Signaling (PLC); (8) Glucocorticoid Receptor (GR) Signaling and Dendritic Cell Maturation) were identified according to analysis of extensive literature.

Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

PubMed

Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

2017-08-16

Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

How Effective Are Clinical Pathways With and Without Online Peer-Review? An Analysis of Bone Metastases Pathway in a Large, Integrated National Cancer Institute-Designated Comprehensive Cancer Center Network

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

Beriwal, Sushil, E-mail: beriwals@upmc.edu; Rajagopalan, Malolan S.; Flickinger, John C.

2012-07-15

Purpose: Clinical pathways are an important tool used to manage the quality in health care by standardizing processes. This study evaluated the impact of the implementation of a peer-reviewed clinical pathway in a large, integrated National Cancer Institute-Designated Comprehensive Cancer Center Network. Methods: In 2003, we implemented a clinical pathway for the management of bone metastases with palliative radiation therapy. In 2009, we required the entry of management decisions into an online tool that records pathway choices. The pathway specified 1 or 5 fractions for symptomatic bone metastases with the option of 10-14 fractions for certain clinical situations. The datamore » were obtained from 13 integrated sites (3 central academic, 10 community locations) from 2003 through 2010. Results: In this study, 7905 sites were treated with 64% of courses delivered in community practice and 36% in academic locations. Academic practices were more likely than community practices to treat with 1-5 fractions (63% vs. 23%; p < 0.0001). The number of delivered fractions decreased gradually from 2003 to 2010 for both academic and community practices (p < 0.0001); however, greater numbers of fractions were selected more often in community practices (p < 0.0001). Using multivariate logistic regression, we found that a significantly greater selection of 1-5 fractions developed after implementation online pathway monitoring (2009) with an odds ratio of 1.2 (confidence interval, 1.1-1.4) for community and 1.3 (confidence interval, 1.1-1.6) for academic practices. The mean number of fractions also decreased after online peer review from 6.3 to 6.0 for academic (p = 0.07) and 9.4 to 9.0 for community practices (p < 0.0001). Conclusion: This is one of the first studies to examine the efficacy of a clinical pathway for radiation oncology in an integrated cancer network. Clinical pathway implementation appears to be effective in changing patterns of care, particularly with online clinical peer review as a valuable aid to encourage adherence to evidence-based practice.« less

Pathway Tools version 13.0: integrated software for pathway/genome informatics and systems biology

PubMed Central

Paley, Suzanne M.; Krummenacker, Markus; Latendresse, Mario; Dale, Joseph M.; Lee, Thomas J.; Kaipa, Pallavi; Gilham, Fred; Spaulding, Aaron; Popescu, Liviu; Altman, Tomer; Paulsen, Ian; Keseler, Ingrid M.; Caspi, Ron

2010-01-01

Pathway Tools is a production-quality software environment for creating a type of model-organism database called a Pathway/Genome Database (PGDB). A PGDB such as EcoCyc integrates the evolving understanding of the genes, proteins, metabolic network and regulatory network of an organism. This article provides an overview of Pathway Tools capabilities. The software performs multiple computational inferences including prediction of metabolic pathways, prediction of metabolic pathway hole fillers and prediction of operons. It enables interactive editing of PGDBs by DB curators. It supports web publishing of PGDBs, and provides a large number of query and visualization tools. The software also supports comparative analyses of PGDBs, and provides several systems biology analyses of PGDBs including reachability analysis of metabolic networks, and interactive tracing of metabolites through a metabolic network. More than 800 PGDBs have been created using Pathway Tools by scientists around the world, many of which are curated DBs for important model organisms. Those PGDBs can be exchanged using a peer-to-peer DB sharing system called the PGDB Registry. PMID:19955237

The implementation of an end-of-life integrated care pathway in a Chinese population.

PubMed

Lo, S-H; Chan, C-Y; Chan, C-H; Sze, W-k; Yuen, K-K; Wong, C-S; Ng, T-Y; Tung, Y

2009-08-01

The integrated care pathway is used in end-of-life care to improve quality of care; the Liverpool Care Pathway (LCP) has been used in Europe and North America. Tuen Mun Hospital is a regional hospital in Hong Kong, China. The End-of-life Care Pathway (ECP) based on the concepts used in the Liverpool Care Pathway, was developed, with modification to suit the local condition. Criteria for entry onto the ECP were that the multidisciplinary team agreed the patient was dying, and was at least two of the following: bedbound; semi-comatose; only able to take sips of fluid; no longer able to take tablets. The ECP template replaced all other inpatient documents. The ECP was implemented in the palliative care unit for terminal cancer patients. An audit was performed to review the result. Fifty-one Chinese patients were included in the audit with mean age 64. The median duration of ECP use was 24 hours. All patients had current medication assessed and non-essential drugs were discontinued. The audit result suggested integrated care pathway in end-of-life care could be implemented successfully in an Oriental culture. The acceptance of using the ECP as a standard clinical practice takes time and education. Appropriate template design and supervision are the keys to success.

Integration of Genome-Scale Modeling and Transcript Profiling Reveals Metabolic Pathways Underlying Light and Temperature Acclimation in Arabidopsis[C][W

PubMed Central

Töpfer, Nadine; Caldana, Camila; Grimbs, Sergio; Willmitzer, Lothar; Fernie, Alisdair R.; Nikoloski, Zoran

2013-01-01

Understanding metabolic acclimation of plants to challenging environmental conditions is essential for dissecting the role of metabolic pathways in growth and survival. As stresses involve simultaneous physiological alterations across all levels of cellular organization, a comprehensive characterization of the role of metabolic pathways in acclimation necessitates integration of genome-scale models with high-throughput data. Here, we present an integrative optimization-based approach, which, by coupling a plant metabolic network model and transcriptomics data, can predict the metabolic pathways affected in a single, carefully controlled experiment. Moreover, we propose three optimization-based indices that characterize different aspects of metabolic pathway behavior in the context of the entire metabolic network. We demonstrate that the proposed approach and indices facilitate quantitative comparisons and characterization of the plant metabolic response under eight different light and/or temperature conditions. The predictions of the metabolic functions involved in metabolic acclimation of Arabidopsis thaliana to the changing conditions are in line with experimental evidence and result in a hypothesis about the role of homocysteine-to-Cys interconversion and Asn biosynthesis. The approach can also be used to reveal the role of particular metabolic pathways in other scenarios, while taking into consideration the entirety of characterized plant metabolism. PMID:23613196

Altered structure-function relations of semantic processing in youths with high-functioning autism: a combined diffusion and functional MRI study.

PubMed

Lo, Yu-Chun; Chou, Tai-Li; Fan, Li-Ying; Gau, Susan Shur-Fen; Chiu, Yen-Nan; Tseng, Wen-Yih Isaac

2013-12-01

Deficits in language and communication are among the core symptoms of autism, a common neurodevelopmental disorder with long-term impairment. Despite the striking nature of the autistic language impairment, knowledge about its corresponding alterations in the brain is still evolving. We hypothesized that the dual stream language network is altered in autism, and that this alteration could be revealed by changes in the relationships between microstructural integrity and functional activation. The study recruited 20 right-handed male youths with autism and 20 carefully matched individually, typically developing (TD) youths. Microstructural integrity of the left dorsal and left ventral pathways responsible for language processing and the functional activation of the connected brain regions were investigated by using diffusion spectrum imaging and functional magnetic resonance imaging of a semantic task, respectively. Youths with autism had significantly poorer language function, and lower functional activation in left dorsal and left ventral regions of the language network, compared with TD youths. The TD group showed a significant correlation of the functional activation of the left dorsal region with microstructural integrity of the left ventral pathway, whereas the autism group showed a significant correlation of the functional activation of the left ventral region with microstructural integrity of the left dorsal pathway, and moreover verbal comprehension index was correlated with microstructural integrity of the left ventral pathway. These altered structure-function relationships in autism suggest possible involvement of the dual pathways in supporting deficient semantic processing. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women.

PubMed

Samadder, N Jewel; Vierkant, Robert A; Tillmans, Lori S; Wang, Alice H; Weisenberger, Daniel J; Laird, Peter W; Lynch, Charles F; Anderson, Kristin E; French, Amy J; Haile, Robert W; Potter, John D; Slager, Susan L; Smyrk, Thomas C; Thibodeau, Stephen N; Cerhan, James R; Limburg, Paul J

2013-08-01

Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Patients' mean age (P = .03) and tumors' anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Network-based study reveals potential infection pathways of hepatitis-C leading to various diseases.

PubMed

Mukhopadhyay, Anirban; Maulik, Ujjwal

2014-01-01

Protein-protein interaction network-based study of viral pathogenesis has been gaining popularity among computational biologists in recent days. In the present study we attempt to investigate the possible pathways of hepatitis-C virus (HCV) infection by integrating the HCV-human interaction network, human protein interactome and human genetic disease association network. We have proposed quasi-biclique and quasi-clique mining algorithms to integrate these three networks to identify infection gateway host proteins and possible pathways of HCV pathogenesis leading to various diseases. Integrated study of three networks, namely HCV-human interaction network, human protein interaction network, and human proteins-disease association network reveals potential pathways of infection by the HCV that lead to various diseases including cancers. The gateway proteins have been found to be biologically coherent and have high degrees in human interactome compared to the other virus-targeted proteins. The analyses done in this study provide possible targets for more effective anti-hepatitis-C therapeutic involvement.

Network-Based Study Reveals Potential Infection Pathways of Hepatitis-C Leading to Various Diseases

PubMed Central

Mukhopadhyay, Anirban; Maulik, Ujjwal

2014-01-01

Protein-protein interaction network-based study of viral pathogenesis has been gaining popularity among computational biologists in recent days. In the present study we attempt to investigate the possible pathways of hepatitis-C virus (HCV) infection by integrating the HCV-human interaction network, human protein interactome and human genetic disease association network. We have proposed quasi-biclique and quasi-clique mining algorithms to integrate these three networks to identify infection gateway host proteins and possible pathways of HCV pathogenesis leading to various diseases. Integrated study of three networks, namely HCV-human interaction network, human protein interaction network, and human proteins-disease association network reveals potential pathways of infection by the HCV that lead to various diseases including cancers. The gateway proteins have been found to be biologically coherent and have high degrees in human interactome compared to the other virus-targeted proteins. The analyses done in this study provide possible targets for more effective anti-hepatitis-C therapeutic involvement. PMID:24743187

mTORC1 and p53

PubMed Central

Hasty, Paul; Sharp, Zelton Dave; Curiel, Tyler J.; Campisi, Judith

2013-01-01

A balance must be struck between cell growth and stress responses to ensure that cells proliferate without accumulating damaged DNA. This balance means that optimal cell proliferation requires the integration of pro-growth and stress-response pathways. mTOR (mechanistic target of rapamycin) is a pleiotropic kinase found in complex 1 (mTORC1). The mTORC1 pathway governs a response to mitogenic signals with high energy levels to promote protein synthesis and cell growth. In contrast, the p53 DNA damage response pathway is the arbiter of cell proliferation, restraining mTORC1 under conditions of genotoxic stress. Recent studies suggest a complicated integration of these pathways to ensure successful cell growth and proliferation without compromising genome maintenance. Deciphering this integration could be key to understanding the potential clinical usefulness of mTORC1 inhibitors like rapamycin. Here we discuss how these p53-mTORC1 interactions might play a role in the suppression of cancer and perhaps the development of cellular senescence and organismal aging. PMID:23255104

Ambient Air Pollution and Newborn Size and Adiposity at Birth: Differences by Maternal Ethnicity (the Born in Bradford Study Cohort).

PubMed

Schembari, Anna; de Hoogh, Kees; Pedersen, Marie; Dadvand, Payam; Martinez, David; Hoek, Gerard; Petherick, Emily S; Wright, John; Nieuwenhuijsen, Mark J

2015-11-01

Exposure to ambient air pollution has been associated with reduced size of newborns; however, the modifying effect of maternal ethnicity remains little explored among South Asians. We investigated ethnic differences in the association between ambient air pollution and newborn's size. Pregnant women were recruited between 2007 and 2010 for the Born in Bradford cohort study, in England. Exposures to particulate matter (≤ 10 μm, PM10; ≤ 2.5 μm, PM2.5), PM2.5 absorbance, and nitrogen oxides (NOx, NO2) were estimated using land-use regressions models. Using multivariate linear regression models, we evaluated effect modification by maternal ethnicity ("white British" or "Pakistani origin," self-reported) on the associations of air pollution and birth weight, head circumference, and triceps and subscapular skinfold thickness. A 5-μg/m3 increase in mean third trimester PM2.5 was associated with significantly lower birth weight and smaller head circumference in children of white British mothers (-43 g; 95% CI: -76, -10 and -0.28 cm; 95% CI: -0.39, -0.17, respectively), but not in children of Pakistani origin (9 g; 95% CI: -17, 35 and -0.08 cm; 95% CI: -0.17, 0.01, respectively) (p(int) = 0.03 and < 0.001). In contrast, PM2.5 was associated with significantly larger triceps and subscapular skinfold thicknesses in children of Pakistani origin (0.17 mm; 95% CI: 0.08, 0.25 and 0.21 mm; 95% CI: 0.12, 0.29, respectively), but not in white British children (-0.02 mm; 95% CI: -0.14, 0.01 and 0.06 mm; 95% CI: -0.06, 0.18, respectively) (p(int) = 0.06 and 0.11). Patterns of associations for PM10 and PM2.5 absorbance according to ethnicity were similar to those for PM2.5, but associations of the outcomes with NO2 and NOx were mostly nonsignificant in both ethnic groups. Our results suggest that associations of ambient PM exposures with newborn size and adiposity differ between white British and Pakistani origin infants. Schembari A, de Hoogh K, Pedersen M, Dadvand P, Martinez D, Hoek G, Petherick ES, Wright J, Nieuwenhuijsen MJ. 2015. Ambient air pollution and newborn size and adiposity at birth: differences by maternal ethnicity (the Born in Bradford study cohort). Environ Health Perspect 123:1208-1215; http://dx.doi.org/10.1289/ehp.1408675.

Ambient Air Pollution and Newborn Size and Adiposity at Birth: Differences by Maternal Ethnicity (the Born in Bradford Study Cohort)

PubMed Central

de Hoogh, Kees; Pedersen, Marie; Dadvand, Payam; Martinez, David; Hoek, Gerard; Petherick, Emily S.; Wright, John; Nieuwenhuijsen, Mark J.

2015-01-01

Background Exposure to ambient air pollution has been associated with reduced size of newborns; however, the modifying effect of maternal ethnicity remains little explored among South Asians. Objectives We investigated ethnic differences in the association between ambient air pollution and newborn’s size. Method Pregnant women were recruited between 2007 and 2010 for the Born in Bradford cohort study, in England. Exposures to particulate matter (≤ 10 μm, PM10; ≤ 2.5 μm, PM2.5), PM2.5 absorbance, and nitrogen oxides (NOx, NO2) were estimated using land-use regressions models. Using multivariate linear regression models, we evaluated effect modification by maternal ethnicity (“white British” or “Pakistani origin,” self-reported) on the associations of air pollution and birth weight, head circumference, and triceps and subscapular skinfold thickness. Results A 5-μg/m3 increase in mean third trimester PM2.5 was associated with significantly lower birth weight and smaller head circumference in children of white British mothers (–43 g; 95% CI: –76, –10 and –0.28 cm; 95% CI: –0.39, –0.17, respectively), but not in children of Pakistani origin (9 g; 95% CI: –17, 35 and –0.08 cm; 95% CI: –0.17, 0.01, respectively) (pint = 0.03 and < 0.001). In contrast, PM2.5 was associated with significantly larger triceps and subscapular skinfold thicknesses in children of Pakistani origin (0.17 mm; 95% CI: 0.08, 0.25 and 0.21 mm; 95% CI: 0.12, 0.29, respectively), but not in white British children (–0.02 mm; 95% CI: –0.14, 0.01 and 0.06 mm; 95% CI: –0.06, 0.18, respectively) (pint = 0.06 and 0.11). Patterns of associations for PM10 and PM2.5 absorbance according to ethnicity were similar to those for PM2.5, but associations of the outcomes with NO2 and NOx were mostly nonsignificant in both ethnic groups. Conclusions Our results suggest that associations of ambient PM exposures with newborn size and adiposity differ between white British and Pakistani origin infants. Citation Schembari A, de Hoogh K, Pedersen M, Dadvand P, Martinez D, Hoek G, Petherick ES, Wright J, Nieuwenhuijsen MJ. 2015. Ambient air pollution and newborn size and adiposity at birth: differences by maternal ethnicity (the Born in Bradford study cohort). Environ Health Perspect 123:1208–1215; http://dx.doi.org/10.1289/ehp.1408675 PMID:25978617

Psychotherapy, psychopathology, research and practice: pathways of connections and integration.

PubMed

Castonguay, Louis G

2011-03-01

This paper describes three pathways of connections between different communities of knowledge seekers: integration of psychotherapeutic approaches, integration of psychotherapy and psychopathology, and integration of science and practice. Some of the issues discussed involve the delineation and investigation of common factors (e.g., principles of change), improvement of major forms of psychotherapy, clinical implications of psychopathology research, as well as current and future directions related to practice-research networks. The aim of this paper is to suggest that building bridges across theoretical orientations, scientific fields, professional experiences, and epistemological views may be a fruitful strategy to improve our understanding and the impact of psychotherapy.

Temporal integration at consecutive processing stages in the auditory pathway of the grasshopper.

PubMed

Wirtssohn, Sarah; Ronacher, Bernhard

2015-04-01

Temporal integration in the auditory system of locusts was quantified by presenting single clicks and click pairs while performing intracellular recordings. Auditory neurons were studied at three processing stages, which form a feed-forward network in the metathoracic ganglion. Receptor neurons and most first-order interneurons ("local neurons") encode the signal envelope, while second-order interneurons ("ascending neurons") tend to extract more complex, behaviorally relevant sound features. In different neuron types of the auditory pathway we found three response types: no significant temporal integration (some ascending neurons), leaky energy integration (receptor neurons and some local neurons), and facilitatory processes (some local and ascending neurons). The receptor neurons integrated input over very short time windows (<2 ms). Temporal integration on longer time scales was found at subsequent processing stages, indicative of within-neuron computations and network activity. These different strategies, realized at separate processing stages and in parallel neuronal pathways within one processing stage, could enable the grasshopper's auditory system to evaluate longer time windows and thus to implement temporal filters, while at the same time maintaining a high temporal resolution. Copyright © 2015 the American Physiological Society.

Inter-area correlations in the ventral visual pathway reflect feature integration

PubMed Central

Freeman, Jeremy; Donner, Tobias H.; Heeger, David J.

2011-01-01

During object perception, the brain integrates simple features into representations of complex objects. A perceptual phenomenon known as visual crowding selectively interferes with this process. Here, we use crowding to characterize a neural correlate of feature integration. Cortical activity was measured with functional magnetic resonance imaging, simultaneously in multiple areas of the ventral visual pathway (V1–V4 and the visual word form area, VWFA, which responds preferentially to familiar letters), while human subjects viewed crowded and uncrowded letters. Temporal correlations between cortical areas were lower for crowded letters than for uncrowded letters, especially between V1 and VWFA. These differences in correlation were retinotopically specific, and persisted when attention was diverted from the letters. But correlation differences were not evident when we substituted the letters with grating patches that were not crowded under our stimulus conditions. We conclude that inter-area correlations reflect feature integration and are disrupted by crowding. We propose that crowding may perturb the transformations between neural representations along the ventral pathway that underlie the integration of features into objects. PMID:21521832

Using Answer Set Programming to Integrate RNA Expression with Signalling Pathway Information to Infer How Mutations Affect Ageing

PubMed Central

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M.

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects. PMID:23251396

Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

PubMed

Papatheodorou, Irene; Ziehm, Matthias; Wieser, Daniela; Alic, Nazif; Partridge, Linda; Thornton, Janet M

2012-01-01

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects.

An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes

PubMed Central

Huard, Jérémy; Mueller, Stephanie; Gilles, Ernst D; Klingmüller, Ursula; Klamt, Steffen

2012-01-01

During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G1 phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels. PMID:22443451

An Evaluation of the Implementation of Maternal Obesity Pathways of Care: A Mixed Methods Study with Data Integration

PubMed Central

Heslehurst, Nicola; Dinsdale, Sarah; Sedgewick, Gillian; Simpson, Helen; Sen, Seema; Summerbell, Carolyn Dawn; Rankin, Judith

2015-01-01

Objectives Maternal obesity has multiple associated risks and requires substantial intervention. This research evaluated the implementation of maternal obesity care pathways from multiple stakeholder perspectives. Study Design A simultaneous mixed methods model with data integration was used. Three component studies were given equal priority. 1: Semi-structured qualitative interviews explored obese pregnant women’s experiences of being on the pathways. 2: A quantitative and qualitative postal survey explored healthcare professionals’ experiences of delivering the pathways. 3: A case note audit quantitatively assessed pathway compliance. Data were integrated using following a thread and convergence coding matrix methods to search for agreement and disagreement between studies. Results Study 1: Four themes were identified: women’s overall (positive and negative) views of the pathways; knowledge and understanding of the pathways; views on clinical and weight management advice and support; and views on the information leaflet. Key results included positive views of receiving additional clinical care, negative experiences of risk communication, and weight management support was considered a priority. Study 2: Healthcare professionals felt the pathways were worthwhile, facilitated good practice, and increased confidence. Training was consistently identified as being required. Healthcare professionals predominantly focussed on women’s response to sensitive obesity communication. Study 3: There was good compliance with antenatal clinical interventions. However, there was poor compliance with public health and postnatal interventions. There were some strong areas of agreement between component studies which can inform future development of the pathways. However, disagreement between studies included a lack of shared priorities between healthcare professionals and women, different perspectives on communication issues, and different perspectives on women’s prioritisation of weight management. Conclusion The differences between healthcare professionals’ and women’s priorities and perspectives are important factors to consider when developing care pathways. Shared perspectives could help facilitate more effective implementation of the pathway interventions that have poor compliance. PMID:26018338

Sustainable and efficient pathways for bioenergy recovery from low-value process streams via bioelectrochemical systems in biorefineries

DOE PAGES

Borole, Abhijeet P.

2015-08-25

Conversion of biomass into bioenergy is possible via multiple pathways resulting in production of biofuels, bioproducts and biopower. Efficient and sustainable conversion of biomass, however, requires consideration of many environmental and societal parameters in order to minimize negative impacts. Integration of multiple conversion technologies and inclusion of upcoming alternatives such as bioelectrochemical systems can minimize these impacts and improve conservation of resources such as hydrogen, water and nutrients via recycle and reuse. This report outlines alternate pathways integrating microbial electrolysis in biorefinery schemes to improve energy efficiency while evaluating environmental sustainability parameters.

Integrating publicly-available data to generate computationally-predicted adverse outcome pathways for hepatic steatosis

EPA Science Inventory

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity ...

Advancing adverse outcome pathways for integrated toxicology and regulatory applications

EPA Science Inventory

Recent regulatory efforts in many countries have focused on a toxicological pathway-based vision for human health assessments relying on in vitro systems and predictive models to generate the toxicological data needed to evaluate chemical hazard. A pathway-based vision is equally...

Distinct Corticostriatal and Intracortical Pathways Mediate Bilateral Sensory Responses in the Striatum.

PubMed

Reig, Ramon; Silberberg, Gilad

2016-12-01

Individual striatal neurons integrate somatosensory information from both sides of the body, however, the afferent pathways mediating these bilateral responses are unclear. Whereas ipsilateral corticostriatal projections are prevalent throughout the neocortex, contralateral projections provide sparse input from primary sensory cortices, in contrast to the dense innervation from motor and frontal regions. There is, therefore, an apparent discrepancy between the observed anatomical pathways and the recorded striatal responses. We used simultaneous in vivo whole-cell and extracellular recordings combined with focal cortical silencing, to dissect the afferent pathways underlying bilateral sensory integration in the mouse striatum. We show that unlike direct corticostriatal projections mediating responses to contralateral whisker deflection, responses to ipsilateral stimuli are mediated mainly by intracortical projections from the contralateral somatosensory cortex (S1). The dominant pathway is the callosal projection from contralateral to ipsilateral S1. Our results suggest a functional difference between the cortico-basal ganglia pathways underlying bilateral sensory and motor processes. © The Author 2016. Published by Oxford University Press.

Everybody wants it done but nobody wants to do it: an exploration of the barrier and enablers of critical components towards creating a clinical pathway for anxiety and depression in cancer.

PubMed

Rankin, Nicole M; Butow, Phyllis N; Thein, Thida; Robinson, Tracy; Shaw, Joanne M; Price, Melanie A; Clover, Kerrie; Shaw, Tim; Grimison, Peter

2015-01-22

This study aimed to explore barriers to and enablers for future implementation of a draft clinical pathway for anxiety and depression in cancer patients in the Australian context. Health professionals reviewed a draft clinical pathway and participated in qualitative interviews about the delivery of psychosocial care in their setting, individual components of the draft pathway, and barriers and enablers for its future implementation. Five interrelated themes were identified: ownership; resources and responsibility; education and training; patient reluctance; and integration with health services beyond oncology. The five themes were perceived as both barriers and enablers and provide a basis for an implementation plan that includes strategies to overcome barriers. The next steps are to design and deliver the clinical pathway with specific implementation strategies that address team ownership, endorsement by leaders, education and training modules designed for health professionals and patients and identify ways to integrate the pathway into existing cancer services.

Bridging the Gap between Theory and Practice in Integrated Care: The Case of the Diabetic Foot Pathway in Tuscany

PubMed Central

Bini, Barbara; Ruggieri, Tommaso Grillo; Piaggesi, Alberto; Ricci, Lucia

2016-01-01

Introduction and Background: As diabetic foot (DF) care benefits from integration, monitoring geographic variations in lower limb Major Amputation rate enables to highlight potential lack of Integrated Care. In Tuscany (Italy), these DF outcomes were good on average but they varied within the region. In order to stimulate an improvement process towards integration, the project aimed to shift health professionals’ focus on the geographic variation issue, promote the Population Medicine approach, and engage professionals in a community of practice. Method: Three strategies were thus carried out: the use of a transparent performance evaluation system based on benchmarking; the use of patient stories and benchmarking analyses on outcomes, service utilization and costs that cross-checked delivery- and population-based perspectives; the establishment of a stable community of professionals to discuss data and practices. Results: The project enabled professionals to shift their focus on geographic variation and to a joint accountability on outcomes and costs for the entire patient pathways. Organizational best practices and gaps in integration were identified and improvement actions towards Integrated Care were implemented. Conclusion and Discussion: For the specific category of care pathways whose geographic variation is related to a lack of Integrated Care, a comprehensive strategy to improve outcomes and reduce equity gaps by diffusing integration should be carried out. PMID:29042842

Sex-Specific Pathways to Early Puberty, Sexual Debut, and Sexual Risk Taking: Tests of an Integrated Evolutionary-Developmental Model

ERIC Educational Resources Information Center

James, Jenee; Ellis, Bruce J.; Schlomer, Gabriel L.; Garber, Judy

2012-01-01

The current study tested sex-specific pathways to early puberty, sexual debut, and sexual risk taking, as specified by an integrated evolutionary-developmental model of adolescent sexual development and behavior. In a prospective study of 238 adolescents (n = 129 girls and n = 109 boys) followed from approximately 12-18 years of age, we tested for…

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA)

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability an...

User-centered evaluation of Arizona BioPathway: an information extraction, integration, and visualization system.

PubMed

Quiñones, Karin D; Su, Hua; Marshall, Byron; Eggers, Shauna; Chen, Hsinchun

2007-09-01

Explosive growth in biomedical research has made automated information extraction, knowledge integration, and visualization increasingly important and critically needed. The Arizona BioPathway (ABP) system extracts and displays biological regulatory pathway information from the abstracts of journal articles. This study uses relations extracted from more than 200 PubMed abstracts presented in a tabular and graphical user interface with built-in search and aggregation functionality. This paper presents a task-centered assessment of the usefulness and usability of the ABP system focusing on its relation aggregation and visualization functionalities. Results suggest that our graph-based visualization is more efficient in supporting pathway analysis tasks and is perceived as more useful and easier to use as compared to a text-based literature-viewing method. Relation aggregation significantly contributes to knowledge-acquisition efficiency. Together, the graphic and tabular views in the ABP Visualizer provide a flexible and effective interface for pathway relation browsing and analysis. Our study contributes to pathway-related research and biological information extraction by assessing the value of a multiview, relation-based interface that supports user-controlled exploration of pathway information across multiple granularities.

Electronic patient information systems and care pathways: the organisational challenges of implementation and integration.

PubMed

Dent, Mike; Tutt, Dylan

2014-09-01

Our interest here is with the 'marriage' of e-patient information systems with care pathways in order to deliver integrated care. We report on the development and implementation of four such pathways within two National Health Service primary care trusts in England: (a) frail elderly care, (b) stroke care, (c) diabetic retinopathy screening and (d) intermediate care. The pathways were selected because each represents a different type of information and data 'couplings', in terms of task interdependency with some pathways/systems reflecting more complex coordinating patterns than others. Our aim here is identify and explain how health professionals and information specialists in two organisational National Health Service primary care trusts organisationally construct and use such systems and, in particular, the implications this has for issues of professional and managerial control and autonomy. The article is informed by an institutionalist analysis. © The Author(s) 2013.

Asymmetric temporal integration of layer 4 and layer 2/3 inputs in visual cortex.

PubMed

Hang, Giao B; Dan, Yang

2011-01-01

Neocortical neurons in vivo receive concurrent synaptic inputs from multiple sources, including feedforward, horizontal, and feedback pathways. Layer 2/3 of the visual cortex receives feedforward input from layer 4 and horizontal input from layer 2/3. Firing of the pyramidal neurons, which carries the output to higher cortical areas, depends critically on the interaction of these pathways. Here we examined synaptic integration of inputs from layer 4 and layer 2/3 in rat visual cortical slices. We found that the integration is sublinear and temporally asymmetric, with larger responses if layer 2/3 input preceded layer 4 input. The sublinearity depended on inhibition, and the asymmetry was largely attributable to the difference between the two inhibitory inputs. Interestingly, the asymmetric integration was specific to pyramidal neurons, and it strongly affected their spiking output. Thus via cortical inhibition, the temporal order of activation of layer 2/3 and layer 4 pathways can exert powerful control of cortical output during visual processing.

Pain management: a review of organisation models with integrated processes for the management of pain in adult cancer patients.

PubMed

Brink-Huis, Anita; van Achterberg, Theo; Schoonhoven, Lisette

2008-08-01

This paper reports a review of the literature conducted to identify organisation models in cancer pain management that contain integrated care processes and describe their effectiveness. Pain is experienced by 30-50% of cancer patients receiving treatment and by 70-90% of those with advanced disease. Efforts to improve pain management have been made through the development and dissemination of clinical guidelines. Early improvements in pain management were focussed on just one or two single processes such as pain assessment and patient education. Little is known about organisational models with multiple integrated processes throughout the course of the disease trajectory and concerning all stages of the care process. Systematic review. The review involved a systematic search of the literature, published between 1986-2006. Subject-specific keywords used to describe patients, disease, pain management interventions and integrated care processes, relevant for this review were selected using the thesaurus of the databases. Institutional models, clinical pathways and consultation services are three alternative models for the integration of care processes in cancer pain management. A clinical pathway is a comprehensive institutionalisation model, whereas a pain consultation service is a 'stand-alone' model that can be integrated in a clinical pathway. Positive patient and process outcomes have been described for all three models, although the level of evidence is generally low. Evaluation of the quality of pain management must involve standardised measurements of both patient and process outcomes. We recommend the development of policies for referrals to a pain consultation service. These policies can be integrated within a clinical pathway. To evaluate the effectiveness of pain management models standardised outcome measures are needed.

PATIKAweb: a Web interface for analyzing biological pathways through advanced querying and visualization.

PubMed

Dogrusoz, U; Erson, E Z; Giral, E; Demir, E; Babur, O; Cetintas, A; Colak, R

2006-02-01

Patikaweb provides a Web interface for retrieving and analyzing biological pathways in the Patika database, which contains data integrated from various prominent public pathway databases. It features a user-friendly interface, dynamic visualization and automated layout, advanced graph-theoretic queries for extracting biologically important phenomena, local persistence capability and exporting facilities to various pathway exchange formats.

Plant MetGenMAP: an integrative analysis system for plant systems biology

USDA-ARS?s Scientific Manuscript database

We have developed a web-based system, Plant MetGenMAP, which can identify significantly altered biochemical pathways and highly affected biological processes, predict functional roles of pathway genes, and potential pathway-related regulatory motifs from transcript and metabolite profile datasets. P...

Identification of Putative Cardiovascular System Developmental Toxicants using a Classification Model based on Signaling Pathway-Adverse Outcome Pathways

EPA Science Inventory

An important challenge for an integrative approach to developmental systems toxicology is associating putative molecular initiating events (MIEs), cell signaling pathways, cell function and modeled fetal exposure kinetics. We have developed a chemical classification model based o...

Integrated Transcriptomic and Epigenomic Analysis of Primary Human Lung Epithelial Cell Differentiation

PubMed Central

Marconett, Crystal N.; Zhou, Beiyun; Rieger, Megan E.; Selamat, Suhaida A.; Dubourd, Mickael; Fang, Xiaohui; Lynch, Sean K.; Stueve, Theresa Ryan; Siegmund, Kimberly D.; Berman, Benjamin P.

2013-01-01

Elucidation of the epigenetic basis for cell-type specific gene regulation is key to gaining a full understanding of how the distinct phenotypes of differentiated cells are achieved and maintained. Here we examined how epigenetic changes are integrated with transcriptional activation to determine cell phenotype during differentiation. We performed epigenomic profiling in conjunction with transcriptomic profiling using in vitro differentiation of human primary alveolar epithelial cells (AEC). This model recapitulates an in vivo process in which AEC transition from one differentiated cell type to another during regeneration following lung injury. Interrogation of histone marks over time revealed enrichment of specific transcription factor binding motifs within regions of changing chromatin structure. Cross-referencing of these motifs with pathways showing transcriptional changes revealed known regulatory pathways of distal alveolar differentiation, such as the WNT and transforming growth factor beta (TGFB) pathways, and putative novel regulators of adult AEC differentiation including hepatocyte nuclear factor 4 alpha (HNF4A), and the retinoid X receptor (RXR) signaling pathways. Inhibition of the RXR pathway confirmed its functional relevance for alveolar differentiation. Our incorporation of epigenetic data allowed specific identification of transcription factors that are potential direct upstream regulators of the differentiation process, demonstrating the power of this approach. Integration of epigenomic data with transcriptomic profiling has broad application for the identification of regulatory pathways in other models of differentiation. PMID:23818859

Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks.

PubMed

Grimes, Mark; Hall, Benjamin; Foltz, Lauren; Levy, Tyler; Rikova, Klarisa; Gaiser, Jeremiah; Cook, William; Smirnova, Ekaterina; Wheeler, Travis; Clark, Neil R; Lachmann, Alexander; Zhang, Bin; Hornbeck, Peter; Ma'ayan, Avi; Comb, Michael

2018-05-22

Protein posttranslational modifications (PTMs) have typically been studied independently, yet many proteins are modified by more than one PTM type, and cell signaling pathways somehow integrate this information. We coupled immunoprecipitation using PTM-specific antibodies with tandem mass tag (TMT) mass spectrometry to simultaneously examine phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normal lung tissue and to cell lines treated with anticancer drugs. This simultaneous, large-scale, integrative analysis of these PTMs using a cluster-filtered network (CFN) approach revealed that cell signaling pathways were outlined by clustering patterns in PTMs. We used the t-distributed stochastic neighbor embedding (t-SNE) method to identify PTM clusters and then integrated each with known protein-protein interactions (PPIs) to elucidate functional cell signaling pathways. The CFN identified known and previously unknown cell signaling pathways in lung cancer cells that were not present in normal lung epithelial tissue. In various proteins modified by more than one type of PTM, the incidence of those PTMs exhibited inverse relationships, suggesting that molecular exclusive "OR" gates determine a large number of signal transduction events. We also showed that the acetyltransferase EP300 appears to be a hub in the network of pathways involving different PTMs. In addition, the data shed light on the mechanism of action of geldanamycin, an HSP90 inhibitor. Together, the findings reveal that cell signaling pathways mediated by acetylation, methylation, and phosphorylation regulate the cytoskeleton, membrane traffic, and RNA binding protein-mediated control of gene expression. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution.

PubMed

Ou, Yang; Shi, Wenjing; Smith, Steven J; Ledna, Catherine M; West, J Jason; Nolte, Christopher G; Loughlin, Daniel H

2018-04-15

There are many technological pathways that can lead to reduced carbon dioxide emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the energy system to compare environmental impacts of alternative low-carbon pathways for the United States. One set of pathways emphasizes nuclear energy and carbon capture and storage, while another set emphasizes renewable energy, including wind, solar, geothermal power, and bioenergy. These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter smaller than 2.5 μm in diameter, and energy-related water demands are evaluated for 50% and 80% carbon dioxide reduction targets in 2050. The renewable low-carbon pathways require less water withdrawal and consumption than the nuclear and carbon capture pathways. However, the renewable low-carbon pathways modeled in this study produce higher particulate matter-related mortality costs due to greater use of biomass in residential heating. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies.

Integrated omics analysis of specialized metabolism in medicinal plants.

PubMed

Rai, Amit; Saito, Kazuki; Yamazaki, Mami

2017-05-01

Medicinal plants are a rich source of highly diverse specialized metabolites with important pharmacological properties. Until recently, plant biologists were limited in their ability to explore the biosynthetic pathways of these metabolites, mainly due to the scarcity of plant genomics resources. However, recent advances in high-throughput large-scale analytical methods have enabled plant biologists to discover biosynthetic pathways for important plant-based medicinal metabolites. The reduced cost of generating omics datasets and the development of computational tools for their analysis and integration have led to the elucidation of biosynthetic pathways of several bioactive metabolites of plant origin. These discoveries have inspired synthetic biology approaches to develop microbial systems to produce bioactive metabolites originating from plants, an alternative sustainable source of medicinally important chemicals. Since the demand for medicinal compounds are increasing with the world's population, understanding the complete biosynthesis of specialized metabolites becomes important to identify or develop reliable sources in the future. Here, we review the contributions of major omics approaches and their integration to our understanding of the biosynthetic pathways of bioactive metabolites. We briefly discuss different approaches for integrating omics datasets to extract biologically relevant knowledge and the application of omics datasets in the construction and reconstruction of metabolic models. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

PubMed Central

Sun, Shuguo; Irvine, Kenneth D.

2016-01-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo. PMID:27268910

Development of a modularized two-step (M2S) chromosome integration technique for integration of multiple transcription units in Saccharomyces cerevisiae.

PubMed

Li, Siwei; Ding, Wentao; Zhang, Xueli; Jiang, Huifeng; Bi, Changhao

2016-01-01

Saccharomyces cerevisiae has already been used for heterologous production of fuel chemicals and valuable natural products. The establishment of complicated heterologous biosynthetic pathways in S. cerevisiae became the research focus of Synthetic Biology and Metabolic Engineering. Thus, simple and efficient genomic integration techniques of large number of transcription units are demanded urgently. An efficient DNA assembly and chromosomal integration method was created by combining homologous recombination (HR) in S. cerevisiae and Golden Gate DNA assembly method, designated as modularized two-step (M2S) technique. Two major assembly steps are performed consecutively to integrate multiple transcription units simultaneously. In Step 1, Modularized scaffold containing a head-to-head promoter module and a pair of terminators was assembled with two genes. Thus, two transcription units were assembled with Golden Gate method into one scaffold in one reaction. In Step 2, the two transcription units were mixed with modules of selective markers and integration sites and transformed into S. cerevisiae for assembly and integration. In both steps, universal primers were designed for identification of correct clones. Establishment of a functional β-carotene biosynthetic pathway in S. cerevisiae within 5 days demonstrated high efficiency of this method, and a 10-transcriptional-unit pathway integration illustrated the capacity of this method. Modular design of transcription units and integration elements simplified assembly and integration procedure, and eliminated frequent designing and synthesis of DNA fragments in previous methods. Also, by assembling most parts in Step 1 in vitro, the number of DNA cassettes for homologous integration in Step 2 was significantly reduced. Thus, high assembly efficiency, high integration capacity, and low error rate were achieved.

Generation of computationally predicted Adverse Outcome Pathway networks through integration of publicly available in vivo, in vitro, phenotype, and biological pathway data.

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework is becoming a widely used tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse ecological and human health outcomes. However, the conventional process...

USE OF PHARMACOKINETIC MODELING TO DESIGN STUDIES FOR PATHWAY-SPECIFIC EXPOSURE MODEL EVALUATION

EPA Science Inventory

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes/pathways. The purpose of this paper is to demonstrate a method to use pharmacokeneti...

AOP-DB: A database resource for the exploration of Adverse Outcome Pathways through integrated association networks.

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability t...

Estimating Environmental Co-benefits of U.S. CO2 Reduction Pathways Using the GCAM-USA Integrated Assessment Model

EPA Science Inventory

Various technological pathways can lead to reduced CO2 emissions. However, different pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. The Global Change Assessment Model (GCAM) is a high resolu...

RaMP: A Comprehensive Relational Database of Metabolomics Pathways for Pathway Enrichment Analysis of Genes and Metabolites

PubMed Central

Zhang, Bofei; Hu, Senyang; Baskin, Elizabeth; Patt, Andrew; Siddiqui, Jalal K.

2018-01-01

The value of metabolomics in translational research is undeniable, and metabolomics data are increasingly generated in large cohorts. The functional interpretation of disease-associated metabolites though is difficult, and the biological mechanisms that underlie cell type or disease-specific metabolomics profiles are oftentimes unknown. To help fully exploit metabolomics data and to aid in its interpretation, analysis of metabolomics data with other complementary omics data, including transcriptomics, is helpful. To facilitate such analyses at a pathway level, we have developed RaMP (Relational database of Metabolomics Pathways), which combines biological pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, WikiPathways, and the Human Metabolome DataBase (HMDB). To the best of our knowledge, an off-the-shelf, public database that maps genes and metabolites to biochemical/disease pathways and can readily be integrated into other existing software is currently lacking. For consistent and comprehensive analysis, RaMP enables batch and complex queries (e.g., list all metabolites involved in glycolysis and lung cancer), can readily be integrated into pathway analysis tools, and supports pathway overrepresentation analysis given a list of genes and/or metabolites of interest. For usability, we have developed a RaMP R package (https://github.com/Mathelab/RaMP-DB), including a user-friendly RShiny web application, that supports basic simple and batch queries, pathway overrepresentation analysis given a list of genes or metabolites of interest, and network visualization of gene-metabolite relationships. The package also includes the raw database file (mysql dump), thereby providing a stand-alone downloadable framework for public use and integration with other tools. In addition, the Python code needed to recreate the database on another system is also publicly available (https://github.com/Mathelab/RaMP-BackEnd). Updates for databases in RaMP will be checked multiple times a year and RaMP will be updated accordingly. PMID:29470400

RaMP: A Comprehensive Relational Database of Metabolomics Pathways for Pathway Enrichment Analysis of Genes and Metabolites.

PubMed

Zhang, Bofei; Hu, Senyang; Baskin, Elizabeth; Patt, Andrew; Siddiqui, Jalal K; Mathé, Ewy A

2018-02-22

The value of metabolomics in translational research is undeniable, and metabolomics data are increasingly generated in large cohorts. The functional interpretation of disease-associated metabolites though is difficult, and the biological mechanisms that underlie cell type or disease-specific metabolomics profiles are oftentimes unknown. To help fully exploit metabolomics data and to aid in its interpretation, analysis of metabolomics data with other complementary omics data, including transcriptomics, is helpful. To facilitate such analyses at a pathway level, we have developed RaMP (Relational database of Metabolomics Pathways), which combines biological pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, WikiPathways, and the Human Metabolome DataBase (HMDB). To the best of our knowledge, an off-the-shelf, public database that maps genes and metabolites to biochemical/disease pathways and can readily be integrated into other existing software is currently lacking. For consistent and comprehensive analysis, RaMP enables batch and complex queries (e.g., list all metabolites involved in glycolysis and lung cancer), can readily be integrated into pathway analysis tools, and supports pathway overrepresentation analysis given a list of genes and/or metabolites of interest. For usability, we have developed a RaMP R package (https://github.com/Mathelab/RaMP-DB), including a user-friendly RShiny web application, that supports basic simple and batch queries, pathway overrepresentation analysis given a list of genes or metabolites of interest, and network visualization of gene-metabolite relationships. The package also includes the raw database file (mysql dump), thereby providing a stand-alone downloadable framework for public use and integration with other tools. In addition, the Python code needed to recreate the database on another system is also publicly available (https://github.com/Mathelab/RaMP-BackEnd). Updates for databases in RaMP will be checked multiple times a year and RaMP will be updated accordingly.

A Model of an Integrated Immune System Pathway in Homo sapiens and Its Interaction with Superantigen Producing Expression Regulatory Pathway in Staphylococcus aureus: Comparing Behavior of Pathogen Perturbed and Unperturbed Pathway

PubMed Central

Tomar, Namrata; De, Rajat K.

2013-01-01

Response of an immune system to a pathogen attack depends on the balance between the host immune defense and the virulence of the pathogen. Investigation of molecular interactions between the proteins of a host and a pathogen helps in identifying the pathogenic proteins. It is necessary to understand the dynamics of a normally behaved host system to evaluate the capacity of its immune system upon pathogen attack. In this study, we have compared the behavior of an unperturbed and pathogen perturbed host system. Moreover, we have developed a formalism under Flux Balance Analysis (FBA) for the optimization of conflicting objective functions. We have constructed an integrated pathway system, which includes Staphylococcal Superantigen (SAg) expression regulatory pathway and TCR signaling pathway of Homo sapiens. We have implemented the method on this pathway system and observed the behavior of host signaling molecules upon pathogen attack. The entire study has been divided into six different cases, based on the perturbed/unperturbed conditions. In other words, we have investigated unperturbed and pathogen perturbed human TCR signaling pathway, with different combinations of optimization of concentrations of regulatory and signaling molecules. One of these cases has aimed at finding out whether minimization of the toxin production in a pathogen leads to the change in the concentration levels of the proteins coded by TCR signaling pathway genes in the infected host. Based on the computed results, we have hypothesized that the balance between TCR signaling inhibitory and stimulatory molecules can keep TCR signaling system into resting/stimulating state, depending upon the perturbation. The proposed integrated host-pathogen interaction pathway model has accurately reflected the experimental evidences, which we have used for validation purpose. The significance of this kind of investigation lies in revealing the susceptible interaction points that can take back the Staphylococcal Enterotoxin (SE)-challenged system within the range of normal behavior. PMID:24324645

A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect

PubMed Central

2013-01-01

Background While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued. Methods Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on ‘serendipitous off-target effects’. Results Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia. Conclusions The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer’s disease. PMID:23885764

Assembly and Multiplex Genome Integration of Metabolic Pathways in Yeast Using CasEMBLR.

PubMed

Jakočiūnas, Tadas; Jensen, Emil D; Jensen, Michael K; Keasling, Jay D

2018-01-01

Genome integration is a vital step for implementing large biochemical pathways to build a stable microbial cell factory. Although traditional strain construction strategies are well established for the model organism Saccharomyces cerevisiae, recent advances in CRISPR/Cas9-mediated genome engineering allow much higher throughput and robustness in terms of strain construction. In this chapter, we describe CasEMBLR, a highly efficient and marker-free genome engineering method for one-step integration of in vivo assembled expression cassettes in multiple genomic sites simultaneously. CasEMBLR capitalizes on the CRISPR/Cas9 technology to generate double-strand breaks in genomic loci, thus prompting native homologous recombination (HR) machinery to integrate exogenously derived homology templates. As proof-of-principle for microbial cell factory development, CasEMBLR was used for one-step assembly and marker-free integration of the carotenoid pathway from 15 exogenously supplied DNA parts into three targeted genomic loci. As a second proof-of-principle, a total of ten DNA parts were assembled and integrated in two genomic loci to construct a tyrosine production strain, and at the same time knocking out two genes. This new method complements and improves the field of genome engineering in S. cerevisiae by providing a more flexible platform for rapid and precise strain building.

Quantum walks in brain microtubules--a biomolecular basis for quantum cognition?

PubMed

Hameroff, Stuart

2014-01-01

Cognitive decisions are best described by quantum mathematics. Do quantum information devices operate in the brain? What would they look like? Fuss and Navarro () describe quantum lattice registers in which quantum superpositioned pathways interact (compute/integrate) as 'quantum walks' akin to Feynman's path integral in a lattice (e.g. the 'Feynman quantum chessboard'). Simultaneous alternate pathways eventually reduce (collapse), selecting one particular pathway in a cognitive decision, or choice. This paper describes how quantum walks in a Feynman chessboard are conceptually identical to 'topological qubits' in brain neuronal microtubules, as described in the Penrose-Hameroff 'Orch OR' theory of consciousness. Copyright © 2013 Cognitive Science Society, Inc.

Early tetrapod evolution and the progressive integration of Permo-Carboniferous terrestrial ecosystems

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

Beerbower, J.R.; Olson, E.C.; Hotton, N. III

1992-01-01

Variation among Permo-Carboniferous tetrapod assemblages demonstrates major transformations in pathways and rates of energy and nutrient transfer, in integration of terrestrial ecosystems and in predominant ecologic modes. Early Carboniferous pathways were through plant detritus to aquatic and terrestrial detritivores and thence to arthropod and vertebrate meso-and macro-predators. Transfer rates (and efficiency) were low as was ecosystem integration; the principal ecologic mode was conservation. Late Carboniferous and Early Permian assemblages demonstrate an expansion in herbivory, primarily in utilization of low-fiber plant tissue by insects. But transfer rates, efficiency and integration were still limited because the larger portion of plant biomass, high-fibermore » tissues, still went into detrital pathways; high-fiber'' herbivores, i.e., tetrapods, were neither abundant or diverse, reflecting limited resources, intense predation and limited capabilities for processing fiber-rich food. The abundance and diversity of tetrapod herbivores in upper Permian assemblages suggests a considerable transfer of energy from high-fiber tissues through these animals to tetrapod predators and thus higher transfer rates and efficiencies. It also brought a shift in ecological mode toward acquisition and regulation and tightened ecosystem integration.« less

Integrative pathway knowledge bases as a tool for systems molecular medicine.

PubMed

Liang, Mingyu

2007-08-20

There exists a sense of urgency to begin to generate a cohesive assembly of biomedical knowledge as the pace of knowledge accumulation accelerates. The urgency is in part driven by the emergence of systems molecular medicine that emphasizes the combination of systems analysis and molecular dissection in the future of medical practice and research. A potentially powerful approach is to build integrative pathway knowledge bases that link organ systems function with molecules.

The NCBI BioSystems database.

PubMed

Geer, Lewis Y; Marchler-Bauer, Aron; Geer, Renata C; Han, Lianyi; He, Jane; He, Siqian; Liu, Chunlei; Shi, Wenyao; Bryant, Stephen H

2010-01-01

The NCBI BioSystems database, found at http://www.ncbi.nlm.nih.gov/biosystems/, centralizes and cross-links existing biological systems databases, increasing their utility and target audience by integrating their pathways and systems into NCBI resources. This integration allows users of NCBI's Entrez databases to quickly categorize proteins, genes and small molecules by metabolic pathway, disease state or other BioSystem type, without requiring time-consuming inference of biological relationships from the literature or multiple experimental datasets.

Pathway Inspector: a pathway based web application for RNAseq analysis of model and non-model organisms.

PubMed

Bianco, Luca; Riccadonna, Samantha; Lavezzo, Enrico; Falda, Marco; Formentin, Elide; Cavalieri, Duccio; Toppo, Stefano; Fontana, Paolo

2017-02-01

Pathway Inspector is an easy-to-use web application helping researchers to find patterns of expression in complex RNAseq experiments. The tool combines two standard approaches for RNAseq analysis: the identification of differentially expressed genes and a topology-based analysis of enriched pathways. Pathway Inspector is equipped with ad hoc interactive graphical interfaces simplifying the discovery of modulated pathways and the integration of the differentially expressed genes in the corresponding pathway topology. Pathway Inspector is available at the website http://admiral.fmach.it/PI and has been developed in Python, making use of the Django Web Framework. Contact:paolo.fontana@fmach.it

Starch biosynthesis in cassava: a genome-based pathway reconstruction and its exploitation in data integration

PubMed Central

2013-01-01

Background Cassava is a well-known starchy root crop utilized for food, feed and biofuel production. However, the comprehension underlying the process of starch production in cassava is not yet available. Results In this work, we exploited the recently released genome information and utilized the post-genomic approaches to reconstruct the metabolic pathway of starch biosynthesis in cassava using multiple plant templates. The quality of pathway reconstruction was assured by the employed parsimonious reconstruction framework and the collective validation steps. Our reconstructed pathway is presented in the form of an informative map, which describes all important information of the pathway, and an interactive map, which facilitates the integration of omics data into the metabolic pathway. Additionally, to demonstrate the advantage of the reconstructed pathways beyond just the schematic presentation, the pathway could be used for incorporating the gene expression data obtained from various developmental stages of cassava roots. Our results exhibited the distinct activities of the starch biosynthesis pathway in different stages of root development at the transcriptional level whereby the activity of the pathway is higher toward the development of mature storage roots. Conclusions To expand its applications, the interactive map of the reconstructed starch biosynthesis pathway is available for download at the SBI group’s website (http://sbi.pdti.kmutt.ac.th/?page_id=33). This work is considered a big step in the quantitative modeling pipeline aiming to investigate the dynamic regulation of starch biosynthesis in cassava roots. PMID:23938102

Starch biosynthesis in cassava: a genome-based pathway reconstruction and its exploitation in data integration.

PubMed

Saithong, Treenut; Rongsirikul, Oratai; Kalapanulak, Saowalak; Chiewchankaset, Porntip; Siriwat, Wanatsanan; Netrphan, Supatcharee; Suksangpanomrung, Malinee; Meechai, Asawin; Cheevadhanarak, Supapon

2013-08-10

Cassava is a well-known starchy root crop utilized for food, feed and biofuel production. However, the comprehension underlying the process of starch production in cassava is not yet available. In this work, we exploited the recently released genome information and utilized the post-genomic approaches to reconstruct the metabolic pathway of starch biosynthesis in cassava using multiple plant templates. The quality of pathway reconstruction was assured by the employed parsimonious reconstruction framework and the collective validation steps. Our reconstructed pathway is presented in the form of an informative map, which describes all important information of the pathway, and an interactive map, which facilitates the integration of omics data into the metabolic pathway. Additionally, to demonstrate the advantage of the reconstructed pathways beyond just the schematic presentation, the pathway could be used for incorporating the gene expression data obtained from various developmental stages of cassava roots. Our results exhibited the distinct activities of the starch biosynthesis pathway in different stages of root development at the transcriptional level whereby the activity of the pathway is higher toward the development of mature storage roots. To expand its applications, the interactive map of the reconstructed starch biosynthesis pathway is available for download at the SBI group's website (http://sbi.pdti.kmutt.ac.th/?page_id=33). This work is considered a big step in the quantitative modeling pipeline aiming to investigate the dynamic regulation of starch biosynthesis in cassava roots.

Regulation of Tissue Growth by the Mammalian Hippo Signaling Pathway

PubMed Central

Watt, Kevin I.; Harvey, Kieran F.; Gregorevic, Paul

2017-01-01

The integrative control of diverse biological processes such as proliferation, differentiation, apoptosis and metabolism is essential to maintain cellular and tissue homeostasis. Disruption of these underlie the development of many disease states including cancer and diabetes, as well as many of the complications that arise as a consequence of aging. These biological outputs are governed by many cellular signaling networks that function independently, and in concert, to convert changes in hormonal, mechanical and metabolic stimuli into alterations in gene expression. First identified in Drosophila melanogaster as a powerful mediator of cell division and apoptosis, the Hippo signaling pathway is a highly conserved regulator of mammalian organ size and functional capacity in both healthy and diseased tissues. Recent studies have implicated the pathway as an effector of diverse physiological cues demonstrating an essential role for the Hippo pathway as an integrative component of cellular homeostasis. In this review, we will: (a) outline the critical signaling elements that constitute the mammalian Hippo pathway, and how they function to regulate Hippo pathway-dependent gene expression and tissue growth, (b) discuss evidence that shows this pathway functions as an effector of diverse physiological stimuli and (c) highlight key questions in this developing field. PMID:29225579

Development of computationally predicted Adverse Outcome Pathway (AOP) networks through data mining and integration of publicly available in vivo, in vitro, phenotype, and biological pathway data

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

Estimating environmental co-benefits of U.S. GHG reduction pathways using the GCAM-USA Integrated Assessment Model (A&WMA Presentation)

EPA Science Inventory

A variety of technological pathways lead to reduced greenhouse gas (GHG) emissions. However, different pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. In this study we use the Global Change ...

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network.

PubMed

Sun, Shuguo; Irvine, Kenneth D

2016-09-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated and to define their respective contributions in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Capital, Alienation, and Challenge: How U.S. Mexican Immigrant Students Build Pathways to College and Career Identities.

PubMed

Cooper, Catherine R; Domínguez, Elizabeth; Cooper, Robert G; Higgins, Ashleigh; Lipka, Alex

2018-06-01

This article considers how the global "academic pipeline problem" constrains immigrant, low-income, and ethnic minority students' pathways to higher education, and how some students build pathways to college and career identities. After aligning theories of social capital, alienation/belonging, and challenge and their integration in Bridging Multiple Worlds Theory, we summarize six longitudinal studies based on this theory from a 23-year university-community partnership serving low-income, primarily U.S. Mexican immigrant youth. Spanning from childhood to early adulthood, the studies revealed two overarching findings: First, students built pathways to college and career identities while experiencing capital, alienation/belonging, and challenges across their evolving cultural worlds. Second, by "giving back" to families, peers, schools, and communities, students became cultural brokers and later, institutional agents, transforming institutional cultures. Findings highlight the value of integrating interdisciplinary theories, research evidence, and educational systems serving diverse communities to open individual pathways and academic pipelines in multicultural societies. © 2018 Wiley Periodicals, Inc.

Competing charge transfer pathways at the photosystem II-electrode interface

PubMed Central

Zhang, Jenny Z.; Sokol, Katarzyna P.; Paul, Nicholas; Romero, Elisabet; van Grondelle, Rienk; Reisner, Erwin

2016-01-01

The integration of the water-oxidation enzyme, photosystem II (PSII), into electrodes allows the electrons extracted from water-oxidation to be harnessed for enzyme characterization and driving novel endergonic reactions. However, PSII continues to underperform in integrated photoelectrochemical systems despite extensive optimization efforts. Here, we performed protein-film photoelectrochemistry on spinach and Thermosynechococcus elongatus PSII, and identified a competing charge transfer pathway at the enzyme-electrode interface that short-circuits the known water-oxidation pathway: photo-induced O2 reduction occurring at the chlorophyll pigments. This undesirable pathway is promoted by the embedment of PSII in an electron-conducting matrix, a common strategy of enzyme immobilization. Anaerobicity helps to recover the PSII photoresponses, and unmasked the onset potentials relating to the QA/QB charge transfer process. These findings have imparted a fuller understanding of the charge transfer pathways within PSII and at photosystem-electrode interfaces, which will lead to more rational design of pigment-containing photoelectrodes in general. PMID:27723748

Kinase Pathway Database: An Integrated Protein-Kinase and NLP-Based Protein-Interaction Resource

PubMed Central

Koike, Asako; Kobayashi, Yoshiyuki; Takagi, Toshihisa

2003-01-01

Protein kinases play a crucial role in the regulation of cellular functions. Various kinds of information about these molecules are important for understanding signaling pathways and organism characteristics. We have developed the Kinase Pathway Database, an integrated database involving major completely sequenced eukaryotes. It contains the classification of protein kinases and their functional conservation, ortholog tables among species, protein–protein, protein–gene, and protein–compound interaction data, domain information, and structural information. It also provides an automatic pathway graphic image interface. The protein, gene, and compound interactions are automatically extracted from abstracts for all genes and proteins by natural-language processing (NLP).The method of automatic extraction uses phrase patterns and the GENA protein, gene, and compound name dictionary, which was developed by our group. With this database, pathways are easily compared among species using data with more than 47,000 protein interactions and protein kinase ortholog tables. The database is available for querying and browsing at http://kinasedb.ontology.ims.u-tokyo.ac.jp/. PMID:12799355

Frontostriatal white matter integrity mediates adult age differences in probabilistic reward learning.

PubMed

Samanez-Larkin, Gregory R; Levens, Sara M; Perry, Lee M; Dougherty, Robert F; Knutson, Brian

2012-04-11

Frontostriatal circuits have been implicated in reward learning, and emerging findings suggest that frontal white matter structural integrity and probabilistic reward learning are reduced in older age. This cross-sectional study examined whether age differences in frontostriatal white matter integrity could account for age differences in reward learning in a community life span sample of human adults. By combining diffusion tensor imaging with a probabilistic reward learning task, we found that older age was associated with decreased reward learning and decreased white matter integrity in specific pathways running from the thalamus to the medial prefrontal cortex and from the medial prefrontal cortex to the ventral striatum. Further, white matter integrity in these thalamocorticostriatal paths could statistically account for age differences in learning. These findings suggest that the integrity of frontostriatal white matter pathways critically supports reward learning. The findings also raise the possibility that interventions that bolster frontostriatal integrity might improve reward learning and decision making.

The NCBI BioSystems database

PubMed Central

Geer, Lewis Y.; Marchler-Bauer, Aron; Geer, Renata C.; Han, Lianyi; He, Jane; He, Siqian; Liu, Chunlei; Shi, Wenyao; Bryant, Stephen H.

2010-01-01

The NCBI BioSystems database, found at http://www.ncbi.nlm.nih.gov/biosystems/, centralizes and cross-links existing biological systems databases, increasing their utility and target audience by integrating their pathways and systems into NCBI resources. This integration allows users of NCBI’s Entrez databases to quickly categorize proteins, genes and small molecules by metabolic pathway, disease state or other BioSystem type, without requiring time-consuming inference of biological relationships from the literature or multiple experimental datasets. PMID:19854944

PAGER 2.0: an update to the pathway, annotated-list and gene-signature electronic repository for Human Network Biology

PubMed Central

Yue, Zongliang; Zheng, Qi; Neylon, Michael T; Yoo, Minjae; Shin, Jimin; Zhao, Zhiying; Tan, Aik Choon

2018-01-01

Abstract Integrative Gene-set, Network and Pathway Analysis (GNPA) is a powerful data analysis approach developed to help interpret high-throughput omics data. In PAGER 1.0, we demonstrated that researchers can gain unbiased and reproducible biological insights with the introduction of PAGs (Pathways, Annotated-lists and Gene-signatures) as the basic data representation elements. In PAGER 2.0, we improve the utility of integrative GNPA by significantly expanding the coverage of PAGs and PAG-to-PAG relationships in the database, defining a new metric to quantify PAG data qualities, and developing new software features to simplify online integrative GNPA. Specifically, we included 84 282 PAGs spanning 24 different data sources that cover human diseases, published gene-expression signatures, drug–gene, miRNA–gene interactions, pathways and tissue-specific gene expressions. We introduced a new normalized Cohesion Coefficient (nCoCo) score to assess the biological relevance of genes inside a PAG, and RP-score to rank genes and assign gene-specific weights inside a PAG. The companion web interface contains numerous features to help users query and navigate the database content. The database content can be freely downloaded and is compatible with third-party Gene Set Enrichment Analysis tools. We expect PAGER 2.0 to become a major resource in integrative GNPA. PAGER 2.0 is available at http://discovery.informatics.uab.edu/PAGER/. PMID:29126216

Lead Isotopes from the Upper Mississippi Valley District: A Regional Perspective

USGS Publications Warehouse

Millen, Timothy M.; Zartman, Robert E.; Heyl, Allen Van

1995-01-01

New lead isotopic data on galena from within and peripheral to the Upper Mississippi Valley lead-zinc district make it possible, by extending coverage to outlying locations, to trace the pathway traversed by the mineralizing fluids beyond the boundary of the main district. All but one of the samples exhibit elevated ratios of the radiogenic isotopes typical of the Upper Mississippi Valley ore deposits; 206PbP04Pb ranges from 19.38 to 24.46, 207PbP04Pb ranges from 15.73 to 16.24, and 208PbP04Pb ranges from 39.24 to 43.69. Galena from the Pints quarry near Waterloo, Iowa, has distinctly lower values of these ratios and may not be related paragenetically to the other samples. Otherwise, the lowest ratios are for samples in the southern part of the region in north-central Illinois, and the highest ratios are for samples to the northeast of the main district in the vicinity of Madison, Wisconsin. Thus, an isotopic pattern rather similar to that observed originally by Heyl and others (1966) prevails regionally, although the predominant fluid flow is now believed to have emanated from the Illinois Basin rather than from the Forest City Basin. Metal-bearing brines being driven northward out of the Illinois Basin probably played the key role in mineralization of the Upper Mississippi Valley district. Both the new and the previously reported lead ratios for the Upper Mississippi Valley district are plotted on 207PbP04Pb and Pb208/pb204Pb versus 206PbP04Pb diagrams, which permit their comparison and the calculation of refined slopes for the expanded data set. A two-stage model age for the time of mineralization can be determined from the 207PbP04Pb_Pb206/Pb204 slope, provided that the source age of the lead is known. With our limited know ledge of this source age, the time of mineralization cannot be tightly constrained but is permissive of a Permian or younger lateral secretion event, as suggested by other geochronological results.

Increased integrity of white matter pathways after dual n-back training.

PubMed

Salminen, Tiina; Mårtensson, Johan; Schubert, Torsten; Kühn, Simone

2016-06-01

Dual n-back WM training has been shown to produce broad transfer effects to different untrained cognitive functions. The task is demanding to the cognitive system because it includes a bi-modal (auditory and visual) dual-task component. A previous WM training study showed increased white matter integrity in the parietal lobe as well as the anterior part of the corpus callosum after visual n-back training. We investigated dual n-back training-related changes in white matter pathways. We anticipated dual n-back training to increase white matter integrity in pathways that connect brain regions related to WM processes. Additionally, we hypothesized that dual n-back training would produce more brain-wide white matter changes than single n-back training because of the involvement of two modalities and the additional dual-task coordination component of the task. The dual n-back training group showed increased white matter integrity (reflected as increased fractional anisotropy, FA) after training. The effects were mostly left lateralized as compared with changes from pretest to posttest in the passive and active control groups. Additionally, significant effects were observed in the anterior part of the corpus callosum, when the training group was compared with the passive control group. There were no changes in pretest to posttest FA changes between the passive and active control groups. The results therefore show that dual n-back training produces increased integrity in white matter pathways connecting different brain regions. The results are discussed in reference to the bi-modal dual-task component of the training task. Copyright © 2016 Elsevier Inc. All rights reserved.

Pathway Inspector: a pathway based web application for RNAseq analysis of model and non-model organisms

PubMed Central

Bianco, Luca; Riccadonna, Samantha; Lavezzo, Enrico; Falda, Marco; Formentin, Elide; Cavalieri, Duccio; Toppo, Stefano

2017-01-01

Abstract Summary: Pathway Inspector is an easy-to-use web application helping researchers to find patterns of expression in complex RNAseq experiments. The tool combines two standard approaches for RNAseq analysis: the identification of differentially expressed genes and a topology-based analysis of enriched pathways. Pathway Inspector is equipped with ad hoc interactive graphical interfaces simplifying the discovery of modulated pathways and the integration of the differentially expressed genes in the corresponding pathway topology. Availability and Implementation: Pathway Inspector is available at the website http://admiral.fmach.it/PI and has been developed in Python, making use of the Django Web Framework. Contact: paolo.fontana@fmach.it PMID:28158604

North American Renewable Integration Study | Energy Analysis | NREL

Science.gov Websites

North American Renewable Integration Study North American Renewable Integration Study NREL's North American Renewable Integration Study (NARIS) will analyze pathways to modernize the North American power planning and operations will help guide and review the study. NARIS will examine the interconnection of U.S

An integrated analysis of genes and functional pathways for aggression in human and rodent models.

PubMed

Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Hess, Jonathan L; Malki, Karim; Glatt, Stephen J; Cormand, Bru; Faraone, Stephen V

2018-06-01

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

Challenges in horizontal model integration.

PubMed

Kolczyk, Katrin; Conradi, Carsten

2016-03-11

Systems Biology has motivated dynamic models of important intracellular processes at the pathway level, for example, in signal transduction and cell cycle control. To answer important biomedical questions, however, one has to go beyond the study of isolated pathways towards the joint study of interacting signaling pathways or the joint study of signal transduction and cell cycle control. Thereby the reuse of established models is preferable, as it will generally reduce the modeling effort and increase the acceptance of the combined model in the field. Obtaining a combined model can be challenging, especially if the submodels are large and/or come from different working groups (as is generally the case, when models stored in established repositories are used). To support this task, we describe a semi-automatic workflow based on established software tools. In particular, two frequent challenges are described: identification of the overlap and subsequent (re)parameterization of the integrated model. The reparameterization step is crucial, if the goal is to obtain a model that can reproduce the data explained by the individual models. For demonstration purposes we apply our workflow to integrate two signaling pathways (EGF and NGF) from the BioModels Database.

Integrating the protein and metabolic engineering toolkits for next-generation chemical biosynthesis.

PubMed

Pirie, Christopher M; De Mey, Marjan; Jones Prather, Kristala L; Ajikumar, Parayil Kumaran

2013-04-19

Through microbial engineering, biosynthesis has the potential to produce thousands of chemicals used in everyday life. Metabolic engineering and synthetic biology are fields driven by the manipulation of genes, genetic regulatory systems, and enzymatic pathways for developing highly productive microbial strains. Fundamentally, it is the biochemical characteristics of the enzymes themselves that dictate flux through a biosynthetic pathway toward the product of interest. As metabolic engineers target sophisticated secondary metabolites, there has been little recognition of the reduced catalytic activity and increased substrate/product promiscuity of the corresponding enzymes compared to those of central metabolism. Thus, fine-tuning these enzymatic characteristics through protein engineering is paramount for developing high-productivity microbial strains for secondary metabolites. Here, we describe the importance of protein engineering for advancing metabolic engineering of secondary metabolism pathways. This pathway integrated enzyme optimization can enhance the collective toolkit of microbial engineering to shape the future of chemical manufacturing.

Integrated pathway-based transcription regulation network mining and visualization based on gene expression profiles.

PubMed

Kibinge, Nelson; Ono, Naoaki; Horie, Masafumi; Sato, Tetsuo; Sugiura, Tadao; Altaf-Ul-Amin, Md; Saito, Akira; Kanaya, Shigehiko

2016-06-01

Conventionally, workflows examining transcription regulation networks from gene expression data involve distinct analytical steps. There is a need for pipelines that unify data mining and inference deduction into a singular framework to enhance interpretation and hypotheses generation. We propose a workflow that merges network construction with gene expression data mining focusing on regulation processes in the context of transcription factor driven gene regulation. The pipeline implements pathway-based modularization of expression profiles into functional units to improve biological interpretation. The integrated workflow was implemented as a web application software (TransReguloNet) with functions that enable pathway visualization and comparison of transcription factor activity between sample conditions defined in the experimental design. The pipeline merges differential expression, network construction, pathway-based abstraction, clustering and visualization. The framework was applied in analysis of actual expression datasets related to lung, breast and prostrate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

PubMed Central

Bertin, Matthew J.; Kleigrewe, Karin; Leão, Tiago F.; Gerwick, Lena

2016-01-01

Filamentous marine cyanobacteria produce bioactive natural products with both potential therapeutic value and capacity to be harmful to human health. Genome sequencing has revealed that cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The biosynthetic pathways that encode cyanobacterial natural products are mostly uncharacterized, and lack of cyanobacterial genetic tools has largely prevented their heterologous expression. Hence, a combination of cutting edge and traditional techniques has been required to elucidate their secondary metabolite biosynthetic pathways. Here, we review the discovery and refined biochemical understanding of the olefin synthase and fatty acid ACP reductase/aldehyde deformylating oxygenase pathways to hydrocarbons, and the curacin A, jamaicamide A, lyngbyabellin, columbamide, and a trans-acyltransferase macrolactone pathway encoding phormidolide. We integrate into this discussion the use of genomics, mass spectrometric networking, biochemical characterization, and isolation and structure elucidation techniques. PMID:26578313

Multisite formative assessment for the Pathways study to prevent obesity in American Indian schoolchildren123

PubMed Central

Gittelsohn, Joel; Evans, Marguerite; Story, Mary; Davis, Sally M; Metcalfe, Lauve; Helitzer, Deborah L; Clay, Theresa E

2016-01-01

We describe the formative assessment process, using an approach based on social learning theory, for the development of a school-based obesity-prevention intervention into which cultural perspectives are integrated. The feasibility phase of the Pathways study was conducted in multiple settings in 6 American Indian nations. The Pathways formative assessment collected both qualitative and quantitative data. The qualitative data identified key social and environmental issues and enabled local people to express their own needs and views. The quantitative, structured data permitted comparison across sites. Both types of data were integrated by using a conceptual and procedural model. The formative assessment results were used to identify and rank the behavioral risk factors that were to become the focus of the Pathways intervention and to provide guidance on developing common intervention strategies that would be culturally appropriate and acceptable to all sites. PMID:10195601

Evolution of the New Pathway curriculum at Harvard Medical School: the new integrated curriculum.

PubMed

Dienstag, Jules L

2011-01-01

In 1985, Harvard Medical School adopted a "New Pathway" curriculum, based on active, adult learning through problem-based, faculty-facilitated small-group tutorials designed to promote lifelong skills of self-directed learning. Despite the successful integration of clinically relevant material in basic science courses, the New Pathway goals were confined primarily to the preclinical years. In addition, the shifting balance in the delivery of health care from inpatient to ambulatory settings limited the richness of clinical education in clinical clerkships, creating obstacles for faculty in their traditional roles as teachers. In 2006, Harvard Medical School adopted a more integrated curriculum based on four principles that emerged after half a decade of self-reflection and planning: (1) integrate the teaching of basic/population science and clinical medicine throughout the entire student experience; (2) reestablish meaningful and intensive faculty-student interactions and reengage the faculty; (3) develop a new model of clinical education that offers longitudinal continuity of patient experience, cross-disciplinary curriculum, faculty mentoring, and student evaluation; and (4) provide opportunities for all students to pursue an in-depth, faculty-mentored scholarly project. These principles of our New Integrated Curriculum reflect our vision for a curriculum that fosters a partnership between students and faculty in the pursuit of scholarship and leadership.

Dynamic Integration of Task-Relevant Visual Features in Posterior Parietal Cortex

PubMed Central

Freedman, David J.

2014-01-01

Summary The primate visual system consists of multiple hierarchically organized cortical areas, each specialized for processing distinct aspects of the visual scene. For example, color and form are encoded in ventral pathway areas such as V4 and inferior temporal cortex, while motion is preferentially processed in dorsal pathway areas such as the middle temporal area. Such representations often need to be integrated perceptually to solve tasks which depend on multiple features. We tested the hypothesis that the lateral intraparietal area (LIP) integrates disparate task-relevant visual features by recording from LIP neurons in monkeys trained to identify target stimuli composed of conjunctions of color and motion features. We show that LIP neurons exhibit integrative representations of both color and motion features when they are task relevant, and task-dependent shifts of both direction and color tuning. This suggests that LIP plays a role in flexibly integrating task-relevant sensory signals. PMID:25199703

Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

PubMed Central

Samuel, Varman T.; Shulman, Gerald I.

2012-01-01

Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

PathMAPA: a tool for displaying gene expression and performing statistical tests on metabolic pathways at multiple levels for Arabidopsis.

PubMed

Pan, Deyun; Sun, Ning; Cheung, Kei-Hoi; Guan, Zhong; Ma, Ligeng; Holford, Matthew; Deng, Xingwang; Zhao, Hongyu

2003-11-07

To date, many genomic and pathway-related tools and databases have been developed to analyze microarray data. In published web-based applications to date, however, complex pathways have been displayed with static image files that may not be up-to-date or are time-consuming to rebuild. In addition, gene expression analyses focus on individual probes and genes with little or no consideration of pathways. These approaches reveal little information about pathways that are key to a full understanding of the building blocks of biological systems. Therefore, there is a need to provide useful tools that can generate pathways without manually building images and allow gene expression data to be integrated and analyzed at pathway levels for such experimental organisms as Arabidopsis. We have developed PathMAPA, a web-based application written in Java that can be easily accessed over the Internet. An Oracle database is used to store, query, and manipulate the large amounts of data that are involved. PathMAPA allows its users to (i) upload and populate microarray data into a database; (ii) integrate gene expression with enzymes of the pathways; (iii) generate pathway diagrams without building image files manually; (iv) visualize gene expressions for each pathway at enzyme, locus, and probe levels; and (v) perform statistical tests at pathway, enzyme and gene levels. PathMAPA can be used to examine Arabidopsis thaliana gene expression patterns associated with metabolic pathways. PathMAPA provides two unique features for the gene expression analysis of Arabidopsis thaliana: (i) automatic generation of pathways associated with gene expression and (ii) statistical tests at pathway level. The first feature allows for the periodical updating of genomic data for pathways, while the second feature can provide insight into how treatments affect relevant pathways for the selected experiment(s).

PathMAPA: a tool for displaying gene expression and performing statistical tests on metabolic pathways at multiple levels for Arabidopsis

PubMed Central

Pan, Deyun; Sun, Ning; Cheung, Kei-Hoi; Guan, Zhong; Ma, Ligeng; Holford, Matthew; Deng, Xingwang; Zhao, Hongyu

2003-01-01

Background To date, many genomic and pathway-related tools and databases have been developed to analyze microarray data. In published web-based applications to date, however, complex pathways have been displayed with static image files that may not be up-to-date or are time-consuming to rebuild. In addition, gene expression analyses focus on individual probes and genes with little or no consideration of pathways. These approaches reveal little information about pathways that are key to a full understanding of the building blocks of biological systems. Therefore, there is a need to provide useful tools that can generate pathways without manually building images and allow gene expression data to be integrated and analyzed at pathway levels for such experimental organisms as Arabidopsis. Results We have developed PathMAPA, a web-based application written in Java that can be easily accessed over the Internet. An Oracle database is used to store, query, and manipulate the large amounts of data that are involved. PathMAPA allows its users to (i) upload and populate microarray data into a database; (ii) integrate gene expression with enzymes of the pathways; (iii) generate pathway diagrams without building image files manually; (iv) visualize gene expressions for each pathway at enzyme, locus, and probe levels; and (v) perform statistical tests at pathway, enzyme and gene levels. PathMAPA can be used to examine Arabidopsis thaliana gene expression patterns associated with metabolic pathways. Conclusion PathMAPA provides two unique features for the gene expression analysis of Arabidopsis thaliana: (i) automatic generation of pathways associated with gene expression and (ii) statistical tests at pathway level. The first feature allows for the periodical updating of genomic data for pathways, while the second feature can provide insight into how treatments affect relevant pathways for the selected experiment(s). PMID:14604444

Systematically Studying Kinase Inhibitor Induced Signaling Network Signatures by Integrating Both Therapeutic and Side Effects

PubMed Central

Shao, Hongwei; Peng, Tao; Ji, Zhiwei; Su, Jing; Zhou, Xiaobo

2013-01-01

Substantial effort in recent years has been devoted to analyzing data based large-scale biological networks, which provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or compounds. In this work, we proposed a novel strategy to investigate kinase inhibitor induced pathway signatures by integrating multiplex data in Library of Integrated Network-based Cellular Signatures (LINCS), e.g. KINOMEscan data and cell proliferation/mitosis imaging data. Using this strategy, we first established a PC9 cell line specific pathway model to investigate the pathway signatures in PC9 cell line when perturbed by a small molecule kinase inhibitor GW843682. This specific pathway revealed the role of PI3K/AKT in modulating the cell proliferation process and the absence of two anti-proliferation links, which indicated a potential mechanism of abnormal expansion in PC9 cell number. Incorporating the pathway model for side effects on primary human hepatocytes, it was used to screen 27 kinase inhibitors in LINCS database and PF02341066, known as Crizotinib, was finally suggested with an optimal concentration 4.6 uM to suppress PC9 cancer cell expansion while avoiding severe damage to primary human hepatocytes. Drug combination analysis revealed that the synergistic effect region can be predicted straightforwardly based on a threshold which is an inherent property of each kinase inhibitor. Furthermore, this integration strategy can be easily extended to other specific cell lines to be a powerful tool for drug screen before clinical trials. PMID:24339888

An integrative systems genetics approach reveals potential causal genes and pathways related to obesity.

PubMed

Kogelman, Lisette J A; Zhernakova, Daria V; Westra, Harm-Jan; Cirera, Susanna; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N

2015-10-20

Obesity is a multi-factorial health problem in which genetic factors play an important role. Limited results have been obtained in single-gene studies using either genomic or transcriptomic data. RNA sequencing technology has shown its potential in gaining accurate knowledge about the transcriptome, and may reveal novel genes affecting complex diseases. Integration of genomic and transcriptomic variation (expression quantitative trait loci [eQTL] mapping) has identified causal variants that affect complex diseases. We integrated transcriptomic data from adipose tissue and genomic data from a porcine model to investigate the mechanisms involved in obesity using a systems genetics approach. Using a selective gene expression profiling approach, we selected 36 animals based on a previously created genomic Obesity Index for RNA sequencing of subcutaneous adipose tissue. Differential expression analysis was performed using the Obesity Index as a continuous variable in a linear model. eQTL mapping was then performed to integrate 60 K porcine SNP chip data with the RNA sequencing data. Results were restricted based on genome-wide significant single nucleotide polymorphisms, detected differentially expressed genes, and previously detected co-expressed gene modules. Further data integration was performed by detecting co-expression patterns among eQTLs and integration with protein data. Differential expression analysis of RNA sequencing data revealed 458 differentially expressed genes. The eQTL mapping resulted in 987 cis-eQTLs and 73 trans-eQTLs (false discovery rate < 0.05), of which the cis-eQTLs were associated with metabolic pathways. We reduced the eQTL search space by focusing on differentially expressed and co-expressed genes and disease-associated single nucleotide polymorphisms to detect obesity-related genes and pathways. Building a co-expression network using eQTLs resulted in the detection of a module strongly associated with lipid pathways. Furthermore, we detected several obesity candidate genes, for example, ENPP1, CTSL, and ABHD12B. To our knowledge, this is the first study to perform an integrated genomics and transcriptomics (eQTL) study using, and modeling, genomic and subcutaneous adipose tissue RNA sequencing data on obesity in a porcine model. We detected several pathways and potential causal genes for obesity. Further validation and investigation may reveal their exact function and association with obesity.

Development of petri net-based dynamic model for improved production of farnesyl pyrophosphate by integrating mevalonate and methylerythritol phosphate pathways in yeast.

PubMed

Baadhe, Rama Raju; Mekala, Naveen Kumar; Palagiri, Satwik Reddy; Parcha, Sreenivasa Rao

2012-07-01

In this case study, we designed a farnesyl pyrophosphate (FPP) biosynthetic network using hybrid functional Petri net with extension (HFPNe) which is derived from traditional Petri net theory and allows easy modeling with graphical approach of various types of entities in the networks together. Our main objective is to improve the production of FPP in yeast, which is further converted to amorphadiene (AD), a precursor of artemisinin (antimalarial drug). Natively, mevalonate (MEV) pathway is present in yeast. Methyl erythritol phosphate pathways (MEP) are present only in higher plant plastids and eubacteria, but not present in yeast. IPP and DAMP are common isomeric intermediate in these two pathways, which immediately yields FPP. By integrating these two pathways in yeast, we augmented the FPP synthesis approximately two folds higher (431.16 U/pt) than in MEV pathway alone (259.91 U/pt) by using HFPNe technique. Further enhanced FPP levels converted to AD by amorphadiene synthase gene yielding 436.5 U/pt of AD which approximately two folds higher compared to the AD (258.5 U/pt) synthesized by MEV pathway exclusively. Simulation and validation processes performed using these models are reliable with identified biological information and data.

Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.

PubMed

Chin, Yoon-Ming; Tan, Lu Ping; Abdul Aziz, Norazlin; Mushiroda, Taisei; Kubo, Michiaki; Mohd Kornain, Noor Kaslina; Tan, Geok Wee; Khoo, Alan Soo-Beng; Krishnan, Gopala; Pua, Kin-Choo; Yap, Yoke-Yeow; Teo, Soo-Hwang; Lim, Paul Vey-Hong; Nakamura, Yusuke; Lum, Chee Lun; Ng, Ching-Ching

2016-10-15

Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort. © 2016 UICC.

Integrated RNA-seq and sRNA-seq analysis reveals miRNA effects on secondary metabolism in Solanum tuberosum L.

PubMed

Qiao, Yan; Zhang, Jinjin; Zhang, Jinwen; Wang, Zhiwei; Ran, An; Guo, Haixia; Wang, Di; Zhang, Junlian

2017-02-01

Light is a major environmental factor that affects metabolic pathways and stimulates the production of secondary metabolites in potato. However, adaptive changes in potato metabolic pathways and physiological functions triggered by light are partly explained by gene expression changes. Regulation of secondary metabolic pathways in potato has been extensively studied at transcriptional level, but little is known about the mechanisms of post-transcriptional regulation by miRNAs. To identify light-responsive miRNAs/mRNAs and construct putative metabolism pathways regulated by the miRNA-mRNA pairs, an integrated omics (sRNAome and transcriptome) analysis was performed to potato under light stimulus. A total of 31 and 48 miRNAs were identified to be differentially expressed in the leaves and tubers, respectively. Among the DEGs, 1353 genes in the leaves and 1841 genes in the tubers were upregulated, while 1595 genes in the leaves and 897 genes in the tubers were downregulated by light. Mapman enrichment analyses showed that genes related to MVA pathway, alkaloids-like, phenylpropanoids, flavonoids, and carotenoids metabolism were significantly upregulated, while genes associated with major CHO metabolism were repressed in the leaves and tubers. Integrated miRNA and mRNA profiles revealed that light-responsive miRNAs are important regulators in alkaloids metabolism, UMP salvage, lipid biosynthesis, and cellulose catabolism. Moreover, several miRNAs may participate in glycoalkaloids metabolism via JA signaling pathway, UDP-glucose biosynthesis and hydroxylation reaction. This study provides a global view of miRNA and mRNA expression profiles in potato response to light, our results suggest that miRNAs might play important roles in secondary metabolic pathways, especially in glycoalkaloid biosynthesis. The findings will enlighten us on the genetic regulation of secondary metabolite pathways and pave the way for future application of genetically engineered potato.

The CWI Pathway: Regulation of the Transcriptional Adaptive Response to Cell Wall Stress in Yeast

PubMed Central

Sanz, Ana Belén; García, Raúl; Rodríguez-Peña, José M.; Arroyo, Javier

2017-01-01

Fungi are surrounded by an essential structure, the cell wall, which not only confers cell shape but also protects cells from environmental stress. As a consequence, yeast cells growing under cell wall damage conditions elicit rescue mechanisms to provide maintenance of cellular integrity and fungal survival. Through transcriptional reprogramming, yeast modulate the expression of genes important for cell wall biogenesis and remodeling, metabolism and energy generation, morphogenesis, signal transduction and stress. The yeast cell wall integrity (CWI) pathway, which is very well conserved in other fungi, is the key pathway for the regulation of this adaptive response. In this review, we summarize the current knowledge of the yeast transcriptional program elicited to counterbalance cell wall stress situations, the role of the CWI pathway in the regulation of this program and the importance of the transcriptional input received by other pathways. Modulation of this adaptive response through the CWI pathway by positive and negative transcriptional feedbacks is also discussed. Since all these regulatory mechanisms are well conserved in pathogenic fungi, improving our knowledge about them will have an impact in the developing of new antifungal therapies. PMID:29371494

Integrating Continuing Professional Development With Health System Reform: Building Pillars of Support.

PubMed

Davis, David A; Rayburn, William F

2016-01-01

Clinical failures sparked a widespread desire for health system reform at the beginning of the 21st century, but related efforts have resulted in changes that are either slow or nonexistent. In response, academic medicine has moved in two directions: (1) system-wide reform using electronic health records, practice networks, and widespread data applications (a macro pathway); and (2) professional development of individual clinicians through continuous performance improvement (a micro pathway). Both pathways exist to improve patient care and population health, yet each suffers from limitations in widespread implementation. The authors call for a better union between these two parallel pathways through four pillars of support: (1) an acknowledgment that both pathways are essential to each other and to the final outcome they intend to achieve, (2) a strong faculty commitment to educate about quality improvement and patient safety at all education levels, (3) a reengineering of tools for professional development to serve as effective change agents, and (4) the development of standards to sustain this alignment of pathways. With these pillars of support integrating continuing professional development with health system reform, the authors envision a better functioning system, with improved metrics and value to enhance patient care and population health.

Iterative optimization of xylose catabolism in Saccharomyces cerevisiae using combinatorial expression tuning.

PubMed

Latimer, Luke N; Dueber, John E

2017-06-01

A common challenge in metabolic engineering is rapidly identifying rate-controlling enzymes in heterologous pathways for subsequent production improvement. We demonstrate a workflow to address this challenge and apply it to improving xylose utilization in Saccharomyces cerevisiae. For eight reactions required for conversion of xylose to ethanol, we screened enzymes for functional expression in S. cerevisiae, followed by a combinatorial expression analysis to achieve pathway flux balancing and identification of limiting enzymatic activities. In the next round of strain engineering, we increased the copy number of these limiting enzymes and again tested the eight-enzyme combinatorial expression library in this new background. This workflow yielded a strain that has a ∼70% increase in biomass yield and ∼240% increase in xylose utilization. Finally, we chromosomally integrated the expression library. This library enriched for strains with multiple integrations of the pathway, which likely were the result of tandem integrations mediated by promoter homology. Biotechnol. Bioeng. 2017;114: 1301-1309. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Developing integrated patient pathways using hybrid simulation

NASA Astrophysics Data System (ADS)

Zulkepli, Jafri; Eldabi, Tillal

2016-10-01

Integrated patient pathways includes several departments, i.e. healthcare which includes emergency care and inpatient ward; intermediate care which patient(s) will stay for a maximum of two weeks and at the same time be assessed by assessment team to find the most suitable care; and social care. The reason behind introducing the intermediate care in western countries was to reduce the rate of patients that stays in the hospital especially for elderly patients. This type of care setting has been considered to be set up in some other countries including Malaysia. Therefore, to assess the advantages of introducing this type of integrated healthcare setting, we suggest develop the model using simulation technique. We argue that single simulation technique is not viable enough to represent this type of patient pathways. Therefore, we suggest develop this model using hybrid techniques, i.e. System Dynamics (SD) and Discrete Event Simulation (DES). Based on hybrid model result, we argued that the result is viable to be as references for decision making process.

A novel chi-square statistic for detecting group differences between pathways in systems epidemiology.

PubMed

Yuan, Zhongshang; Ji, Jiadong; Zhang, Tao; Liu, Yi; Zhang, Xiaoshuai; Chen, Wei; Xue, Fuzhong

2016-12-20

Traditional epidemiology often pays more attention to the identification of a single factor rather than to the pathway that is related to a disease, and therefore, it is difficult to explore the disease mechanism. Systems epidemiology aims to integrate putative lifestyle exposures and biomarkers extracted from multiple omics platforms to offer new insights into the pathway mechanisms that underlie disease at the human population level. One key but inadequately addressed question is how to develop powerful statistics to identify whether one candidate pathway is associated with a disease. Bearing in mind that a pathway difference can result from not only changes in the nodes but also changes in the edges, we propose a novel statistic for detecting group differences between pathways, which in principle, captures the nodes changes and edge changes, as well as simultaneously accounting for the pathway structure simultaneously. The proposed test has been proven to follow the chi-square distribution, and various simulations have shown it has better performance than other existing methods. Integrating genome-wide DNA methylation data, we analyzed one real data set from the Bogalusa cohort study and significantly identified a potential pathway, Smoking → SOCS3 → PIK3R1, which was strongly associated with abdominal obesity. The proposed test was powerful and efficient at identifying pathway differences between two groups, and it can be extended to other disciplines that involve statistical comparisons between pathways. The source code in R is available on our website. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution

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

Ou, Yang; Shi, Wenjing; Smith, Steven J.

There are many technological pathways that can lead to reduced carbon dioxide (CO 2) emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the U.S. energy system to compare environmental impacts of alternative low-carbon pathways. One set of pathways emphasizes nuclear energy and carbon capture and storage (NUC/CCS), while another set emphasizes renewable energy (RE). These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter less thanmore » 2.5 microns in diameter (PM2.5), and energy-related water demands are evaluated for 50% and 80% CO 2 reduction targets in the U.S. in 2050. The RE low-carbon pathways require less water withdrawal and consumption than the NUC/CCS pathways because of the large cooling demands of nuclear power and CCS. However, the NUC/CCS low-carbon pathways produce greater health benefits, mainly because the NUC/CCS assumptions result in less primary PM2.5 emissions from residential wood combustion. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies. An important finding is that biomass in the building sector can offset some of the health co-benefits of the low-carbon pathways even though it plays only a minor role in reducing CO 2 emissions.« less

Extended fusion yield integral using pathway idea in case of Shock-compressed heated plasma

NASA Astrophysics Data System (ADS)

Kumar, Dilip; Haubold, Hans

The extended non-resonant thermonuclear reaction rate probability integral obtained in Haubold and Kumar [Haubold, H.J. and Kumar, D.: 2008, Extension of thermonuclear functions through the pathway model including Maxwell-Boltzmann and Tsallis distributions, Astroparticle Physics, 29, 70-76] is used to evaluate the fusion energy by itegrating it over temperature. The closed form representation of the extended reaction rate integral via Meijer's G-function is expressed as a solution of a homogeneous differential equation. A physical model of Guderley[Guderley G. :1942, Starke kugelige und zylindrische Verdichtungsstsse in der Nhe des Kugelmittelpunktes bzw. der Zylinderachse, Luftfahrtforschung, 19, 302] has been considered for the laser driven hydrodynamical process in a compressed fusion plasma and heated strong spherical shock wave. The fusion yield integral obtained in the paper is compared with the standard fusion yield ob-tained by Haubold and John [Haubold, H.J. and John, R.W.:1981, Analytical representation of the thermonuclear reaction rate and fusion energy production in a spherical plasma shock wave, Plasma Physics, 5, 399-411]. The pathway parameter used in this paper is given an interpretation in terms of moments.

Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma.

PubMed

Green, Michael R; Aya-Bonilla, Carlos; Gandhi, Maher K; Lea, Rod A; Wellwood, Jeremy; Wood, Peter; Marlton, Paula; Griffiths, Lyn R

2011-05-01

Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non-Hodgkin's lymphoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By integrating genome-wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including amplification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, amplification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA-mediated knock-down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic amplification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy. 2011 Wiley-Liss, Inc.

Internationally Educated Health Professionals in Canada: Navigating Three Policy Subsystems Along the Pathway to Practice.

PubMed

Paul, Robert; Martimianakis, Maria Athina Tina; Johnstone, Julie; McNaughton, Nancy; Austin, Zubin

2017-05-01

The integration of internationally educated health professionals (IEHPs) into the health workforces of their adopted countries is an issue that has challenged policy makers and policy scholars for decades. In this article, the authors explore the implications of the ideological underpinnings of the policy subsystems that IEHPs must navigate in seeking employment in Canada, with a focus on Ontario.Using a policy subsystem approach, in 2015 the authors analyzed a large preexisting data set composed of articles, governmental reports, Web sites, and transcripts of interviews and focus groups conducted in Ontario with IEHPs, health care executives, human resource managers, and job counselors to IEHPs. Through this analysis, they identified three policy subsystems-the immigration system, the educational and licensure/regulatory system, and the health human resources system-that conflict ideologically and, as a result, create barriers to IEHP integration.To make substantive progress on IEHP integration in Canada, four questions should be considered. First, how can researchers bring new research methods to bear to explore why no jurisdiction has been able to create an integrated pathway to practice for IEHPs? Second, how and to what end are the institutions within the three policy subsystems regulating the IEHP pathway to practice? Third, how might the educational and licensure/regulatory policy subsystem create alternative health care employment options for IEHPs? Finally, how might health professions educators pursue a leadership role in the creation of an overarching institution to manage the pathway to practice for IEHPs?

MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin

PubMed Central

Yun, Jina; Puri, Rajat; Yang, Huan; Lizzio, Michael A; Wu, Chunlai; Sheng, Zu-Hang; Guo, Ming

2014-01-01

Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD. DOI: http://dx.doi.org/10.7554/eLife.01958.001 PMID:24898855

The New Interventional Radiology Pathways: Options for Implementation.

PubMed

Recht, Michael; McKinney, J Mark; Alleman, Anthony M; Lowe, Lisa H; Spies, James B

2016-07-01

The new interventional radiology (IR) pathways have generated much discussion with articles and editorials pointing out perceived advantages and disadvantages compared to the current pathways. To briefly review, under the new system, there are three pathways to enter IR: the integrated (INT) IR residency, the independent (IND) IR residency, and the early specialization in interventional radiology (ESIR) program. The pathways have been designed to provide maximum flexibility to programs for implementation and to radiology residents for planning their subspecialty training. As a result, there are many potential permutations for these training programs, and understanding the variety of options can be a challenge at first. We offer three potential solutions, based on the different circumstances or requirements a department might face. The first two solutions involve integrated programs created through newly funded and converted diagnostic radiology slots, respectively. The third involves establishing ESIR and IND programs only. Hopefully, the examples provided will be useful for those currently planning for the future of their IR training programs. Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

PathwayAccess: CellDesigner plugins for pathway databases.

PubMed

Van Hemert, John L; Dickerson, Julie A

2010-09-15

CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

BiologicalNetworks 2.0 - an integrative view of genome biology data

PubMed Central

2010-01-01

Background A significant problem in the study of mechanisms of an organism's development is the elucidation of interrelated factors which are making an impact on the different levels of the organism, such as genes, biological molecules, cells, and cell systems. Numerous sources of heterogeneous data which exist for these subsystems are still not integrated sufficiently enough to give researchers a straightforward opportunity to analyze them together in the same frame of study. Systematic application of data integration methods is also hampered by a multitude of such factors as the orthogonal nature of the integrated data and naming problems. Results Here we report on a new version of BiologicalNetworks, a research environment for the integral visualization and analysis of heterogeneous biological data. BiologicalNetworks can be queried for properties of thousands of different types of biological entities (genes/proteins, promoters, COGs, pathways, binding sites, and other) and their relations (interactions, co-expression, co-citations, and other). The system includes the build-pathways infrastructure for molecular interactions/relations and module discovery in high-throughput experiments. Also implemented in BiologicalNetworks are the Integrated Genome Viewer and Comparative Genomics Browser applications, which allow for the search and analysis of gene regulatory regions and their conservation in multiple species in conjunction with molecular pathways/networks, experimental data and functional annotations. Conclusions The new release of BiologicalNetworks together with its back-end database introduces extensive functionality for a more efficient integrated multi-level analysis of microarray, sequence, regulatory, and other data. BiologicalNetworks is freely available at http://www.biologicalnetworks.org. PMID:21190573

An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types

PubMed Central

Park, Sunho; Kim, Seung-Jun; Yu, Donghyeon; Peña-Llopis, Samuel; Gao, Jianjiong; Park, Jin Suk; Chen, Beibei; Norris, Jessie; Wang, Xinlei; Chen, Min; Kim, Minsoo; Yong, Jeongsik; Wardak, Zabi; Choe, Kevin; Story, Michael; Starr, Timothy; Cheong, Jae-Ho; Hwang, Tae Hyun

2016-01-01

Motivation: Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. Results: We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. Availability and implementation: The code is available at: http://www.taehyunlab.org. Contact: jhcheong@yuhs.ac or taehyun.hwang@utsouthwestern.edu or taehyun.cs@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26635139

Integrating Contextualized Math in the MultiCraft Curricula at Sauk Valley Community College. Pathways to Results: Implementation Partnerships Strategy Brief

ERIC Educational Resources Information Center

Rockey, Marci

2016-01-01

Sauk Valley Community College (SVCC) has returned to the Pathways to Results (PTR) process to analyze and improve a new pathway each year for the last five years. They have become so invested in PTR that they have institutionalized its use into their approach to program review and continuous improvement, creating an institutional PTR team…

Integrated device architectures for electrochromic devices

DOEpatents

Frey, Jonathan Mack; Berland, Brian Spencer

2015-04-21

This disclosure describes systems and methods for creating monolithically integrated electrochromic devices which may be a flexible electrochromic device. Monolithic integration of thin film electrochromic devices may involve the electrical interconnection of multiple individual electrochromic devices through the creation of specific structures such as conductive pathway or insulating isolation trenches.

Neuroendocrine integration of nutritional signals on reproduction.

PubMed

Evans, Maggie C; Anderson, Greg M

2017-02-01

Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility. © 2017 Society for Endocrinology.

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

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

Fukunaga, Satoki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558; Kakehashi, Anna

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective ofmore » initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.« less

Integrating gene and protein expression data with genome-scale metabolic networks to infer functional pathways.

PubMed

Pey, Jon; Valgepea, Kaspar; Rubio, Angel; Beasley, John E; Planes, Francisco J

2013-12-08

The study of cellular metabolism in the context of high-throughput -omics data has allowed us to decipher novel mechanisms of importance in biotechnology and health. To continue with this progress, it is essential to efficiently integrate experimental data into metabolic modeling. We present here an in-silico framework to infer relevant metabolic pathways for a particular phenotype under study based on its gene/protein expression data. This framework is based on the Carbon Flux Path (CFP) approach, a mixed-integer linear program that expands classical path finding techniques by considering additional biophysical constraints. In particular, the objective function of the CFP approach is amended to account for gene/protein expression data and influence obtained paths. This approach is termed integrative Carbon Flux Path (iCFP). We show that gene/protein expression data also influences the stoichiometric balancing of CFPs, which provides a more accurate picture of active metabolic pathways. This is illustrated in both a theoretical and real scenario. Finally, we apply this approach to find novel pathways relevant in the regulation of acetate overflow metabolism in Escherichia coli. As a result, several targets which could be relevant for better understanding of the phenomenon leading to impaired acetate overflow are proposed. A novel mathematical framework that determines functional pathways based on gene/protein expression data is presented and validated. We show that our approach is able to provide new insights into complex biological scenarios such as acetate overflow in Escherichia coli.

Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways.

PubMed

Chong, Zhao Zhong; Li, Faqi; Maiese, Kenneth

2007-06-01

Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during beta-amyloid (Abeta1-42) exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3beta (GSK-3beta) and beta-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3beta and maintains beta-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3beta, and beta-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

The Role of Lamination in Neocortical Function

DTIC Science & Technology

1991-12-20

U. Studies of the Tectofugal System: Tectal pathways to the telencephalon in birds and mammals. The tecto-thalamo-telencephalic visual pathway is...significance of lamination of the telencephalon . Visual Structures and Integrated Functions, Research Notes in Neural Computing (Michael Arbib and J6rg

An Integrative data mining approach to identifying Adverse Outcome Pathway (AOP) Signatures

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or populatio...

An Integrative Data Mining Approach to Identify Adverse Outcome Pathway Signatures

EPA Science Inventory

Adverse Outcome Pathways (AOPs) provide a formal framework for describing the mechanisms underlying the toxicity of chemicals in our environment. This process improves our ability to incorporate high-throughput toxicity testing (HTT) results and biomarker information on early key...

Mitochondrial AKAP1 supports mTOR pathway and tumor growth.

PubMed

Rinaldi, Laura; Sepe, Maria; Delle Donne, Rossella; Conte, Kristel; Arcella, Antonietta; Borzacchiello, Domenica; Amente, Stefano; De Vita, Fernanda; Porpora, Monia; Garbi, Corrado; Oliva, Maria A; Procaccini, Claudio; Faicchia, Deriggio; Matarese, Giuseppe; Zito Marino, Federica; Rocco, Gaetano; Pignatiello, Sara; Franco, Renato; Insabato, Luigi; Majello, Barbara; Feliciello, Antonio

2017-06-01

Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy.

Integration of Personalized Healthcare Pathways in an ICT Platform for Diabetes Managements: A Small-Scale Exploratory Study.

PubMed

Fico, Giuseppe; Fioravanti, Alessio; Arredondo, Maria Teresa; Gorman, Joe; Diazzi, Chiara; Arcuri, Giovanni; Conti, Claudio; Pirini, Giampiero

2016-01-01

The availability of new tools able to support patient monitoring and personalized care may substantially improve the quality of chronic disease management. A personalized healthcare pathway (PHP) has been developed for diabetes disease management and integrated into an information and communication technology system to accomplish a shift from organization-centered care to patient-centered care. A small-scale exploratory study was conducted to test the platform. Preliminary results are presented that shed light on how the PHP influences system usage and performance outcomes.

Discovery of new candidate genes for rheumatoid arthritis through integration of genetic association data with expression pathway analysis.

PubMed

Shchetynsky, Klementy; Diaz-Gallo, Lina-Marcella; Folkersen, Lasse; Hensvold, Aase Haj; Catrina, Anca Irinel; Berg, Louise; Klareskog, Lars; Padyukov, Leonid

2017-02-02

Here we integrate verified signals from previous genetic association studies with gene expression and pathway analysis for discovery of new candidate genes and signaling networks, relevant for rheumatoid arthritis (RA). RNA-sequencing-(RNA-seq)-based expression analysis of 377 genes from previously verified RA-associated loci was performed in blood cells from 5 newly diagnosed, non-treated patients with RA, 7 patients with treated RA and 12 healthy controls. Differentially expressed genes sharing a similar expression pattern in treated and untreated RA sub-groups were selected for pathway analysis. A set of "connector" genes derived from pathway analysis was tested for differential expression in the initial discovery cohort and validated in blood cells from 73 patients with RA and in 35 healthy controls. There were 11 qualifying genes selected for pathway analysis and these were grouped into two evidence-based functional networks, containing 29 and 27 additional connector molecules. The expression of genes, corresponding to connector molecules was then tested in the initial RNA-seq data. Differences in the expression of ERBB2, TP53 and THOP1 were similar in both treated and non-treated patients with RA and an additional nine genes were differentially expressed in at least one group of patients compared to healthy controls. The ERBB2, TP53. THOP1 expression profile was successfully replicated in RNA-seq data from peripheral blood mononuclear cells from healthy controls and non-treated patients with RA, in an independent collection of samples. Integration of RNA-seq data with findings from association studies, and consequent pathway analysis implicate new candidate genes, ERBB2, TP53 and THOP1 in the pathogenesis of RA.

User Interface Requirements for Web-Based Integrated Care Pathways: Evidence from the Evaluation of an Online Care Pathway Investigation Tool.

PubMed

Balatsoukas, Panos; Williams, Richard; Davies, Colin; Ainsworth, John; Buchan, Iain

2015-11-01

Integrated care pathways (ICPs) define a chronological sequence of steps, most commonly diagnostic or treatment, to be followed in providing care for patients. Care pathways help to ensure quality standards are met and to reduce variation in practice. Although research on the computerisation of ICP progresses, there is still little knowledge on what are the requirements for designing user-friendly and usable electronic care pathways, or how users (normally health care professionals) interact with interfaces that support design, analysis and visualisation of ICPs. The purpose of the study reported in this paper was to address this gap by evaluating the usability of a novel web-based tool called COCPIT (Collaborative Online Care Pathway Investigation Tool). COCPIT supports the design, analysis and visualisation of ICPs at the population level. In order to address the aim of this study, an evaluation methodology was designed based on heuristic evaluations and a mixed method usability test. The results showed that modular visualisation and direct manipulation of information related to the design and analysis of ICPs is useful for engaging and stimulating users. However, designers should pay attention to issues related to the visibility of the system status and the match between the system and the real world, especially in relation to the display of statistical information about care pathways and the editing of clinical information within a care pathway. The paper concludes with recommendations for interface design.

An integrated approach to demonstrating the ANR pathway of proanthocyanidin biosynthesis in plants.

PubMed

Peng, Qing-Zhong; Zhu, Yue; Liu, Zhong; Du, Ci; Li, Ke-Gang; Xie, De-Yu

2012-09-01

Proanthocyanidins (PAs) are oligomers or polymers of plant flavan-3-ols and are important to plant adaptation in extreme environmental conditions. The characterization of anthocyanidin reductase (ANR) and leucoanthocyanidin reductase (LAR) has demonstrated the different biogenesis of four stereo-configurations of flavan-3-ols. It is important to understand whether ANR and the ANR pathway widely occur in the plant kingdom. Here, we report an integrated approach to demonstrate the ANR pathway in plants. This includes different methods to extract native ANR from different tissues of eight angiosperm plants (Lotus corniculatus, Desmodium uncinatum, Medicago sativa, Hordeum vulgare, Vitis vinifera, Vitis bellula, Parthenocissus heterophylla, and Cerasus serrulata) and one fern plant (Dryopteris pycnopteroides), a general enzymatic analysis approach to demonstrate the ANR activity, high-performance liquid chromatography-based fingerprinting to demonstrate (-)-epicatechin and other flavan-3-ol molecules, and phytochemical analysis of PAs. Results demonstrate that in addition to leaves of M. sativa, tissues of other eight plants contain an active ANR pathway. Particularly, the leaves, flowers and pods of D. uncinatum, which is a model plant to study LAR and the LAR pathways, are demonstrated to express an active ANR pathway. This finding suggests that the ANR pathway involves PA biosynthesis in D. uncinatum. In addition, a sequence BLAST analysis reveals that ANR homologs have been sequenced in plants from both gymnosperms and angiosperms. These data show that the ANR pathway to PA biosynthesis occurs in both seed and seedless vascular plants.

Modeling of nitrous oxide production by autotrophic ammonia-oxidizing bacteria with multiple production pathways.

PubMed

Ni, Bing-Jie; Peng, Lai; Law, Yingyu; Guo, Jianhua; Yuan, Zhiguo

2014-04-01

Autotrophic ammonia oxidizing bacteria (AOB) have been recognized as a major contributor to N2O production in wastewater treatment systems. However, so far N2O models have been proposed based on a single N2O production pathway by AOB, and there is still a lack of effective approach for the integration of these models. In this work, an integrated mathematical model that considers multiple production pathways is developed to describe N2O production by AOB. The pathways considered include the nitrifier denitrification pathway (N2O as the final product of AOB denitrification with NO2(-) as the terminal electron acceptor) and the hydroxylamine (NH2OH) pathway (N2O as a byproduct of incomplete oxidation of NH2OH to NO2(-)). In this model, the oxidation and reduction processes are modeled separately, with intracellular electron carriers introduced to link the two types of processes. The model is calibrated and validated using experimental data obtained with two independent nitrifying cultures. The model satisfactorily describes the N2O data from both systems. The model also predicts shifts of the dominating pathway at various dissolved oxygen (DO) and nitrite levels, consistent with previous hypotheses. This unified model is expected to enhance our ability to predict N2O production by AOB in wastewater treatment systems under varying operational conditions.

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

PubMed

Gallon, Lorenzo; Mathew, James M; Bontha, Sai Vineela; Dumur, Catherine I; Dalal, Pranav; Nadimpalli, Lakshmi; Maluf, Daniel G; Shetty, Aneesha A; Ildstad, Suzanne T; Leventhal, Joseph R; Mas, Valeria R

2018-02-01

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways. Copyright © 2018 by the American Society of Nephrology.

The adverse outcome pathway for skin sensitisation: Moving closer to replacing animal testing.

PubMed

Schultz, Terry W; Dimitrova, Gergana; Dimitrov, Sabcho; Mekenyan, Ovanes G

2016-10-01

This article outlines the work of the Organisation for Economic Co-operation and Development (OECD) that led to being jointly awarded the 2015 Lush Black Box Prize. The award-winning work centred on the development of 'The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins'. This Adverse Outcome Pathway (AOP) has provided the mechanistic basis for the integration of skin sensitisation-related information. Recent developments in integrated approaches to testing and assessment, based on the AOP, are summarised. The impact of the AOP on regulatory policy and on the Three Rs are discussed. An overview of the next generation of the skin sensitisation AOP module in the OECD QSAR Toolbox, based on more-recent work at the Laboratory of Mathematical Chemistry, is also presented. 2016 FRAME.

Constructing Adverse Outcome Pathways: a Demonstration of an Ontology-based Semantics Mapping Approach

EPA Science Inventory

Adverse outcome pathway (AOP) provides a conceptual framework to evaluate and integrate chemical toxicity and its effects across the levels of biological organization. As such, it is essential to develop a resource-efficient and effective approach to extend molecular initiating ...

How might flukes and tapeworms maintain genome integrity without a canonical piRNA pathway?

PubMed Central

Skinner, Danielle E.; Rinaldi, Gabriel; Koziol, Uriel; Brehm, Klaus; Brindley, Paul J.

2014-01-01

Surveillance by RNA interference is central to controlling the mobilization of transposable elements (TEs). In stem cells, Piwi argonaute (Ago) proteins and associated proteins repress mobilization of TEs to maintain genome integrity. This defense mechanism targeting TEs is termed the Piwi-interacting RNA (Piwi-piRNA) pathway. In this Opinion, we draw attention to the situation that the genomes of cestodes and trematodes have lost the piwi and vasa genes that are hallmark characters of the germline multipotency program. This absence of Piwi-like Agos and Vasa helicases prompts the question: how does the germline of these flatworms withstand mobilization of TEs? Here we present an interpretation of mechanisms likely to defend the germline integrity of parasitic flatworms. PMID:24485046

Simultaneous utilization of cellobiose, xylose, and acetic acid from lignocellulosic biomass for biofuel production by an engineered yeast platform.

PubMed

Wei, Na; Oh, Eun Joong; Million, Gyver; Cate, Jamie H D; Jin, Yong-Su

2015-06-19

The inability of fermenting microorganisms to use mixed carbon components derived from lignocellulosic biomass is a major technical barrier that hinders the development of economically viable cellulosic biofuel production. In this study, we integrated the fermentation pathways of both hexose and pentose sugars and an acetic acid reduction pathway into one Saccharomyces cerevisiae strain for the first time using synthetic biology and metabolic engineering approaches. The engineered strain coutilized cellobiose, xylose, and acetic acid to produce ethanol with a substantially higher yield and productivity than the control strains, and the results showed the unique synergistic effects of pathway coexpression. The mixed substrate coutilization strategy is important for making complete and efficient use of cellulosic carbon and will contribute to the development of consolidated bioprocessing for cellulosic biofuel. The study also presents an innovative metabolic engineering approach whereby multiple substrate consumption pathways can be integrated in a synergistic way for enhanced bioconversion.

ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells.

PubMed

Wang, Haitao; Behrens, Edward M; Pignolo, Robert J; Kaplan, Frederick S

2018-04-01

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions. Copyright © 2018 Elsevier Inc. All rights reserved.

Model framework for integrating multiple exposure pathways to chemicals in household cleaning products.

PubMed

Shin, H-M; McKone, T E; Bennett, D H

2017-07-01

We present a screening-level exposure-assessment method which integrates exposure from all plausible exposure pathways as a result of indoor residential use of cleaning products. The exposure pathways we considered are (i) exposure to a user during product use via inhalation and dermal, (ii) exposure to chemical residues left on clothing, (iii) exposure to all occupants from the portion released indoors during use via inhalation and dermal, and (iv) exposure to the general population due to down-the-drain disposal via inhalation and ingestion. We use consumer product volatilization models to account for the chemical fractions volatilized to air (f volatilized ) and disposed down the drain (f down-the-drain ) during product use. For each exposure pathway, we use a fate and exposure model to estimate intake rates (iR) in mg/kg/d. Overall, the contribution of the four exposure pathways to the total exposure varies by the type of cleaning activities and with chemical properties. By providing a more comprehensive exposure model and by capturing additional exposures from often-overlooked exposure pathways, our method allows us to compare the relative contribution of various exposure routes and could improve high-throughput exposure assessment for chemicals in cleaning products. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Recovery from the DNA Replication Checkpoint

PubMed Central

Chaudhury, Indrajit; Koepp, Deanna M.

2016-01-01

Checkpoint recovery is integral to a successful checkpoint response. Checkpoint pathways monitor progress during cell division so that in the event of an error, the checkpoint is activated to block the cell cycle and activate repair pathways. Intrinsic to this process is that once repair has been achieved, the checkpoint signaling pathway is inactivated and cell cycle progression resumes. We use the term “checkpoint recovery” to describe the pathways responsible for the inactivation of checkpoint signaling and cell cycle re-entry after the initial stress has been alleviated. The DNA replication or S-phase checkpoint monitors the integrity of DNA synthesis. When replication stress is encountered, replication forks are stalled, and the checkpoint signaling pathway is activated. Central to recovery from the S-phase checkpoint is the restart of stalled replication forks. If checkpoint recovery fails, stalled forks may become unstable and lead to DNA breaks or unusual DNA structures that are difficult to resolve, causing genomic instability. Alternatively, if cell cycle resumption mechanisms become uncoupled from checkpoint inactivation, cells with under-replicated DNA might proceed through the cell cycle, also diminishing genomic stability. In this review, we discuss the molecular mechanisms that contribute to inactivation of the S-phase checkpoint signaling pathway and the restart of replication forks during recovery from replication stress. PMID:27801838

Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis.

PubMed

Song, Zhenhua; Zhang, Chi; He, Lingxiao; Sui, Yanfang; Lin, Xiafei; Pan, Jingjing

2018-06-12

Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post-transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes. Copyright © 2018 Elsevier Inc. All rights reserved.

The use of social network analysis to examine the transmission of Salmonella spp. within a vertically integrated broiler enterprise.

PubMed

Crabb, Helen Kathleen; Allen, Joanne Lee; Devlin, Joanne Maree; Firestone, Simon Matthew; Stevenson, Mark Anthony; Gilkerson, James Rudkin

2018-05-01

To better understand factors influencing infectious agent dispersal within a livestock population information is needed on the nature and frequency of contacts between farm enterprises. This study uses social network analysis to describe the contact network within a vertically integrated broiler poultry enterprise to identify the potential horizontal and vertical transmission pathways for Salmonella spp. Nodes (farms, sheds, production facilities) were identified and the daily movement of commodities (eggs, birds, feed, litter) and people between nodes were extracted from routinely kept farm records. Three time periods were examined in detail, 1- and 8- and 17-weeks of the production cycle and contact networks were described for all movements, and by commodity and production type. All nodes were linked by at least one movement during the study period but network density was low indicating that all potential pathways between nodes did not exist. Salmonella spp. transmission via vertical or horizontal pathways can only occur along directed pathways when those pathways are present. Only two locations (breeder or feed nodes) were identified where the transmission of a single Salmonella spp. clone could theoretically percolate through the network to the broiler or processing nodes. Only the feed transmission pathway directly connected all parts of the network. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structural integrity of frontostriatal connections predicts longitudinal changes in self-esteem.

PubMed

Chavez, Robert S; Heatherton, Todd F

2017-06-01

Diverse neurological and psychiatric conditions are marked by a diminished sense of positive self-regard, and reductions in self-esteem are associated with risk for these disorders. Recent evidence has shown that the connectivity of frontostriatal circuitry reflects individual differences in self-esteem. However, it remains an open question as to whether the integrity of these connections can predict self-esteem changes over larger timescales. Using diffusion magnetic resonance imaging and probabilistic tractography, we demonstrate that the integrity of white matter pathways linking the medial prefrontal cortex to the ventral striatum predicts changes in self-esteem 8 months after initial scanning in a sample of 30 young adults. Individuals with greater integrity of this pathway during the scanning session at Time 1 showed increased levels of self-esteem at follow-up, whereas individuals with lower integrity showed stifled or decreased levels of self-esteem. These results provide evidence that frontostriatal white matter integrity predicts the trajectory of self-esteem development in early adulthood, which may contribute to blunted levels of positive self-regard seen in multiple psychiatric conditions, including depression and anxiety.

Structural Integrity of Frontostriatal Connections Predicts Longitudinal Changes in Self-esteem

PubMed Central

Chavez, Robert S.; Heatherton, Todd F.

2016-01-01

Diverse neurological and psychiatric conditions are marked by a diminished sense of positive self-regard, and reductions in self-esteem are associated with risk for these disorders. Recent evidence has shown that the connectivity of frontostriatal circuitry reflects individual differences in self-esteem. However, it remains an open question as to whether the integrity of these connections can predict self-esteem changes over larger timescales. Using diffusion magnetic resonance imaging and probabilistic tractography, we demonstrate that the integrity of white matter pathways linking the medial prefrontal cortex to the ventral striatum predicts changes in self-esteem eight months after initial scanning in sample of thirty young adults. Individuals with greater integrity of this pathway during the scanning session at Time 1 showed increased levels of self-esteem at follow-up, whereas individuals with lower integrity showed stifled or decreased levels of self-esteem. These results provide evidence that frontostriatal white matter integrity predicts the trajectory of self-esteem development in early adulthood, which may contribute to blunted levels of positive self-regard seen in multiple psychiatric conditions including depression and anxiety. PMID:26966986

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

What’s the Damage? The Impact of Pathogens on Pathways that Maintain Host Genome Integrity

PubMed Central

Weitzman, Matthew D.; Weitzman, Jonathan B.

2014-01-01

Maintaining genome integrity and transmission of intact genomes is critical for cellular, organismal, and species survival. Cells can detect damaged DNA, activate checkpoints, and either enable DNA repair or trigger apoptosis to eliminate the damaged cell. Aberrations in these mechanisms lead to somatic mutations and genetic instability, which are hallmarks of cancer. Considering the long history of host-microbe coevolution, an impact of microbial infection on host genome integrity is not unexpected, and emerging links between microbial infections and oncogenesis further reinforce this idea. In this review, we compare strategies employed by viruses, bacteria, and parasites to alter, subvert, or otherwise manipulate host DNA damage and repair pathways. We highlight how microbes contribute to tumorigenesis by directly inducing DNA damage, inactivating checkpoint controls, or manipulating repair processes. We also discuss indirect effects resulting from inflammatory responses, changes in cellular metabolism, nuclear architecture, and epigenome integrity, and the associated evolutionary tradeoffs. PMID:24629335

Concordant integrative gene set enrichment analysis of multiple large-scale two-sample expression data sets.

PubMed

Lai, Yinglei; Zhang, Fanni; Nayak, Tapan K; Modarres, Reza; Lee, Norman H; McCaffrey, Timothy A

2014-01-01

Gene set enrichment analysis (GSEA) is an important approach to the analysis of coordinate expression changes at a pathway level. Although many statistical and computational methods have been proposed for GSEA, the issue of a concordant integrative GSEA of multiple expression data sets has not been well addressed. Among different related data sets collected for the same or similar study purposes, it is important to identify pathways or gene sets with concordant enrichment. We categorize the underlying true states of differential expression into three representative categories: no change, positive change and negative change. Due to data noise, what we observe from experiments may not indicate the underlying truth. Although these categories are not observed in practice, they can be considered in a mixture model framework. Then, we define the mathematical concept of concordant gene set enrichment and calculate its related probability based on a three-component multivariate normal mixture model. The related false discovery rate can be calculated and used to rank different gene sets. We used three published lung cancer microarray gene expression data sets to illustrate our proposed method. One analysis based on the first two data sets was conducted to compare our result with a previous published result based on a GSEA conducted separately for each individual data set. This comparison illustrates the advantage of our proposed concordant integrative gene set enrichment analysis. Then, with a relatively new and larger pathway collection, we used our method to conduct an integrative analysis of the first two data sets and also all three data sets. Both results showed that many gene sets could be identified with low false discovery rates. A consistency between both results was also observed. A further exploration based on the KEGG cancer pathway collection showed that a majority of these pathways could be identified by our proposed method. This study illustrates that we can improve detection power and discovery consistency through a concordant integrative analysis of multiple large-scale two-sample gene expression data sets.

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

PubMed Central

Moreno-Moral, Aida

2016-01-01

ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes.

PubMed

Moreno-Moral, Aida; Petretto, Enrico

2016-10-01

Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. © 2016. Published by The Company of Biologists Ltd.

Creating a Structured Adverse Outcome Pathway Knowledgebase via Ontology-Based Annotations

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework is increasingly used to integrate data based on traditional and emerging toxicity testing paradigms. As the number of AOP descriptions has increased, so has the need to define the AOP in computable terms. Herein, we present a comprehens...

Moving from Seemless to Seamless Pathways for Students.

ERIC Educational Resources Information Center

McClure, Glennis; Ross, Richard

In 1994, the Nebraska Articulation Planning Team (NAPT) was created to investigate opportunities for establishing horizontal and vertical articulation, curriculum integration, and staff development in the state to provide students with seamless pathways in their movement along the educational continuum. During the 1994-95 academic year, NAPT…

Enhancing a Pathway-Genome Database (PGDB) to capture subcellular localization of metabolites and enzymes: the nucleotide-sugar biosynthetic pathways of Populus trichocarpa.

PubMed

Nag, Ambarish; Karpinets, Tatiana V; Chang, Christopher H; Bar-Peled, Maor

2012-01-01

Understanding how cellular metabolism works and is regulated requires that the underlying biochemical pathways be adequately represented and integrated with large metabolomic data sets to establish a robust network model. Genetically engineering energy crops to be less recalcitrant to saccharification requires detailed knowledge of plant polysaccharide structures and a thorough understanding of the metabolic pathways involved in forming and regulating cell-wall synthesis. Nucleotide-sugars are building blocks for synthesis of cell wall polysaccharides. The biosynthesis of nucleotide-sugars is catalyzed by a multitude of enzymes that reside in different subcellular organelles, and precise representation of these pathways requires accurate capture of this biological compartmentalization. The lack of simple localization cues in genomic sequence data and annotations however leads to missing compartmentalization information for eukaryotes in automatically generated databases, such as the Pathway-Genome Databases (PGDBs) of the SRI Pathway Tools software that drives much biochemical knowledge representation on the internet. In this report, we provide an informal mechanism using the existing Pathway Tools framework to integrate protein and metabolite sub-cellular localization data with the existing representation of the nucleotide-sugar metabolic pathways in a prototype PGDB for Populus trichocarpa. The enhanced pathway representations have been successfully used to map SNP abundance data to individual nucleotide-sugar biosynthetic genes in the PGDB. The manually curated pathway representations are more conducive to the construction of a computational platform that will allow the simulation of natural and engineered nucleotide-sugar precursor fluxes into specific recalcitrant polysaccharide(s). Database URL: The curated Populus PGDB is available in the BESC public portal at http://cricket.ornl.gov/cgi-bin/beocyc_home.cgi and the nucleotide-sugar biosynthetic pathways can be directly accessed at http://cricket.ornl.gov:1555/PTR/new-image?object=SUGAR-NUCLEOTIDES.

Enhancing a Pathway-Genome Database (PGDB) to capture subcellular localization of metabolites and enzymes: the nucleotide-sugar biosynthetic pathways of Populus trichocarpa

PubMed Central

Nag, Ambarish; Karpinets, Tatiana V.; Chang, Christopher H.; Bar-Peled, Maor

2012-01-01

Understanding how cellular metabolism works and is regulated requires that the underlying biochemical pathways be adequately represented and integrated with large metabolomic data sets to establish a robust network model. Genetically engineering energy crops to be less recalcitrant to saccharification requires detailed knowledge of plant polysaccharide structures and a thorough understanding of the metabolic pathways involved in forming and regulating cell-wall synthesis. Nucleotide-sugars are building blocks for synthesis of cell wall polysaccharides. The biosynthesis of nucleotide-sugars is catalyzed by a multitude of enzymes that reside in different subcellular organelles, and precise representation of these pathways requires accurate capture of this biological compartmentalization. The lack of simple localization cues in genomic sequence data and annotations however leads to missing compartmentalization information for eukaryotes in automatically generated databases, such as the Pathway-Genome Databases (PGDBs) of the SRI Pathway Tools software that drives much biochemical knowledge representation on the internet. In this report, we provide an informal mechanism using the existing Pathway Tools framework to integrate protein and metabolite sub-cellular localization data with the existing representation of the nucleotide-sugar metabolic pathways in a prototype PGDB for Populus trichocarpa. The enhanced pathway representations have been successfully used to map SNP abundance data to individual nucleotide-sugar biosynthetic genes in the PGDB. The manually curated pathway representations are more conducive to the construction of a computational platform that will allow the simulation of natural and engineered nucleotide-sugar precursor fluxes into specific recalcitrant polysaccharide(s). Database URL: The curated Populus PGDB is available in the BESC public portal at http://cricket.ornl.gov/cgi-bin/beocyc_home.cgi and the nucleotide-sugar biosynthetic pathways can be directly accessed at http://cricket.ornl.gov:1555/PTR/new-image?object=SUGAR-NUCLEOTIDES. PMID:22465851

Integrating genomics and proteomics data to predict drug effects using binary linear programming.

PubMed

Ji, Zhiwei; Su, Jing; Liu, Chenglin; Wang, Hongyan; Huang, Deshuang; Zhou, Xiaobo

2014-01-01

The Library of Integrated Network-Based Cellular Signatures (LINCS) project aims to create a network-based understanding of biology by cataloging changes in gene expression and signal transduction that occur when cells are exposed to a variety of perturbations. It is helpful for understanding cell pathways and facilitating drug discovery. Here, we developed a novel approach to infer cell-specific pathways and identify a compound's effects using gene expression and phosphoproteomics data under treatments with different compounds. Gene expression data were employed to infer potential targets of compounds and create a generic pathway map. Binary linear programming (BLP) was then developed to optimize the generic pathway topology based on the mid-stage signaling response of phosphorylation. To demonstrate effectiveness of this approach, we built a generic pathway map for the MCF7 breast cancer cell line and inferred the cell-specific pathways by BLP. The first group of 11 compounds was utilized to optimize the generic pathways, and then 4 compounds were used to identify effects based on the inferred cell-specific pathways. Cross-validation indicated that the cell-specific pathways reliably predicted a compound's effects. Finally, we applied BLP to re-optimize the cell-specific pathways to predict the effects of 4 compounds (trichostatin A, MS-275, staurosporine, and digoxigenin) according to compound-induced topological alterations. Trichostatin A and MS-275 (both HDAC inhibitors) inhibited the downstream pathway of HDAC1 and caused cell growth arrest via activation of p53 and p21; the effects of digoxigenin were totally opposite. Staurosporine blocked the cell cycle via p53 and p21, but also promoted cell growth via activated HDAC1 and its downstream pathway. Our approach was also applied to the PC3 prostate cancer cell line, and the cross-validation analysis showed very good accuracy in predicting effects of 4 compounds. In summary, our computational model can be used to elucidate potential mechanisms of a compound's efficacy.

Cortical inter-hemispheric circuits for multimodal vocal learning in songbirds.

PubMed

Paterson, Amy K; Bottjer, Sarah W

2017-10-15

Vocal learning in songbirds and humans is strongly influenced by social interactions based on sensory inputs from several modalities. Songbird vocal learning is mediated by cortico-basal ganglia circuits that include the SHELL region of lateral magnocellular nucleus of the anterior nidopallium (LMAN), but little is known concerning neural pathways that could integrate multimodal sensory information with SHELL circuitry. In addition, cortical pathways that mediate the precise coordination between hemispheres required for song production have been little studied. In order to identify candidate mechanisms for multimodal sensory integration and bilateral coordination for vocal learning in zebra finches, we investigated the anatomical organization of two regions that receive input from SHELL: the dorsal caudolateral nidopallium (dNCL SHELL ) and a region within the ventral arcopallium (Av). Anterograde and retrograde tracing experiments revealed a topographically organized inter-hemispheric circuit: SHELL and dNCL SHELL , as well as adjacent nidopallial areas, send axonal projections to ipsilateral Av; Av in turn projects to contralateral SHELL, dNCL SHELL , and regions of nidopallium adjacent to each. Av on each side also projects directly to contralateral Av. dNCL SHELL and Av each integrate inputs from ipsilateral SHELL with inputs from sensory regions in surrounding nidopallium, suggesting that they function to integrate multimodal sensory information with song-related responses within LMAN-SHELL during vocal learning. Av projections share this integrated information from the ipsilateral hemisphere with contralateral sensory and song-learning regions. Our results suggest that the inter-hemispheric pathway through Av may function to integrate multimodal sensory feedback with vocal-learning circuitry and coordinate bilateral vocal behavior. © 2017 Wiley Periodicals, Inc.

YAP and TAZ: a nexus for Hippo signaling and beyond

PubMed Central

Guan, Kun-Liang

2015-01-01

The Hippo pathway is a potent regulator of cellular proliferation, differentiation, and tissue homeostasis. Here we review the regulatory mechanisms of the Hippo pathway and discuss the function of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ), the prime mediators of the Hippo pathway, in stem cell biology and tissue regeneration. We highlight their activities in both the nucleus and the cytoplasm and discuss their role as a signaling nexus and integrator of several other prominent signaling pathways such as the Wnt, G protein-coupled receptor (GPCR), epidermal growth factor (EGF), BMP/transforming growth factor beta (TGFβ), and Notch pathways. PMID:26045258

Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis.

PubMed

Ward, Stacey A; Rubin, Joshua B

2015-08-06

The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tumors, presenting opportunities for the study of combinatorial therapies.

The Pathway Tools software.

PubMed

Karp, Peter D; Paley, Suzanne; Romero, Pedro

2002-01-01

Bioinformatics requires reusable software tools for creating model-organism databases (MODs). The Pathway Tools is a reusable, production-quality software environment for creating a type of MOD called a Pathway/Genome Database (PGDB). A PGDB such as EcoCyc (see http://ecocyc.org) integrates our evolving understanding of the genes, proteins, metabolic network, and genetic network of an organism. This paper provides an overview of the four main components of the Pathway Tools: The PathoLogic component supports creation of new PGDBs from the annotated genome of an organism. The Pathway/Genome Navigator provides query, visualization, and Web-publishing services for PGDBs. The Pathway/Genome Editors support interactive updating of PGDBs. The Pathway Tools ontology defines the schema of PGDBs. The Pathway Tools makes use of the Ocelot object database system for data management services for PGDBs. The Pathway Tools has been used to build PGDBs for 13 organisms within SRI and by external users.

Integrated metabolomics and proteomics highlight altered nicotinamide and polyamine pathways in lung adenocarcinoma

PubMed Central

Fahrmann, Johannes F.; Grapov, Dmitry; Wanichthanarak, Kwanjeera; DeFelice, Brian C.; Salemi, Michelle R.; Rom, William N.; Gandara, David R.; Phinney, Brett S.; Fiehn, Oliver; Pass, Harvey

2017-01-01

Abstract Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma (1): increased glycosylation and glutaminolysis (2); elevated Nrf2 activation (3); increase in nicotinic and nicotinamide salvaging pathways and (4) elevated polyamine biosynthesis linked to differential regulation of the s-adenosylmethionine/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompany early stage lung tumorigenesis and highlight potential therapeutic targets. PMID:28049629

[Development and implementation of an integrated care pathway at the POLIKUM health centers using the example of anemia].

PubMed

Bierbaum, M; Grad, M O; Wulff, H; Kewenig, S; Schöffski, O

2014-04-01

Integrated treatment pathways are an appropriate means for increasing the quality of treatment and outcome via process optimization. Taking the POLIKUM Health Centers as an example, we intend to demonstrate how the implementation can be effected for the indication of anemia. The development and implementation were executed by an interdisciplinary workgroup in several workshops. In addition, the diagnoses and hemoglobin values of all patients with requests for hemograms were obtained and analyzed at two locations. Developing the pathway required significantly greater efforts than initially planned. The biggest challenge was to adequately map the complexity of the different forms of anemia and, concomitantly, to design a pathway that can actually be realized in everyday life. Moreover, evaluation of the patient data demonstrated that there are a large number of cases where existing anemias are not reflected in the respective diagnoses. While the ultimate effects of the new pathway cannot yet be assessed conclusively, it was possible to obtain valuable findings for practical use even at this point. Despite the limitations of the sample, the surprisingly high number of undetected anemias should give physicians cause for taking diagnostic measures even in patients with mild anemia.

Transcript Profile of Flowering Regulatory Genes in VcFT-Overexpressing Blueberry Plants

PubMed Central

Walworth, Aaron E.; Chai, Benli; Song, Guo-qing

2016-01-01

In order to identify genetic components in flowering pathways of highbush blueberry (Vaccinium corymbosum L.), a transcriptome reference composed of 254,396 transcripts and 179,853 gene contigs was developed by assembly of 72.7 million reads using Trinity. Using this transcriptome reference and a query of flowering pathway genes of herbaceous plants, we identified potential flowering pathway genes/transcripts of blueberry. Transcriptome analysis of flowering pathway genes was then conducted on leaf tissue samples of transgenic blueberry cv. Aurora (‘VcFT-Aurora’), which overexpresses a blueberry FLOWERING LOCUS T-like gene (VcFT). Sixty-one blueberry transcripts of 40 genes showed high similarities to 33 known flowering-related genes of herbaceous plants, of which 17 down-regulated and 16 up-regulated genes were identified in ‘VcFT-Aurora’. All down-regulated genes encoded transcription factors/enzymes upstream in the signaling pathway containing VcFT. A blueberry CONSTANS-LIKE 5-like (VcCOL5) gene was down-regulated and associated with five other differentially expressed (DE) genes in the photoperiod-mediated flowering pathway. Three down-regulated genes, i.e., a MADS-AFFECTING FLOWERING 2-like gene (VcMAF2), a MADS-AFFECTING FLOWERING 5-like gene (VcMAF5), and a VERNALIZATION1-like gene (VcVRN1), may function as integrators in place of FLOWERING LOCUS C (FLC) in the vernalization pathway. Because no CONSTAN1-like or FLOWERING LOCUS C-like genes were found in blueberry, VcCOL5 and VcMAF2/VcMAF5 or VRN1 might be the major integrator(s) in the photoperiod- and vernalization-mediated flowering pathway, respectively. The major down-stream genes of VcFT, i.e., SUPPRESSOR of Overexpression of Constans 1-like (VcSOC1), LEAFY-like (VcLFY), APETALA1-like (VcAP1), CAULIFLOWER 1-like (VcCAL1), and FRUITFULL-like (VcFUL) genes were present and showed high similarity to their orthologues in herbaceous plants. Moreover, overexpression of VcFT promoted expression of all of these VcFT downstream genes. These results suggest that VcFT’s down-stream genes appear conserved in blueberry. PMID:27271296

Transcript Profile of Flowering Regulatory Genes in VcFT-Overexpressing Blueberry Plants.

PubMed

Walworth, Aaron E; Chai, Benli; Song, Guo-Qing

2016-01-01

In order to identify genetic components in flowering pathways of highbush blueberry (Vaccinium corymbosum L.), a transcriptome reference composed of 254,396 transcripts and 179,853 gene contigs was developed by assembly of 72.7 million reads using Trinity. Using this transcriptome reference and a query of flowering pathway genes of herbaceous plants, we identified potential flowering pathway genes/transcripts of blueberry. Transcriptome analysis of flowering pathway genes was then conducted on leaf tissue samples of transgenic blueberry cv. Aurora ('VcFT-Aurora'), which overexpresses a blueberry FLOWERING LOCUS T-like gene (VcFT). Sixty-one blueberry transcripts of 40 genes showed high similarities to 33 known flowering-related genes of herbaceous plants, of which 17 down-regulated and 16 up-regulated genes were identified in 'VcFT-Aurora'. All down-regulated genes encoded transcription factors/enzymes upstream in the signaling pathway containing VcFT. A blueberry CONSTANS-LIKE 5-like (VcCOL5) gene was down-regulated and associated with five other differentially expressed (DE) genes in the photoperiod-mediated flowering pathway. Three down-regulated genes, i.e., a MADS-AFFECTING FLOWERING 2-like gene (VcMAF2), a MADS-AFFECTING FLOWERING 5-like gene (VcMAF5), and a VERNALIZATION1-like gene (VcVRN1), may function as integrators in place of FLOWERING LOCUS C (FLC) in the vernalization pathway. Because no CONSTAN1-like or FLOWERING LOCUS C-like genes were found in blueberry, VcCOL5 and VcMAF2/VcMAF5 or VRN1 might be the major integrator(s) in the photoperiod- and vernalization-mediated flowering pathway, respectively. The major down-stream genes of VcFT, i.e., SUPPRESSOR of Overexpression of Constans 1-like (VcSOC1), LEAFY-like (VcLFY), APETALA1-like (VcAP1), CAULIFLOWER 1-like (VcCAL1), and FRUITFULL-like (VcFUL) genes were present and showed high similarity to their orthologues in herbaceous plants. Moreover, overexpression of VcFT promoted expression of all of these VcFT downstream genes. These results suggest that VcFT's down-stream genes appear conserved in blueberry.

Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment With Valproic Acid and Fresh Frozen Plasma.

PubMed

Nikolian, Vahagn C; Dekker, Simone E; Bambakidis, Ted; Higgins, Gerald A; Dennahy, Isabel S; Georgoff, Patrick E; Williams, Aaron M; Andjelkovic, Anuska V; Alam, Hasan B

2018-01-01

Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.

Insulation of the σF Regulatory System in Bacillus subtilis

PubMed Central

Carniol, Karen; Kim, Tae-Jong; Price, Chester W.; Losick, Richard

2004-01-01

The transcription factors σF and σB are related RNA polymerase sigma factors that govern dissimilar networks of adaptation to stress conditions in Bacillus subtilis. The two factors are controlled by closely related regulatory pathways, involving protein kinases and phosphatases. We report that insulation of the σF pathway from the σB pathway involves the integrated action of both the cognate kinase and the cognate phosphatase. PMID:15205443

Chiropractic Integrated Care Pathway for Low Back Pain in Veterans: Results of a Delphi Consensus Process.

PubMed

Lisi, Anthony J; Salsbury, Stacie A; Hawk, Cheryl; Vining, Robert D; Wallace, Robert B; Branson, Richard; Long, Cynthia R; Burgo-Black, A Lucille; Goertz, Christine M

2018-02-01

The purpose of this study was to develop an integrated care pathway for doctors of chiropractic, primary care providers, and mental health professionals who manage veterans with low back pain, with or without mental health comorbidity, within Department of Veterans Affairs health care facilities. The research method used was a consensus process. A multidisciplinary investigative team reviewed clinical guidelines and Veterans Affairs pain and mental health initiatives to develop seed statements and care algorithms to guide chiropractic management and collaborative care of veterans with low back pain. A 5-member advisory committee approved initial recommendations. Veterans Affairs-based panelists (n = 58) evaluated the pathway via e-mail using a modified RAND/UCLA methodology. Consensus was defined as agreement by 80% of panelists. The modified Delphi process was conducted in July to December 2016. Most (93%) seed statements achieved consensus during the first round, with all statements reaching consensus after 2 rounds. The final care pathway addressed the topics of informed consent, clinical evaluation including history and examination, screening for red flags, documentation, diagnostic imaging, patient-reported outcomes, adverse event reporting, chiropractic treatment frequency and duration standards, tailored approaches to chiropractic care in veteran populations, and clinical presentation of common mental health conditions. Care algorithms outlined chiropractic case management and interprofessional collaboration and referrals between doctors of chiropractic and primary care and mental health providers. This study offers an integrative care pathway that includes chiropractic care for veterans with low back pain. Copyright © 2018. Published by Elsevier Inc.

The λ Integrase Site-specific Recombination Pathway

PubMed Central

LANDY, ARTHUR

2017-01-01

The site-specific recombinase encoded by bacteriophage λ (Int) is responsible for integrating and excising the viral chromosome into and out of the chromosome of its Escherichia coli host. Int carries out a reaction that is highly directional, tightly regulated, and depends upon an ensemble of accessory DNA bending proteins acting on 240 bp of DNA encoding 16 protein binding sites. This additional complexity enables two pathways, integrative and excisive recombination, whose opposite, and effectively irreversible, directions are dictated by different physiological and environmental signals. Int recombinase is a heterobivalent DNA binding protein and each of the four Int protomers, within a multiprotein 400 kDa recombinogenic complex, is thought to bind and, with the aid of DNA bending proteins, bridge one arm- and one core-type DNA site. In the 12 years since the publication of the last review focused solely on the λ site-specific recombination pathway in Mobile DNA II, there has been a great deal of progress in elucidating the molecular details of this pathway. The most dramatic advances in our understanding of the reaction have been in the area of X-ray crystallography where protein-DNA structures have now been determined for of all of the DNA-protein interfaces driving the Int pathway. Building on this foundation of structures, it has been possible to derive models for the assembly of components that determine the regulatory apparatus in the P-arm, and for the overall architectures that define excisive and integrative recombinogenic complexes. The most fundamental additional mechanistic insights derive from the application of hexapeptide inhibitors and single molecule kinetics. PMID:26104711

Pathways to Mathematics: Longitudinal Predictors of Performance

ERIC Educational Resources Information Center

LeFevre, Jo-Anne; Fast, Lisa; Skwarchuk, Sheri-Lynn; Smith-Chant, Brenda L.; Bisanz, Jeffrey; Kamawar, Deepthi; Penner-Wilger, Marcie

2010-01-01

A model of the relations among cognitive precursors, early numeracy skill, and mathematical outcomes was tested for 182 children from 4.5 to 7.5 years of age. The model integrates research from neuroimaging, clinical populations, and normal development in children and adults. It includes 3 precursor pathways: quantitative, linguistic, and spatial…

Pathways to Success: Using Technologies To Reach Distant Learners.

ERIC Educational Resources Information Center

Annenberg/CPB Project, Washington, DC.

This report contains information on institutions that submitted proposals for integrating technology in education to the Annenberg/CPB (Corporation for Public Broadcasting) Project's New Pathways to a Degree program. It is noted that, although the 243 proposals received contained a number of innovative ideas about how to use technologies to…

Estimating Environmental Co-benefits of U.S. GHG Reduction Pathways Using the GCAM-USA Integrated Assessment Model

EPA Science Inventory

Previous studies have shown that mitigating climate change through curbing greenhouse gas (GHG) emissions can bring about substantial environmental co-benefits, such as for air quality and reductions in energy-related water demand. A variety of pathways are available for reducing...

Career Pathways in School-to-Work Systems. Resource Bulletin.

ERIC Educational Resources Information Center

National School-to-Work Opportunities Office, Washington, DC.

Many students in today's high schools choose courses and work experiences in an unplanned, aimless manner that often results in limited career options and undeveloped potential. Innovative educators across the nation have responded by restructuring schools around career pathways, which are integrated, multiyear sequences of career guidance,…

Developmental Pathways and Technology: The Foundations of Enhanced Intellectual Excellence.

ERIC Educational Resources Information Center

Williamson, Edward A.; Slye, Gail L.

The combination of technology applications and an understanding of developmental pathways theory enhances intellectual growth for preservice teachers. Utilizing the theories developed by Dr. James Comer and integrating them with state of the art technological applications, this paper describes one model of preservice education that has been…

Text Mining in Cancer Gene and Pathway Prioritization

PubMed Central

Luo, Yuan; Riedlinger, Gregory; Szolovits, Peter

2014-01-01

Prioritization of cancer implicated genes has received growing attention as an effective way to reduce wet lab cost by computational analysis that ranks candidate genes according to the likelihood that experimental verifications will succeed. A multitude of gene prioritization tools have been developed, each integrating different data sources covering gene sequences, differential expressions, function annotations, gene regulations, protein domains, protein interactions, and pathways. This review places existing gene prioritization tools against the backdrop of an integrative Omic hierarchy view toward cancer and focuses on the analysis of their text mining components. We explain the relatively slow progress of text mining in gene prioritization, identify several challenges to current text mining methods, and highlight a few directions where more effective text mining algorithms may improve the overall prioritization task and where prioritizing the pathways may be more desirable than prioritizing only genes. PMID:25392685

Text mining in cancer gene and pathway prioritization.

PubMed

Luo, Yuan; Riedlinger, Gregory; Szolovits, Peter

2014-01-01

Prioritization of cancer implicated genes has received growing attention as an effective way to reduce wet lab cost by computational analysis that ranks candidate genes according to the likelihood that experimental verifications will succeed. A multitude of gene prioritization tools have been developed, each integrating different data sources covering gene sequences, differential expressions, function annotations, gene regulations, protein domains, protein interactions, and pathways. This review places existing gene prioritization tools against the backdrop of an integrative Omic hierarchy view toward cancer and focuses on the analysis of their text mining components. We explain the relatively slow progress of text mining in gene prioritization, identify several challenges to current text mining methods, and highlight a few directions where more effective text mining algorithms may improve the overall prioritization task and where prioritizing the pathways may be more desirable than prioritizing only genes.

Developing an integrated self: academic and ethnic identities among ethnically diverse college students.

PubMed

Syed, Moin

2010-11-01

The purpose of the present study was to investigate the development of college students' major selection and whether and how this choice is associated with their developing ethnic identities. Ninety ethnically diverse college students were interviewed in their first, sophomore, and senior years. Mixed-method analyses revealed 5 theoretically consistent pathways of how students configured their ethnic identities and majors over time: low awareness, consciousness-raised, high awareness, integrating, and compartmentalized. These pathways were differentially related to students' ethnicities and majors, suggesting that students' identity experiences are moderated by their chosen majors. The results of this study underscore the contribution of a longitudinal, life-span, approach to identity development for understanding the diversity in identity pathways during college. The findings also have implications for practical purposes, particularly for advising, counseling, and curriculum development.

Heterologous expression of the mevalonic acid pathway in cyanobacteria enhances endogenous carbon partitioning to isoprene.

PubMed

Bentley, Fiona K; Zurbriggen, Andreas; Melis, Anastasios

2014-01-01

Heterologous expression of the isoprene synthase gene in the cyanobacterium Synechocystis PCC 6803 conferred upon these microorganisms the property of photosynthetic isoprene (C₅H₈) hydrocarbons production. Continuous production of isoprene from CO₂ and H₂O was achieved in the light, occurring via the endogenous methylerythritol-phosphate (MEP) pathway, in tandem with the growth of Synechocystis. This work addressed the issue of photosynthetic carbon partitioning between isoprene and biomass in Synechocystis. Evidence is presented to show heterologous genomic integration and cellular expression of the mevalonic acid (MVA) pathway genes in Synechocystis endowing a non-native pathway for carbon flux amplification to isopentenyl-diphosphate (IPP) and dimethylallyl-diphosphate (DMAPP) precursors of isoprene. Heterologous expression of the isoprene synthase in combination with the MVA pathway enzymes resulted in photosynthetic isoprene yield improvement by approximately 2.5-fold, compared with that measured in cyanobacteria transformed with the isoprene synthase gene only. These results suggest that the MVA pathway introduces a bypass in the flux of endogenous cellular substrate in Synechocystis to IPP and DMAPP, overcoming flux limitations of the native MEP pathway. The work employed a novel chromosomal integration and expression of synthetic gene operons in Synechocystis, comprising up to four genes under the control of a single promoter, and expressing three operons simultaneously. This is the first time an entire biosynthetic pathway with seven recombinant enzymes has been heterologously expressed in a photosynthetic microorganism. It constitutes contribution to the genetic engineering toolkit of photosynthetic microorganisms and a paradigm in the pursuit of photosynthetic approaches for the renewable generation of high-impact products.

Exercise-driven metabolic pathways in healthy cartilage.

PubMed

Blazek, A D; Nam, J; Gupta, R; Pradhan, M; Perera, P; Weisleder, N L; Hewett, T E; Chaudhari, A M; Lee, B S; Leblebicioglu, B; Butterfield, T A; Agarwal, S

2016-07-01

Exercise is vital for maintaining cartilage integrity in healthy joints. Here we examined the exercise-driven transcriptional regulation of genes in healthy rat articular cartilage to dissect the metabolic pathways responsible for the potential benefits of exercise. Transcriptome-wide gene expression in the articular cartilage of healthy Sprague-Dawley female rats exercised daily (low intensity treadmill walking) for 2, 5, or 15 days was compared to that of non-exercised rats, using Affymetrix GeneChip arrays. Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO)-term enrichment and Functional Annotation analysis of differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genome (KEGG) pathway mapper was used to identify the metabolic pathways regulated by exercise. Microarray analysis revealed that exercise-induced 644 DEGs in healthy articular cartilage. The DAVID bioinformatics tool demonstrated high prevalence of functional annotation clusters with greater enrichment scores and GO-terms associated with extracellular matrix (ECM) biosynthesis/remodeling and inflammation/immune response. The KEGG database revealed that exercise regulates 147 metabolic pathways representing molecular interaction networks for Metabolism, Genetic Information Processing, Environmental Information Processing, Cellular Processes, Organismal Systems, and Diseases. These pathways collectively supported the complex regulation of the beneficial effects of exercise on the cartilage. Overall, the findings highlight that exercise is a robust transcriptional regulator of a wide array of metabolic pathways in healthy cartilage. The major actions of exercise involve ECM biosynthesis/cartilage strengthening and attenuation of inflammatory pathways to provide prophylaxis against onset of arthritic diseases in healthy cartilage. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The DUF59 Family Gene AE7 Acts in the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Maintain Nuclear Genome Integrity in Arabidopsis[C][W][OA

PubMed Central

Luo, Dexian; Bernard, Delphine G.; Balk, Janneke; Hai, Huang; Cui, Xiaofeng

2012-01-01

Eukaryotic organisms have evolved a set of strategies to safeguard genome integrity, but the underlying mechanisms remain poorly understood. Here, we report that ASYMMETRIC LEAVES1/2 ENHANCER7 (AE7), an Arabidopsis thaliana gene encoding a protein in the evolutionarily conserved Domain of Unknown Function 59 family, participates in the cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway to maintain genome integrity. The severe ae7-2 allele is embryo lethal, whereas plants with the weak ae7 (ae7-1) allele are viable but exhibit highly accumulated DNA damage that activates the DNA damage response to arrest the cell cycle. AE7 is part of a protein complex with CIA1, NAR1, and MET18, which are highly conserved in eukaryotes and are involved in the biogenesis of cytosolic and nuclear Fe-S proteins. ae7-1 plants have lower activities of the cytosolic [4Fe-4S] enzyme aconitase and the nuclear [4Fe-4S] enzyme DNA glycosylase ROS1. Additionally, mutations in the gene encoding the mitochondrial ATP binding cassette transporter ATM3/ABCB25, which is required for the activity of cytosolic Fe-S enzymes in Arabidopsis, also result in defective genome integrity similar to that of ae7-1. These results indicate that AE7 is a central member of the CIA pathway, linking plant mitochondria to nuclear genome integrity through assembly of Fe-S proteins. PMID:23104832

Selection of transformation-efficient barley genotypes based on TFA (transformation amenability) haplotype and higher resolution mapping of the TFA loci.

PubMed

Hisano, Hiroshi; Meints, Brigid; Moscou, Matthew J; Cistue, Luis; Echávarri, Begoña; Sato, Kazuhiro; Hayes, Patrick M

2017-04-01

The genetic substitution of transformation amenability alleles from 'Golden Promise' can facilitate the development of transformation-efficient lines from recalcitrant barley cultivars. Barley (Hordeum vulgare) cv. 'Golden Promise' is one of the most useful and well-studied cultivars for genetic manipulation. In a previous report, we identified several transformation amenability (TFA) loci responsible for Agrobacterium-mediated transformation using the F 2 generation of immature embryos, derived from 'Haruna Nijo' × 'Golden Promise,' as explants. In this report, we describe higher density mapping of these TFA regions with additional SNP markers using the same transgenic plants. To demonstrate the robustness of transformability alleles at the TFA loci, we genotyped 202 doubled haploid progeny from the cross 'Golden Promise' × 'Full Pint.' Based on SNP genotype, we selected lines having 'Golden Promise' alleles at TFA loci and used them for transformation. Of the successfully transformed lines, DH120366 came the closest to achieving a level of transformation efficiency comparable to 'Golden Promise.' The results validate that the genetic substitution of TFA alleles from 'Golden Promise' can facilitate the development of transformation-efficient lines from recalcitrant barley cultivars.

Heat penetration and thermocouple location in home canning.

PubMed

Etzel, Mark R; Willmore, Paola; Ingham, Barbara H

2015-01-01

We processed applesauce, tomato juice, and cranberries in pint jars in a boiling water canner to test thermal processing theories against home canning of high-acid foods. For each product, thermocouples were placed at various heights in the jar. Values for f h (heating), f cl (cooling), and F 82.2°C (lethality) were determined for each thermocouple location, and did not depend substantially on thermocouple location in accordance with heat transfer theory. There was a cold spot in the jar, but the cold spot during heating became the hot spot during cooling. During heating, the geometric center was the last to heat, and remained coldest the longest, but during coooling, it was also the last to cool, and remained hottest the longest. The net effect was that calculated lethality in home canning was not affected by thermocouple location. Most of the lethality during home canning occurred during air cooling, making cooling of home canned foods of great importance. Calculated lethality was far greater than the required 5-log reduction of spores in tomato juice and vegetative cells in cranberries, suggesting a wide margin of safety for approved home-canning processes for high-acid foods.

Heat penetration and thermocouple location in home canning

PubMed Central

Etzel, Mark R; Willmore, Paola; Ingham, Barbara H

2015-01-01

We processed applesauce, tomato juice, and cranberries in pint jars in a boiling water canner to test thermal processing theories against home canning of high-acid foods. For each product, thermocouples were placed at various heights in the jar. Values for fh (heating), fcl (cooling), and F82.2°C (lethality) were determined for each thermocouple location, and did not depend substantially on thermocouple location in accordance with heat transfer theory. There was a cold spot in the jar, but the cold spot during heating became the hot spot during cooling. During heating, the geometric center was the last to heat, and remained coldest the longest, but during coooling, it was also the last to cool, and remained hottest the longest. The net effect was that calculated lethality in home canning was not affected by thermocouple location. Most of the lethality during home canning occurred during air cooling, making cooling of home canned foods of great importance. Calculated lethality was far greater than the required 5-log reduction of spores in tomato juice and vegetative cells in cranberries, suggesting a wide margin of safety for approved home-canning processes for high-acid foods. PMID:25649758

3. Credit BG. The interior of the control room appears ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. Credit BG. The interior of the control room appears in this view, looking north (0°). The control console in the room center permitted remote control of various propellant grinders and mixers in surrounding buildings. Television monitors (absent from their mounts in this view) permitted direct viewing of operating machinery. From foreground to background: Panel (1) contains OGAR warning light switches for Curing Buildings E-39, E-40, E-41 and E-86; (O=off, G=green safe, A=amber caution, R=red danger) Panel (2) E-85 Oxidizer Dryer Building console: OGAR switch Panel (3) E-84 Oxidizer Grinder Building console: controls for vibrator, feed, and hammer; Panel (4) E-36 Oxidizer Grinder Building console: controls for vibrator, feed, hammer, attritor, and SWECO ("SWECO" undefined) Panels (5) & (6) blank Panel (7) E-38 Mixer & Casting Building console: vacuum pump, blender, heating and cooling controls Panel (8) E-37 Mixer & Casting Building console: motor controls for 1 pint, 1 gallon, 5 gallon and 30 gallon mixers; vacuum pump, deluge (fire suppression), pot up/down, vibrator, feed, and SWECO. - Jet Propulsion Laboratory Edwards Facility, Weigh & Control Building, Edwards Air Force Base, Boron, Kern County, CA

How might flukes and tapeworms maintain genome integrity without a canonical piRNA pathway?

PubMed

Skinner, Danielle E; Rinaldi, Gabriel; Koziol, Uriel; Brehm, Klaus; Brindley, Paul J

2014-03-01

Surveillance by RNA interference is central to controlling the mobilization of transposable elements (TEs). In stem cells, Piwi argonaute (Ago) proteins and associated proteins repress mobilization of TEs to maintain genome integrity. This defense mechanism targeting TEs is termed the Piwi-interacting RNA (piRNA) pathway. In this opinion article, we draw attention to the situation that the genomes of cestodes and trematodes have lost the piwi and vasa genes that are hallmark characters of the germline multipotency program. This absence of Piwi-like Agos and Vasa helicases prompts the question: how does the germline of these flatworms withstand mobilization of TEs? Here, we present an interpretation of mechanisms likely to defend the germline integrity of parasitic flatworms. Copyright © 2014 Elsevier Ltd. All rights reserved.

Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response

PubMed Central

van der Lee, Robin; ter Horst, Rob; Szklarczyk, Radek; Netea, Mihai G.; Andeweg, Arno C.; van Kuppeveld, Frank J. M.; Huynen, Martijn A.

2015-01-01

The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research. PMID:26485378

Predictive toxicology using systemic biology and liver microfluidic “on chip” approaches: Application to acetaminophen injury

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

Prot, Jean-Matthieu; Bunescu, Andrei; Elena-Herrmann, Bénédicte

2012-03-15

We have analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP). Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treatedmore » biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic collected profiles allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology. -- Highlights: ► We cultivated liver cells in microfluidic biochips ► We integrated transcriptomic, proteomic and metabolomics profiles ► Pathways reconstructions were proposed in control and acetaminophen treated cultures ► Biomarkers were identified ► Comparisons with in vivo studies were proposed.« less

Integrated Proteomic Approaches for Understanding Toxicity of Environmental Chemicals

EPA Science Inventory

To apply quantitative proteomic analysis to the evaluation of toxicity of environmental chemicals, we have developed an integrated proteomic technology platform. This platform has been applied to the analysis of the toxic effects and pathways of many important environmental chemi...

Integrating gene expression data with demographic, clinical, and environmental exposure information to reveal endotypes of childhood asthma

EPA Science Inventory

RATIONALE. Childhood asthma is a multifactorial disease whose pathogenesis involves complex interplay between genetic susceptibility and modulating external factors. Therefore, effectively characterizing these multiple etiological pathways, or “endotypes”, requires an integrative...

INTEGRATED HUMAN EXPOSURE SOURCE-TO-DOSE MODELING

EPA Science Inventory

The NERL human exposure research program is designed to provide a sound, scientifically-based approach to understanding how people are actually exposed to pollutants and the factors and pathways influencing exposure and dose. This research project serves to integrate and incorpo...

Integrated QSAR study for inhibitors of hedgehog signal pathway against multiple cell lines:a collaborative filtering method

PubMed Central

2012-01-01

Background The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. Results In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several possible chemical modifications to improve the inhibitor affinity towards multiple targets in the Hedgehog Signaling Pathway. Conclusions Our model with the feature selection strategy presented here is efficient, robust, and flexible, and can be easily extended to model large-scale multiple cell line/QSAR data. The data and scripts for collaborative QSAR modeling are available in the Additional file 1. PMID:22849868

Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

PubMed

Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

2012-07-31

The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several possible chemical modifications to improve the inhibitor affinity towards multiple targets in the Hedgehog Signaling Pathway. Our model with the feature selection strategy presented here is efficient, robust, and flexible, and can be easily extended to model large-scale multiple cell line/QSAR data. The data and scripts for collaborative QSAR modeling are available in the Additional file 1.

EDdb: a web resource for eating disorder and its application to identify an extended adipocytokine signaling pathway related to eating disorder.

PubMed

Zhao, Min; Li, XiaoMo; Qu, Hong

2013-12-01

Eating disorder is a group of physiological and psychological disorders affecting approximately 1% of the female population worldwide. Although the genetic epidemiology of eating disorder is becoming increasingly clear with accumulated studies, the underlying molecular mechanisms are still unclear. Recently, integration of various high-throughput data expanded the range of candidate genes and started to generate hypotheses for understanding potential pathogenesis in complex diseases. This article presents EDdb (Eating Disorder database), the first evidence-based gene resource for eating disorder. Fifty-nine experimentally validated genes from the literature in relation to eating disorder were collected as the core dataset. Another four datasets with 2824 candidate genes across 601 genome regions were expanded based on the core dataset using different criteria (e.g., protein-protein interactions, shared cytobands, and related complex diseases). Based on human protein-protein interaction data, we reconstructed a potential molecular sub-network related to eating disorder. Furthermore, with an integrative pathway enrichment analysis of genes in EDdb, we identified an extended adipocytokine signaling pathway in eating disorder. Three genes in EDdb (ADIPO (adiponectin), TNF (tumor necrosis factor) and NR3C1 (nuclear receptor subfamily 3, group C, member 1)) link the KEGG (Kyoto Encyclopedia of Genes and Genomes) "adipocytokine signaling pathway" with the BioCarta "visceral fat deposits and the metabolic syndrome" pathway to form a joint pathway. In total, the joint pathway contains 43 genes, among which 39 genes are related to eating disorder. As the first comprehensive gene resource for eating disorder, EDdb ( http://eddb.cbi.pku.edu.cn ) enables the exploration of gene-disease relationships and cross-talk mechanisms between related disorders. Through pathway statistical studies, we revealed that abnormal body weight caused by eating disorder and obesity may both be related to dysregulation of the novel joint pathway of adipocytokine signaling. In addition, this joint pathway may be the common pathway for body weight regulation in complex human diseases related to unhealthy lifestyle.

A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations.

PubMed

Zhang, Han; Wheeler, William; Hyland, Paula L; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

2016-06-01

Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs.

A Powerful Procedure for Pathway-Based Meta-analysis Using Summary Statistics Identifies 43 Pathways Associated with Type II Diabetes in European Populations

PubMed Central

Zhang, Han; Wheeler, William; Hyland, Paula L.; Yang, Yifan; Shi, Jianxin; Chatterjee, Nilanjan; Yu, Kai

2016-01-01

Meta-analysis of multiple genome-wide association studies (GWAS) has become an effective approach for detecting single nucleotide polymorphism (SNP) associations with complex traits. However, it is difficult to integrate the readily accessible SNP-level summary statistics from a meta-analysis into more powerful multi-marker testing procedures, which generally require individual-level genetic data. We developed a general procedure called Summary based Adaptive Rank Truncated Product (sARTP) for conducting gene and pathway meta-analysis that uses only SNP-level summary statistics in combination with genotype correlation estimated from a panel of individual-level genetic data. We demonstrated the validity and power advantage of sARTP through empirical and simulated data. We conducted a comprehensive pathway-based meta-analysis with sARTP on type 2 diabetes (T2D) by integrating SNP-level summary statistics from two large studies consisting of 19,809 T2D cases and 111,181 controls with European ancestry. Among 4,713 candidate pathways from which genes in neighborhoods of 170 GWAS established T2D loci were excluded, we detected 43 T2D globally significant pathways (with Bonferroni corrected p-values < 0.05), which included the insulin signaling pathway and T2D pathway defined by KEGG, as well as the pathways defined according to specific gene expression patterns on pancreatic adenocarcinoma, hepatocellular carcinoma, and bladder carcinoma. Using summary data from 8 eastern Asian T2D GWAS with 6,952 cases and 11,865 controls, we showed 7 out of the 43 pathways identified in European populations remained to be significant in eastern Asians at the false discovery rate of 0.1. We created an R package and a web-based tool for sARTP with the capability to analyze pathways with thousands of genes and tens of thousands of SNPs. PMID:27362418

Similarities and differences between the Wnt and reelin pathways in the forming brain.

PubMed

Reiner, Orly; Sapir, Tamar

2005-01-01

One of the key features in development is the reutilization of successful signaling pathways. Here, we emphasize the involvement of the Wnt pathway, one of the five kinds of signal transduction pathway predominating early embryonic development of all animals, in regulating the formation of brain structure. We discuss the interrelationships between the Wnt and reelin pathways in the regulation of cortical layering. We summarize data emphasizing key molecules, which, when mutated, result in abnormal brain development. This integrated view, which is based on conservation of pathways, reveals the relative position of participants in the pathway, points to control mechanisms, and allows raising testable working hypotheses. Nevertheless, although signaling pathways are highly conserved from flies to humans, the overall morphology is not. We propose that future studies directed at understanding of diversification will provide fruitful insights on mammalian brain formation.

Developing molecular tools for Chlamydomonas reinhardtii

NASA Astrophysics Data System (ADS)

Noor-Mohammadi, Samaneh

Microalgae have garnered increasing interest over the years for their ability to produce compounds ranging from biofuels to neutraceuticals. A main focus of researchers has been to use microalgae as a natural bioreactor for the production of valuable and complex compounds. Recombinant protein expression in the chloroplasts of green algae has recently become more routine; however, the heterologous expression of multiple proteins or complete biosynthetic pathways remains a significant challenge. To take full advantage of these organisms' natural abilities, sophisticated molecular tools are needed to be able to introduce and functionally express multiple gene biosynthetic pathways in its genome. To achieve the above objective, we have sought to establish a method to construct, integrate and express multigene operons in the chloroplast and nuclear genome of the model microalgae Chlamydomonas reinhardtii. Here we show that a modified DNA Assembler approach can be used to rapidly assemble multiple-gene biosynthetic pathways in yeast and then integrate these assembled pathways at a site-specific location in the chloroplast, or by random integration in the nuclear genome of C. reinhardtii. As a proof of concept, this method was used to successfully integrate and functionally express up to three reporter proteins (AphA6, AadA, and GFP) in the chloroplast of C. reinhardtii and up to three reporter proteins (Ble, AphVIII, and GFP) in its nuclear genome. An analysis of the relative gene expression of the engineered strains showed significant differences in the mRNA expression levels of the reporter genes and thus highlights the importance of proper promoter/untranslated-region selection when constructing a target pathway. In addition, this work focuses on expressing the cofactor regeneration enzyme phosphite dehydrogenase (PTDH) in the chloroplast and nuclear genomes of C. reinhardtii. The PTDH enzyme converts phosphite into phosphate and NAD(P)+ into NAD(P)H. The reduced nicotinamide cofactor NAD(P)H plays a pivotal role in many biochemical oxidation and reduction reactions, thus this enzyme would allow regeneration of NAD(P)H in a microalgae strain over-expressing a NAD(P)H-dependent oxidoreductase. A phosphite dehydrogenase gene was introduced into the chloroplast genome (codon optimized) and nuclear genome of C. reinhardtii by biolistic transformation and electroporation in separate events, respectively. Successful expression of the heterologous protein was confirmed by transcript analysis and protein analysis. In conclusion, this new method represents a useful genetic tool in the construction and integration of complex biochemical pathways into the chloroplast or nuclear genome of microalgae, and this should aid current efforts to engineer algae for recombinant protein expression, biofuels production and production of other desirable natural products.

Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.

PubMed

Arneson, Douglas; Bhattacharya, Anindya; Shu, Le; Mäkinen, Ville-Petteri; Yang, Xia

2016-09-09

Human diseases are commonly the result of multidimensional changes at molecular, cellular, and systemic levels. Recent advances in genomic technologies have enabled an outpour of omics datasets that capture these changes. However, separate analyses of these various data only provide fragmented understanding and do not capture the holistic view of disease mechanisms. To meet the urgent needs for tools that effectively integrate multiple types of omics data to derive biological insights, we have developed Mergeomics, a computational pipeline that integrates multidimensional disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease development. To make the Mergeomics pipeline available to a wider research community, we have implemented an online, user-friendly web server ( http://mergeomics. idre.ucla.edu/ ). The web server features a modular implementation of the Mergeomics pipeline with detailed tutorials. Additionally, it provides curated genomic resources including tissue-specific expression quantitative trait loci, ENCODE functional annotations, biological pathways, and molecular networks, and offers interactive visualization of analytical results. Multiple computational tools including Marker Dependency Filtering (MDF), Marker Set Enrichment Analysis (MSEA), Meta-MSEA, and Weighted Key Driver Analysis (wKDA) can be used separately or in flexible combinations. User-defined summary-level genomic association datasets (e.g., genetic, transcriptomic, epigenomic) related to a particular disease or phenotype can be uploaded and computed real-time to yield biologically interpretable results, which can be viewed online and downloaded for later use. Our Mergeomics web server offers researchers flexible and user-friendly tools to facilitate integration of multidimensional data into holistic views of disease mechanisms in the form of tissue-specific key regulators, biological pathways, and gene networks.

Recurrent Targeted Genes of Hepatitis B Virus in the Liver Cancer Genomes Identified by a Next-Generation Sequencing–Based Approach

PubMed Central

Ding, Dong; Lou, Xiaoyan; Hua, Dasong; Yu, Wei; Li, Lisha; Wang, Jun; Gao, Feng; Zhao, Na; Ren, Guoping; Li, Lanjuan; Lin, Biaoyang

2012-01-01

Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV)–related hepatocellular carcinomas (HCCs). Here we devised a massive anchored parallel sequencing (MAPS) method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV–related HCC tissues (cancer and adjacent tissues), we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs) with precise HBV–Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1) containing IPR003961 (Fibronectin, type III domain), 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1) containing IPR013032 (EGF-like region, conserved site), and three genes (PDE7A, PDE4B, PDE11A) containing IPR002073 (3′, 5′-cyclic-nucleotide phosphodiesterase). Enriched pathways include hsa04512 (ECM-receptor interaction), hsa04510 (Focal adhesion), and hsa04012 (ErbB signaling pathway). Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1) and telomerase reverse transcriptase (TERT1), two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5), phosphatase and actin regulator 4 (PHACTR4), and RNA binding protein fox-1 homolog (C. elegans) 1 (RBFOX1). Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This global survey of HBV integration events, together with recently published whole-genome sequencing analyses, furthered our understanding of the HBV–related HCC. PMID:23236287

Seeking unique and common biological themes in multiple gene lists or datasets: pathway pattern extraction pipeline for pathway-level comparative analysis.

PubMed

Yi, Ming; Mudunuri, Uma; Che, Anney; Stephens, Robert M

2009-06-29

One of the challenges in the analysis of microarray data is to integrate and compare the selected (e.g., differential) gene lists from multiple experiments for common or unique underlying biological themes. A common way to approach this problem is to extract common genes from these gene lists and then subject these genes to enrichment analysis to reveal the underlying biology. However, the capacity of this approach is largely restricted by the limited number of common genes shared by datasets from multiple experiments, which could be caused by the complexity of the biological system itself. We now introduce a new Pathway Pattern Extraction Pipeline (PPEP), which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of the pathway-level enrichment patterns across multiple gene lists. As an exploratory tool, this analysis pipeline may help reveal the underlying biological themes at both the pathway and gene levels. The analysis scheme provided by PPEP begins with multiple gene lists, which may be derived from different studies in terms of the biological contexts, applied technologies, or methodologies. These lists are then subjected to pathway-level comparative analysis for extraction of pathway-level patterns. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways or biological processes from different but relevant biological systems using a combination of statistical enrichment measurements, pathway-level pattern extraction, and graphical display of the relationships of genes and their associated pathways as Gene-Term Association Networks (GTANs) within the WPS platform. As a proof of concept, we have used the new method to analyze many datasets from our collaborators as well as some public microarray datasets. This tool provides a new pathway-level analysis scheme for integrative and comparative analysis of data derived from different but relevant systems. The tool is freely available as a Pathway Pattern Extraction Pipeline implemented in our existing software package WPS, which can be obtained at http://www.abcc.ncifcrf.gov/wps/wps_index.php.

Alleviating Autonomic Dysreflexia after Spinal Cord Injury

DTIC Science & Technology

2017-12-01

autonomic disorders greatly influence the functional, psychological , and socioeconomic aspects of patients’ lives. Compared to numer- ous...The disruption of descending autonomic pathways renders abnormalities in multiple organ systems including cardiovascular function, respiration...the rise in blood pressure, the integration center in the brainstem transmits signals to the heart via parasympathetic pathways to reduce the heart

Integrating Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Estimate Exposure-relevant Responses

EPA Science Inventory

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vi...

Southern Pennsylvania's Industrial Pipeline: "Pathways" Program Helps Local Manufacturers Find Quality Workers

ERIC Educational Resources Information Center

Dixon, John; Girifalco, Tony; Yakabosky, Walt

2008-01-01

This article describes the Applied Engineering Technology (AET) Career and Educational Pathways Program, which helps local manufacturers find quality workers. The program features 32 high schools, three community colleges, and 10 four-year institutions offering an integrated regional system of applied engineering education. The goal is to enroll…

Building an Adverse Outcome Pathway Framework through HTS Data and Literature Mining Integration (FutureToxII)

EPA Science Inventory

Interpreting EPA’s ToxCast in vitro assay data in the context of Adverse Outcome Pathway (AOP) development is a significant challenge. While chemical activation in these assays may shed light on the molecular initiating event, the downstream effect of these activities at higher ...

Building Integrated Pathways to Sustainable Careers: An Introduction to the Accelerated Opportunity Initiative

ERIC Educational Resources Information Center

Pleasants, Rachel

2011-01-01

"Accelerating Opportunity" responds to the nation's growing need for improved pathways from Adult Basic Education (ABE) to credentials of value in the labor market. It builds on promising practices developed in "Breaking Through," an initiative of Jobs for the Future and the National Council for Workforce Education, and…

A novel personal health system with integrated decision support and guidance for the management of chronic liver disease.

PubMed

Kiefer, Stephan; Schäfer, Michael; Bransch, Marco; Brimmers, Peter; Bartolomé, Diego; Baños, Janie; Orr, James; Jones, Dave; Jara, Maximilian; Stockmann, Martin

2014-01-01

A personal health system platform for the management of patients with chronic liver disease that incorporates a novel approach to integrate decision support and guidance through care pathways for patients and their doctors is presented in this paper. The personal health system incorporates an integrated decision support engine that guides patients and doctors through the management of the disease by issuing tasks and providing recommendations to both the care team and the patient and by controlling the execution of a Care Flow Plan based on the results of tasks and the monitored health status of the patient. This Care Flow Plan represents a formal, business process based model of disease management designed off-line by domain experts on the basis of clinical guidelines, knowledge of care pathways and an organisational model for integrated, patient-centred care. In this way, remote monitoring and treatment are dynamically adapted to the patient's actual condition and clinical symptoms and allow flexible delivery of care with close integration of specialists, therapists and care-givers.

The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production.

PubMed

Valiante, Vito

2017-12-06

The fungal cell wall is the external and first layer that fungi use to interact with the environment. Every stress signal, before being translated into an appropriate stress response, needs to overtake this layer. Many signaling pathways are involved in translating stress signals, but the cell wall integrity (CWI) signaling pathway is the one responsible for the maintenance and biosynthesis of the fungal cell wall. In fungi, the CWI signal is composed of a mitogen-activated protein kinase (MAPK) module. After the start of the phosphorylation cascade, the CWI signal induces the expression of cell-wall-related genes. However, the function of the CWI signal is not merely the activation of cell wall biosynthesis, but also the regulation of expression and production of specific molecules that are used by fungi to better compete in the environment. These molecules are normally defined as secondary metabolites or natural products. This review is focused on secondary metabolites affected by the CWI signal pathway with a special focus on relevant natural products such as melanins, mycotoxins, and antibacterial compounds.

Redesigning service delivery for hypertensive patients: a methodological guideline to improve the management of chronic diseases.

PubMed

Ippolito, Adelaide; Cannavacciuolo, Lorella; Ponsiglione, Cristina; De Luca, Nicola; Iaccarino, Guido; Illario, Maddalena

2014-04-01

Best care is not necessarily the most expensive, but the most appropriate, and prevention is the most powerful tool to promote health. A novel approach might envision the reduction of hospital admittance (thus meeting a requirement from long term condition patients: they would rather not being hospitalized!) and the enforcement of peripheral (both on the territory and at home) assistance. In this direction, experiences of reshaping new service deliveries towards an integrated disease management, namely clinical pathways, can be observed in Europe and in different parts of the world. Aim of this paper is to provide a methodological guideline to support the management in planning clinical pathways, also outlining the main barriers limiting the process. In particular, we present the results of planning a clinical pathway at the Centre for Hypertension of the Federico II University Hospital (Naples, Italy). The case study showed that the introduction of a similar service impacts on the organisation of the structure. An analysis of organizational processes "as are" and the re-design of processes "to be" are necessary to integrate the clinical pathway into the actual activities.

Cell-Specific Imd-NF-κB Responses Enable Simultaneous Antibacterial Immunity and Intestinal Epithelial Cell Shedding upon Bacterial Infection.

PubMed

Zhai, Zongzhao; Boquete, Jean-Philippe; Lemaitre, Bruno

2018-05-03

Intestinal infection triggers potent immune responses to combat pathogens and concomitantly drives epithelial renewal to maintain barrier integrity. Current models propose that epithelial renewal is primarily driven by damage caused by reactive oxygen species (ROS). Here we found that in Drosophila, the Imd-NF-κB pathway controlled enterocyte (EC) shedding upon infection, via a mechanism independent of ROS-associated apoptosis. Mechanistically, the Imd pathway synergized with JNK signaling to induce epithelial cell shedding specifically in the context of bacterial infection, requiring also the reduced expression of the transcription factor GATAe. Furthermore, cell-specific NF-κB responses enabled simultaneous production of antimicrobial peptides (AMPs) and epithelial shedding in different EC populations. Thus, the Imd-NF-κB pathway is central to the intestinal antibacterial response by mediating both AMP production and the maintenance of barrier integrity. Considering the similarities between Drosophila Imd signaling and mammalian TNFR pathway, our findings suggest the existence of an evolutionarily conserved genetic program in immunity-induced epithelial shedding. Copyright © 2018 Elsevier Inc. All rights reserved.

A reproducible approach to high-throughput biological data acquisition and integration

PubMed Central

Rahnavard, Gholamali; Waldron, Levi; McIver, Lauren; Shafquat, Afrah; Franzosa, Eric A.; Miropolsky, Larissa; Sweeney, Christopher

2015-01-01

Modern biological research requires rapid, complex, and reproducible integration of multiple experimental results generated both internally and externally (e.g., from public repositories). Although large systematic meta-analyses are among the most effective approaches both for clinical biomarker discovery and for computational inference of biomolecular mechanisms, identifying, acquiring, and integrating relevant experimental results from multiple sources for a given study can be time-consuming and error-prone. To enable efficient and reproducible integration of diverse experimental results, we developed a novel approach for standardized acquisition and analysis of high-throughput and heterogeneous biological data. This allowed, first, novel biomolecular network reconstruction in human prostate cancer, which correctly recovered and extended the NFκB signaling pathway. Next, we investigated host-microbiome interactions. In less than an hour of analysis time, the system retrieved data and integrated six germ-free murine intestinal gene expression datasets to identify the genes most influenced by the gut microbiota, which comprised a set of immune-response and carbohydrate metabolism processes. Finally, we constructed integrated functional interaction networks to compare connectivity of peptide secretion pathways in the model organisms Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa. PMID:26157642

Apoptosis by dietary agents for prevention and treatment of prostate cancer

PubMed Central

Khan, Naghma; Adhami, Vaqar Mustafa; Mukhtar, Hasan

2010-01-01

Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials. PMID:19926708

A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals.

PubMed

Davière, Jean-Michel; Achard, Patrick

2016-01-04

Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Overcoming the matched-sample bottleneck: an orthogonal approach to integrate omic data.

PubMed

Nguyen, Tin; Diaz, Diana; Tagett, Rebecca; Draghici, Sorin

2016-07-12

MicroRNAs (miRNAs) are small non-coding RNA molecules whose primary function is to regulate the expression of gene products via hybridization to mRNA transcripts, resulting in suppression of translation or mRNA degradation. Although miRNAs have been implicated in complex diseases, including cancer, their impact on distinct biological pathways and phenotypes is largely unknown. Current integration approaches require sample-matched miRNA/mRNA datasets, resulting in limited applicability in practice. Since these approaches cannot integrate heterogeneous information available across independent experiments, they neither account for bias inherent in individual studies, nor do they benefit from increased sample size. Here we present a novel framework able to integrate miRNA and mRNA data (vertical data integration) available in independent studies (horizontal meta-analysis) allowing for a comprehensive analysis of the given phenotypes. To demonstrate the utility of our method, we conducted a meta-analysis of pancreatic and colorectal cancer, using 1,471 samples from 15 mRNA and 14 miRNA expression datasets. Our two-dimensional data integration approach greatly increases the power of statistical analysis and correctly identifies pathways known to be implicated in the phenotypes. The proposed framework is sufficiently general to integrate other types of data obtained from high-throughput assays.

Projecting state-level air pollutant emissions using an integrated assessment model: GCAM-USA.

EPA Science Inventory

Integrated Assessment Models (IAMs) characterize the interactions among human and earth systems. IAMs typically have been applied to investigate future energy, land use, and emission pathways at global to continental scales. Recent directions in IAM development include enhanced t...

Pathways of Interdisciplinary Cognition

ERIC Educational Resources Information Center

Nikitina, Svetlana

2005-01-01

In this article, I propose that at the juncture of disciplines, the mind is involved in at least 3 cognitive activities: overcoming internal monologism or monodisciplinarity, attaining provisional integration, and questioning the integration as necessarily partial. This claim is supported by interview data I collected primarily from faculty…

Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI.

PubMed

Chan, Kevin C; Kancherla, Swarupa; Fan, Shu-Juan; Wu, Ed X

2014-12-09

Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Long-Term Effects of Neonatal Hypoxia-Ischemia on Structural and Physiological Integrity of the Eye and Visual Pathway by Multimodal MRI

PubMed Central

Chan, Kevin C.; Kancherla, Swarupa; Fan, Shu-Juan; Wu, Ed X.

2015-01-01

Purpose. Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. Methods. Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. Results. Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. Conclusions. High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury. PMID:25491295

Co-regulation of pluripotency and genetic integrity at the genomic level.

PubMed

Cooper, Daniel J; Walter, Christi A; McCarrey, John R

2014-11-01

The Disposable Soma Theory holds that genetic integrity will be maintained at more pristine levels in germ cells than in somatic cells because of the unique role germ cells play in perpetuating the species. We tested the hypothesis that the same concept applies to pluripotent cells compared to differentiated cells. Analyses of transcriptome and cistrome databases, along with canonical pathway analysis and chromatin immunoprecipitation confirmed differential expression of DNA repair and cell death genes in embryonic stem cells and induced pluripotent stem cells relative to fibroblasts, and predicted extensive direct and indirect interactions between the pluripotency and genetic integrity gene networks in pluripotent cells. These data suggest that enhanced maintenance of genetic integrity is fundamentally linked to the epigenetic state of pluripotency at the genomic level. In addition, these findings demonstrate how a small number of key pluripotency factors can regulate large numbers of downstream genes in a pathway-specific manner. Copyright © 2014. Published by Elsevier B.V.

[New integrated care model for older people admitted to Intermediate Care Units in Catalonia: A quasi-experimental study protocol].

PubMed

Santaeugènia, Sebastià J; García-Lázaro, Manuela; Alventosa, Ana María; Gutiérrez-Benito, Alícia; Monterde, Albert; Cunill, Joan

To evaluate the clinical effectiveness of an intermediate care model based on a system of care focused on integrated care pathways compared to the traditional model of geriatric care (usual care) in Catalonia. The design is a quasi-experimental pre-post non-randomised study with non-synchronous control group. The intervention consists of the development and implementation of integrated care pathways and the creation of specialised interdisciplinary teams in each of the processes. The two groups will be compared for demographic, clinical variables on admission and discharge, geriatric syndromes, and use of resources. This quasi-experimental study, aims to assess the clinical impact of the transformation of a traditional model of geriatric care to an intermediate care model in an integrated healthcare organisation. It is believed that the results of this study may be useful for future randomised controlled studies. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

A qualitative study of the perspectives of key stakeholders on the delivery of clinical academic training in the East Midlands.

PubMed

Green, Ruth H; Evans, Val; MacLeod, Sheona; Barratt, Jonathan

2018-02-01

Major changes in the design and delivery of clinical academic training in the United Kingdom have occurred yet there has been little exploration of the perceptions of integrated clinic academic trainees or educators. We obtained the views of a range of key stakeholders involved in clinical academic training in the East Midlands. A qualitative study with inductive iterative thematic content analysis of findings from trainee surveys and facilitated focus groups. The East Midlands School of Clinical Academic Training. Integrated Clinical Academic Trainees, clinical and academic educators involved in clinical academic training. The experience, opinions and beliefs of key stakeholders about barriers and enablers in the delivery of clinical academic training. We identified key themes many shared by both trainees and educators. These highlighted issues in the systems and process of the integrated academic pathways, career pathways, supervision and support, the assessment process and the balance between clinical and academic training. Our findings help inform the future development of integrated academic training programmes.

Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease

PubMed Central

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre FR; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2016-01-01

Objective Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. PMID:25977570

Integrated turbomachine oxygen plant

DOEpatents

Anand, Ashok Kumar; DePuy, Richard Anthony; Muthaiah, Veerappan

2014-06-17

An integrated turbomachine oxygen plant includes a turbomachine and an air separation unit. One or more compressor pathways flow compressed air from a compressor through one or more of a combustor and a turbine expander to cool the combustor and/or the turbine expander. An air separation unit is operably connected to the one or more compressor pathways and is configured to separate the compressed air into oxygen and oxygen-depleted air. A method of air separation in an integrated turbomachine oxygen plant includes compressing a flow of air in a compressor of a turbomachine. The compressed flow of air is flowed through one or more of a combustor and a turbine expander of the turbomachine to cool the combustor and/or the turbine expander. The compressed flow of air is directed to an air separation unit and is separated into oxygen and oxygen-depleted air.

Meta-analysis of pathway enrichment: combining independent and dependent omics data sets.

PubMed

Kaever, Alexander; Landesfeind, Manuel; Feussner, Kirstin; Morgenstern, Burkhard; Feussner, Ivo; Meinicke, Peter

2014-01-01

A major challenge in current systems biology is the combination and integrative analysis of large data sets obtained from different high-throughput omics platforms, such as mass spectrometry based Metabolomics and Proteomics or DNA microarray or RNA-seq-based Transcriptomics. Especially in the case of non-targeted Metabolomics experiments, where it is often impossible to unambiguously map ion features from mass spectrometry analysis to metabolites, the integration of more reliable omics technologies is highly desirable. A popular method for the knowledge-based interpretation of single data sets is the (Gene) Set Enrichment Analysis. In order to combine the results from different analyses, we introduce a methodical framework for the meta-analysis of p-values obtained from Pathway Enrichment Analysis (Set Enrichment Analysis based on pathways) of multiple dependent or independent data sets from different omics platforms. For dependent data sets, e.g. obtained from the same biological samples, the framework utilizes a covariance estimation procedure based on the nonsignificant pathways in single data set enrichment analysis. The framework is evaluated and applied in the joint analysis of Metabolomics mass spectrometry and Transcriptomics DNA microarray data in the context of plant wounding. In extensive studies of simulated data set dependence, the introduced correlation could be fully reconstructed by means of the covariance estimation based on pathway enrichment. By restricting the range of p-values of pathways considered in the estimation, the overestimation of correlation, which is introduced by the significant pathways, could be reduced. When applying the proposed methods to the real data sets, the meta-analysis was shown not only to be a powerful tool to investigate the correlation between different data sets and summarize the results of multiple analyses but also to distinguish experiment-specific key pathways.

Cortico-Cortical White Matter Motor Pathway Microstructure Is Related to Psychomotor Retardation in Major Depressive Disorder

PubMed Central

Bracht, Tobias; Federspiel, Andrea; Schnell, Susanne; Horn, Helge; Höfle, Oliver; Wiest, Roland; Dierks, Thomas; Strik, Werner; Müller, Thomas J.; Walther, Sebastian

2012-01-01

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD. PMID:23284950

Cortico-cortical white matter motor pathway microstructure is related to psychomotor retardation in major depressive disorder.

PubMed

Bracht, Tobias; Federspiel, Andrea; Schnell, Susanne; Horn, Helge; Höfle, Oliver; Wiest, Roland; Dierks, Thomas; Strik, Werner; Müller, Thomas J; Walther, Sebastian

2012-01-01

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.

An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.

PubMed

Guedj, Faycal; Pennings, Jeroen LA; Massingham, Lauren J; Wick, Heather C; Siegel, Ashley E; Tantravahi, Umadevi; Bianchi, Diana W

2016-09-02

Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn, and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice.

Integrating physical and genetic maps: from genomes to interaction networks

PubMed Central

Beyer, Andreas; Bandyopadhyay, Sourav; Ideker, Trey

2009-01-01

Physical and genetic mapping data have become as important to network biology as they once were to the Human Genome Project. Integrating physical and genetic networks currently faces several challenges: increasing the coverage of each type of network; establishing methods to assemble individual interaction measurements into contiguous pathway models; and annotating these pathways with detailed functional information. A particular challenge involves reconciling the wide variety of interaction types that are currently available. For this purpose, recent studies have sought to classify genetic and physical interactions along several complementary dimensions, such as ordered versus unordered, alleviating versus aggravating, and first versus second degree. PMID:17703239

An integrative method for testing form–function linkages and reconstructed evolutionary pathways of masticatory specialization

PubMed Central

Tseng, Z. Jack; Flynn, John J.

2015-01-01

Morphology serves as a ubiquitous proxy in macroevolutionary studies to identify potential adaptive processes and patterns. Inferences of functional significance of phenotypes or their evolution are overwhelmingly based on data from living taxa. Yet, correspondence between form and function has been tested in only a few model species, and those linkages are highly complex. The lack of explicit methodologies to integrate form and function analyses within a deep-time and phylogenetic context weakens inferences of adaptive morphological evolution, by invoking but not testing form–function linkages. Here, we provide a novel approach to test mechanical properties at reconstructed ancestral nodes/taxa and the strength and direction of evolutionary pathways in feeding biomechanics, in a case study of carnivorous mammals. Using biomechanical profile comparisons that provide functional signals for the separation of feeding morphologies, we demonstrate, using experimental optimization criteria on estimation of strength and direction of functional changes on a phylogeny, that convergence in mechanical properties and degree of evolutionary optimization can be decoupled. This integrative approach is broadly applicable to other clades, by using quantitative data and model-based tests to evaluate interpretations of function from morphology and functional explanations for observed macroevolutionary pathways. PMID:25994295

The F-box protein Fbp1 functions in the invasive growth and cell wall integrity mitogen-activated protein kinase (MAPK) pathways in Fusarium oxysporum.

PubMed

Miguel-Rojas, Cristina; Hera, Concepcion

2016-01-01

F-box proteins determine substrate specificity of the ubiquitin-proteasome system. Previous work has demonstrated that the F-box protein Fbp1, a component of the SCF(Fbp1) E3 ligase complex, is essential for invasive growth and virulence of the fungal plant pathogen Fusarium oxysporum. Here, we show that, in addition to invasive growth, Fbp1 also contributes to vegetative hyphal fusion and fungal adhesion to tomato roots. All of these functions have been shown previously to require the mitogen-activated protein kinase (MAPK) Fmk1. We found that Fbp1 is required for full phosphorylation of Fmk1, indicating that Fbp1 regulates virulence and invasive growth via the Fmk1 pathway. Moreover, the Δfbp1 mutant is hypersensitive to sodium dodecylsulfate (SDS) and calcofluor white (CFW) and shows reduced phosphorylation levels of the cell wall integrity MAPK Mpk1 after SDS treatment. Collectively, these results suggest that Fbp1 contributes to both the invasive growth and cell wall integrity MAPK pathways of F. oxysporum. © 2015 BSPP AND JOHN WILEY & SONS LTD.

Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery.

PubMed

Bosl, William J

2007-02-15

Expert knowledge in journal articles is an important source of data for reconstructing biological pathways and creating new hypotheses. An important need for medical research is to integrate this data with high throughput sources to build useful models that span several scales. Researchers traditionally use mental models of pathways to integrate information and development new hypotheses. Unfortunately, the amount of information is often overwhelming and these are inadequate for predicting the dynamic response of complex pathways. Hierarchical computational models that allow exploration of semi-quantitative dynamics are useful systems biology tools for theoreticians, experimentalists and clinicians and may provide a means for cross-communication. A novel approach for biological pathway modeling based on hybrid intelligent systems or soft computing technologies is presented here. Intelligent hybrid systems, which refers to several related computing methods such as fuzzy logic, neural nets, genetic algorithms, and statistical analysis, has become ubiquitous in engineering applications for complex control system modeling and design. Biological pathways may be considered to be complex control systems, which medicine tries to manipulate to achieve desired results. Thus, hybrid intelligent systems may provide a useful tool for modeling biological system dynamics and computational exploration of new drug targets. A new modeling approach based on these methods is presented in the context of hedgehog regulation of the cell cycle in granule cells. Code and input files can be found at the Bionet website: www.chip.ord/~wbosl/Software/Bionet. This paper presents the algorithmic methods needed for modeling complicated biochemical dynamics using rule-based models to represent expert knowledge in the context of cell cycle regulation and tumor growth. A notable feature of this modeling approach is that it allows biologists to build complex models from their knowledge base without the need to translate that knowledge into mathematical form. Dynamics on several levels, from molecular pathways to tissue growth, are seamlessly integrated. A number of common network motifs are examined and used to build a model of hedgehog regulation of the cell cycle in cerebellar neurons, which is believed to play a key role in the etiology of medulloblastoma, a devastating childhood brain cancer.

Systems for implementing best practice for a chronic disease: management of osteoarthritis of the hip and knee.

PubMed

Brand, C; Cox, S

2006-03-01

Effective implementation of evidence-based care has been associated with better health outcomes; however, evidence-based clinical practice guidelines have been used with varying success. This study aimed to develop integrative tools to support implementation of best practice recommendations for nonsurgical management of osteoarthritis (OA) of the hip and knee and to identify barriers to effective implementation. Published, peer reviewed clinical practice guidelines were updated and translated into an OA care pathway. Key decision nodes in the pathway were identified by a Multidisciplinary Working Group. Qualitative research methods were used to inform pathway development and to identify barriers and enablers for pathway implementation. Qualitative components included purposively selected stakeholder focus groups, key informant interviews and patient process mapping of 10 patient journeys in different settings over a 3-month period. All interviews, facilitated by a trained project officer, were semistructured, recorded, then thematically analysed and summarized. An OA care pathway, clinician and patient toolkits were developed that met the needs of multidisciplinary end-users. Several system- and setting-specific barriers to pathway implementation were identified. Opportunities to improve patient access, interprofessional communication, patient information and education and continuity of care processes were identified. Integrative tools for implementation of best evidence care for patients with OA of the hip and knee were tailored to end-user needs and preferences. Multiple barriers exist that potentially limit effective implementation of best evidence. Comprehensive assessment of barriers and enablers to effective guideline or pathway implementation is recommended before implementation and evaluation.

Identification of Significant Gene Signatures and Prognostic Biomarkers for Patients With Cervical Cancer by Integrated Bioinformatic Methods

PubMed Central

Li, Xiaofang; Tian, Run; Gao, Hugh; Yan, Feng; Ying, Le; Yang, Yongkang; Yang, Pei

2018-01-01

Cervical cancer is the leading cause of death with gynecological malignancies. We aimed to explore the molecular mechanism of carcinogenesis and biomarkers for cervical cancer by integrated bioinformatic analysis. We employed RNA-sequencing details of 254 cervical squamous cell carcinomas and 3 normal samples from The Cancer Genome Atlas. To explore the distinct pathways, messenger RNA expression was submitted to a Gene Set Enrichment Analysis. Kyoto Encyclopedia of Genes and Genomes and protein–protein interaction network analysis of differentially expressed genes were performed. Then, we conducted pathway enrichment analysis for modules acquired in protein–protein interaction analysis and obtained a list of pathways in every module. After intersecting the results from the 3 approaches, we evaluated the survival rates of both mutual pathways and genes in the pathway, and 5 survival-related genes were obtained. Finally, Cox hazards ratio analysis of these 5 genes was performed. DNA replication pathway (P < .001; 12 genes included) was suggested to have the strongest association with the prognosis of cervical squamous cancer. In total, 5 of the 12 genes, namely, minichromosome maintenance 2, minichromosome maintenance 4, minichromosome maintenance 5, proliferating cell nuclear antigen, and ribonuclease H2 subunit A were significantly correlated with survival. Minichromosome maintenance 5 was shown as an independent prognostic biomarker for patients with cervical cancer. This study identified a distinct pathway (DNA replication). Five genes which may be prognostic biomarkers and minichromosome maintenance 5 were identified as independent prognostic biomarkers for patients with cervical cancer. PMID:29642758

The β-cyanoalanine synthase pathway: beyond cyanide detoxification.

PubMed

Machingura, Marylou; Salomon, Eitan; Jez, Joseph M; Ebbs, Stephen D

2016-10-01

Production of cyanide through biological and environmental processes requires the detoxification of this metabolic poison. In the 1960s, discovery of the β-cyanoalanine synthase (β-CAS) pathway in cyanogenic plants provided the first insight on cyanide detoxification in nature. Fifty years of investigations firmly established the protective role of the β-CAS pathway in cyanogenic plants and its role in the removal of cyanide produced from ethylene synthesis in plants, but also revealed the importance of this pathway for plant growth and development and the integration of nitrogen and sulfur metabolism. This review describes the β-CAS pathway, its distribution across and within higher plants, and the diverse biological functions of the pathway in cyanide assimilation, plant growth and development, stress tolerance, regulation of cyanide and sulfide signalling, and nitrogen and sulfur metabolism. The collective roles of the β-CAS pathway highlight its potential evolutionary and ecological importance in plants. © 2016 John Wiley & Sons Ltd.

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

PubMed

Blom, Jan J; Giove, Thomas J; Favazza, Tara L; Akula, James D; Eldred, William D

2011-06-01

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

Separate Brain Circuits Support Integrative and Semantic Priming in the Human Language System.

PubMed

Feng, Gangyi; Chen, Qi; Zhu, Zude; Wang, Suiping

2016-07-01

Semantic priming is a crucial phenomenon to study the organization of semantic memory. A novel type of priming effect, integrative priming, has been identified behaviorally, whereby a prime word facilitates recognition of a target word when the 2 concepts can be combined to form a unitary representation. We used both functional and anatomical imaging approaches to investigate the neural substrates supporting such integrative priming, and compare them with those in semantic priming. Similar behavioral priming effects for both semantic (Bread-Cake) and integrative conditions (Cherry-Cake) were observed when compared with an unrelated condition. However, a clearly dissociated brain response was observed between these 2 types of priming. The semantic-priming effect was localized to the posterior superior temporal and middle temporal gyrus. In contrast, the integrative-priming effect localized to the left anterior inferior frontal gyrus and left anterior temporal cortices. Furthermore, fiber tractography showed that the integrative-priming regions were connected via uncinate fasciculus fiber bundle forming an integrative circuit, whereas the semantic-priming regions connected to the posterior frontal cortex via separated pathways. The results point to dissociable neural pathways underlying the 2 distinct types of priming, illuminating the neural circuitry organization of semantic representation and integration. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

High throughput gene expression profiling: a molecular approach to integrative physiology

PubMed Central

Liang, Mingyu; Cowley, Allen W; Greene, Andrew S

2004-01-01

Integrative physiology emphasizes the importance of understanding multiple pathways with overlapping, complementary, or opposing effects and their interactions in the context of intact organisms. The DNA microarray technology, the most commonly used method for high-throughput gene expression profiling, has been touted as an integrative tool that provides insights into regulatory pathways. However, the physiology community has been slow in acceptance of these techniques because of early failure in generating useful data and the lack of a cohesive theoretical framework in which experiments can be analysed. With recent advances in both technology and analysis, we propose a concept of multidimensional integration of physiology that incorporates data generated by DNA microarray and other functional, genomic, and proteomic approaches to achieve a truly integrative understanding of physiology. Analysis of several studies performed in simpler organisms or in mammalian model animals supports the feasibility of such multidimensional integration and demonstrates the power of DNA microarray as an indispensable molecular tool for such integration. Evaluation of DNA microarray techniques indicates that these techniques, despite limitations, have advanced to a point where the question-driven profiling research has become a feasible complement to the conventional, hypothesis-driven research. With a keen sense of homeostasis, global regulation, and quantitative analysis, integrative physiologists are uniquely positioned to apply these techniques to enhance the understanding of complex physiological functions. PMID:14678487

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23*

PubMed Central

Han, Xiaobin; Xiao, Zhousheng; Quarles, L. Darryl

2015-01-01

Fibroblastic growth factor receptor 1 (FGFR1) signaling pathways are implicated in the regulation of FGF-23 gene transcription, but the molecular pathways remain poorly defined. We used low molecular weight (LMW, 18 kDa) FGF-2 and high molecular weight (HMW) FGF-2 isoforms, which, respectively, activate cell surface FGF receptors and intranuclear FGFR1, to determine the roles of membrane FGFRs and integrative nuclear FGFR1 signaling (INFS) in the regulation of FGF-23 gene transcription in osteoblasts. We found that LMW-FGF-2 induced NFAT and Ets1 binding to conserved cis-elements in the proximal FGF-23 promoter and stimulated FGF-23 promoter activity through PLCγ/calcineurin/NFAT and MAPK pathways in SaOS-2 and MC3T3-E1 osteoblasts. In contrast, HMW-FGF-2 stimulated FGF-23 promoter activity in osteoblasts through a cAMP-dependent binding of FGFR1 and cAMP-response element-binding protein (CREB) to a conserved cAMP response element (CRE) contiguous with the NFAT binding site in the FGF-23 promoter. Mutagenesis of the NFAT and CRE binding sites, respectively, inhibited the effects of LMW-FGF-2 and HMW-FGF-23 to stimulate FGF-23 promoter activity. FGF-2 activation of both membrane FGFRs and INFS-dependent FGFR1 pathways may provide a means to integrate systemic and local regulation of FGF-23 transcription under diverse physiological and pathological conditions. PMID:25752607

Tolerant industrial yeast Saccharomyces cerevisiae posses a more robust cell wall integrity signaling pathway against 2-furaldehyde and 5-(hydroxymethyl)-2-furaldehyde.

PubMed

Liu, Z Lewis; Wang, Xu; Weber, Scott A

2018-06-20

Cell wall integrity signaling pathway in Saccharomyces cerevisiae is a conserved function for detecting and responding to cell stress conditions but less understood for industrial yeast. We examined gene expression dynamics for a tolerant industrial yeast strain NRRL Y-50049 in response to challenges of furfural and HMF through comparative quantitative gene expression analysis using pathway-based qRT-PCR array assays. All tested genes from Y-50049, except for MLP2, demonstrated more resistant and significantly increased gene expression than that from a laboratory strain BY4741. While all five sensor encoding genes WSC1, WSC2, WSC3, MID2 and MTL1 from both strains were activated in response to the furfural-HMF treatment, WSC3 from Y-50049 demonstrated the most increased expression over time compared with any other sensor genes. These results suggested the industrial yeast poses more robust cell wall integrity pathway, and gene WSC3 could have the special capability for signal transmission against furfural and HMF. Among five single nucleotide variations discovered in WSC3 from Y-50049, three were found to be non-synonymous mutations resulting in amino acid alterations of Ser 158  → Tyr 158 , Val 186  → Ile 186 , and Glu 430  → Asp 430 . Our results suggest the industrial yeast as a more desirable delivery vehicle for the next-generation biocatalyst development. Published by Elsevier B.V.

Identification of miRNA-Mediated Core Gene Module for Glioma Patient Prediction by Integrating High-Throughput miRNA, mRNA Expression and Pathway Structure

PubMed Central

Han, Junwei; Shang, Desi; Zhang, Yunpeng; Zhang, Wei; Yao, Qianlan; Han, Lei; Xu, Yanjun; Yan, Wei; Bao, Zhaoshi; You, Gan; Jiang, Tao; Kang, Chunsheng; Li, Xia

2014-01-01

The prognosis of glioma patients is usually poor, especially in patients with glioblastoma (World Health Organization (WHO) grade IV). The regulatory functions of microRNA (miRNA) on genes have important implications in glioma cell survival. However, there are not many studies that have investigated glioma survival by integrating miRNAs and genes while also considering pathway structure. In this study, we performed sample-matched miRNA and mRNA expression profilings to systematically analyze glioma patient survival. During this analytical process, we developed pathway-based random walk to identify a glioma core miRNA-gene module, simultaneously considering pathway structure information and multi-level involvement of miRNAs and genes. The core miRNA-gene module we identified was comprised of four apparent sub-modules; all four sub-modules displayed a significant correlation with patient survival in the testing set (P-values≤0.001). Notably, one sub-module that consisted of 6 miRNAs and 26 genes also correlated with survival time in the high-grade subgroup (WHO grade III and IV), P-value = 0.0062. Furthermore, the 26-gene expression signature from this sub-module had robust predictive power in four independent, publicly available glioma datasets. Our findings suggested that the expression signatures, which were identified by integration of miRNA and gene level, were closely associated with overall survival among the glioma patients with various grades. PMID:24809850

Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism

PubMed Central

Sychev, Zoi E.; Hu, Alex; Lagunoff, Michael

2017-01-01

Kaposi’s Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi’s Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell-signaling pathways to activate endothelial cells including major metabolic pathways involved in lipid metabolism. To identify the underlying cellular mechanisms of KSHV alteration of host signaling and endothelial cell activation, we identified changes in the host proteome, phosphoproteome and transcriptome landscape following KSHV infection of endothelial cells. A Steiner forest algorithm was used to integrate the global data sets and, together with transcriptome based predicted transcription factor activity, cellular networks altered by latent KSHV were predicted. Several interesting pathways were identified, including peroxisome biogenesis. To validate the predictions, we showed that KSHV latent infection increases the number of peroxisomes per cell. Additionally, proteins involved in peroxisomal lipid metabolism of very long chain fatty acids, including ABCD3 and ACOX1, are required for the survival of latently infected cells. In summary, novel cellular pathways altered during herpesvirus latency that could not be predicted by a single systems biology platform, were identified by integrated proteomics and transcriptomics data analysis and when correlated with our metabolomics data revealed that peroxisome lipid metabolism is essential for KSHV latent infection of endothelial cells. PMID:28257516

Effectiveness of Telerehabilitation for OIF/OEF returnees with Combat Related Trauma

DTIC Science & Technology

2018-04-01

validated health outcome instruments that capture physical function, cognition, mental health status and integration into society. We have enrolled a total...community integration over time. 2) The presence of comorbid Post Traumatic Stress Disorders was a significant predictor in reported patient health 3...Individualized treatment pathways may be needed for rehabilitation and ultimate integration into society and 4) Veterans have expressed appreciation for

Application of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to advance cumulative risk assessment by integrating human health and ecological endpoints

EPA Science Inventory

Evaluating risk of adverse outcomes from chemical exposure is essential for understanding the impacts of environmental contaminants. While human health outcomes are of primary concern and are often the focus of risk assessments, important non-human species are also exposed to co...

An application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks to mechanistically integrate data sources across multiple species into cumulative risk assessment (CRA)

EPA Science Inventory

Toxicologists use dose-response data from both in vivo and in vitro experiments to evaluate the effects of chemical contaminants on organisms. Cumulative risk assessments (CRAs) consider the effects of multiple stressors on multiple endpoints, and utilize environmental exposure ...

Comprehensive School Mental Health: An Integrated "School-Based Pathway to Care" Model for Canadian Secondary Schools

ERIC Educational Resources Information Center

Wei, Yifeng; Kutcher, Stan; Szumilas, Magdalena

2011-01-01

Adolescence is a critical period for the promotion of mental health and the treatment of mental disorders. Schools are well-positioned to address adolescent mental health. This paper describes a school mental health model, "School-Based Pathway to Care," for Canadian secondary schools that links schools with primary care providers and…

Winding Pathways to Engagement: Creating a Front Door

ERIC Educational Resources Information Center

Kniffin, Lori E.; Shaffer, Timothy J.; Tolar, Mary H.

2016-01-01

Service-learning and community engagement (SLCE) practitioner-scholars--meaning all who do the work of SLCE with a commitment to integrating practice and study--find avenues to this work in a variety of ways. Through custom-made pathways, graduate students are forced to articulate and define their place in the academy, which can enhance voice,…

An Institutional Three-Stage Framework: Elevating Academic Writing and Integrity Standards of International Pathway Students

ERIC Educational Resources Information Center

Velliaris, Donna M.; Breen, Paul

2016-01-01

In this paper, the authors explore a holistic three-stage framework currently used by the Eynesbury Institute of Business and Technology (EIBT), focused on academic staff identification and remediation processes for the prevention of (un)intentional student plagiarism. As a pre-university pathway provider--whose student body is 98%…

The New Juan Crow in Education: Revealing Panoptic Measures and Inequitable Resources That Hinder Latina/o Postsecondary Pathways

ERIC Educational Resources Information Center

Madrigal-Garcia, Yanira I.; Acevedo-Gil, Nancy

2016-01-01

This qualitative study examined the distribution of inequitable resources, a culture of control, and implications for postsecondary pathways for Latinas/os in five California high schools. This study integrated critical race theory in education, school culture, and the concept of "panopticon" to examine school structures, climate, and…

The Hippo pathway: regulators and regulations

PubMed Central

Yu, Fa-Xing; Guan, Kun-Liang

2013-01-01

Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions. PMID:23431053

Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway.

PubMed

Le Sage, Valerie; Cinti, Alessandro; Amorim, Raquel; Mouland, Andrew J

2016-05-24

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs.

PANDA: pathway and annotation explorer for visualizing and interpreting gene-centric data.

PubMed

Hart, Steven N; Moore, Raymond M; Zimmermann, Michael T; Oliver, Gavin R; Egan, Jan B; Bryce, Alan H; Kocher, Jean-Pierre A

2015-01-01

Objective. Bringing together genomics, transcriptomics, proteomics, and other -omics technologies is an important step towards developing highly personalized medicine. However, instrumentation has advances far beyond expectations and now we are able to generate data faster than it can be interpreted. Materials and Methods. We have developed PANDA (Pathway AND Annotation) Explorer, a visualization tool that integrates gene-level annotation in the context of biological pathways to help interpret complex data from disparate sources. PANDA is a web-based application that displays data in the context of well-studied pathways like KEGG, BioCarta, and PharmGKB. PANDA represents data/annotations as icons in the graph while maintaining the other data elements (i.e., other columns for the table of annotations). Custom pathways from underrepresented diseases can be imported when existing data sources are inadequate. PANDA also allows sharing annotations among collaborators. Results. In our first use case, we show how easy it is to view supplemental data from a manuscript in the context of a user's own data. Another use-case is provided describing how PANDA was leveraged to design a treatment strategy from the somatic variants found in the tumor of a patient with metastatic sarcomatoid renal cell carcinoma. Conclusion. PANDA facilitates the interpretation of gene-centric annotations by visually integrating this information with context of biological pathways. The application can be downloaded or used directly from our website: http://bioinformaticstools.mayo.edu/research/panda-viewer/.

Functional Analysis of OMICs Data and Small Molecule Compounds in an Integrated "Knowledge-Based" Platform.

PubMed

Dubovenko, Alexey; Nikolsky, Yuri; Rakhmatulin, Eugene; Nikolskaya, Tatiana

2017-01-01

Analysis of NGS and other sequencing data, gene variants, gene expression, proteomics, and other high-throughput (OMICs) data is challenging because of its biological complexity and high level of technical and biological noise. One way to deal with both problems is to perform analysis with a high fidelity annotated knowledgebase of protein interactions, pathways, and functional ontologies. This knowledgebase has to be structured in a computer-readable format and must include software tools for managing experimental data, analysis, and reporting. Here, we present MetaCore™ and Key Pathway Advisor (KPA), an integrated platform for functional data analysis. On the content side, MetaCore and KPA encompass a comprehensive database of molecular interactions of different types, pathways, network models, and ten functional ontologies covering human, mouse, and rat genes. The analytical toolkit includes tools for gene/protein list enrichment analysis, statistical "interactome" tool for the identification of over- and under-connected proteins in the dataset, and a biological network analysis module made up of network generation algorithms and filters. The suite also features Advanced Search, an application for combinatorial search of the database content, as well as a Java-based tool called Pathway Map Creator for drawing and editing custom pathway maps. Applications of MetaCore and KPA include molecular mode of action of disease research, identification of potential biomarkers and drug targets, pathway hypothesis generation, analysis of biological effects for novel small molecule compounds and clinical applications (analysis of large cohorts of patients, and translational and personalized medicine).

The Fanconi anaemia pathway: new players and new functions.

PubMed

Ceccaldi, Raphael; Sarangi, Prabha; D'Andrea, Alan D

2016-06-01

The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.

An Automated Pipeline for Engineering Many-Enzyme Pathways: Computational Sequence Design, Pathway Expression-Flux Mapping, and Scalable Pathway Optimization.

PubMed

Halper, Sean M; Cetnar, Daniel P; Salis, Howard M

2018-01-01

Engineering many-enzyme metabolic pathways suffers from the design curse of dimensionality. There are an astronomical number of synonymous DNA sequence choices, though relatively few will express an evolutionary robust, maximally productive pathway without metabolic bottlenecks. To solve this challenge, we have developed an integrated, automated computational-experimental pipeline that identifies a pathway's optimal DNA sequence without high-throughput screening or many cycles of design-build-test. The first step applies our Operon Calculator algorithm to design a host-specific evolutionary robust bacterial operon sequence with maximally tunable enzyme expression levels. The second step applies our RBS Library Calculator algorithm to systematically vary enzyme expression levels with the smallest-sized library. After characterizing a small number of constructed pathway variants, measurements are supplied to our Pathway Map Calculator algorithm, which then parameterizes a kinetic metabolic model that ultimately predicts the pathway's optimal enzyme expression levels and DNA sequences. Altogether, our algorithms provide the ability to efficiently map the pathway's sequence-expression-activity space and predict DNA sequences with desired metabolic fluxes. Here, we provide a step-by-step guide to applying the Pathway Optimization Pipeline on a desired multi-enzyme pathway in a bacterial host.

Integrating emotional and psychological support into the end-stage renal disease pathway: a protocol for mixed methods research to identify patients' lower-level support needs and how these can most effectively be addressed.

PubMed

Taylor, Francesca; Taylor, Celia; Baharani, Jyoti; Nicholas, Johann; Combes, Gill

2016-08-02

As a result of difficulties related to their illness, diagnosis and treatment, patients with end-stage renal disease experience significant emotional and psychological problems, which untreated can have considerable negative impact on their health and wellbeing. Despite evidence that patients desire improved support, management of their psychosocial problems, particularly at the lower-level, remains sub-optimal. There is limited understanding of the specific support that patients need and want, from whom, and when, and also a lack of data on what helps and hinders renal staff in identifying and responding to their patients' support needs, and how barriers to doing so might be overcome. Through this research we therefore seek to determine what, when, and how, support for patients with lower-level emotional and psychological problems should be integrated into the end-stage renal disease pathway. The research will involve two linked, multicentre studies, designed to identify and consider the perspectives of patients at five different stages of the end-stage renal disease pathway (Study 1), and renal staff working with them (Study 2). A convergent, parallel mixed methods design will be employed for both studies, with quantitative and qualitative data collected separately. For each study, the data sets will be analysed separately and the results then compared or combined using interpretive analysis. A further stage of synthesis will employ data-driven thematic analysis to identify: triangulation and frequency of themes across pathway stages; patterns and plausible explanations of effects. There is an important need for this research given the high frequency of lower-level distress experienced by end-stage renal disease patients and lack of progress to date in integrating support for their lower-level psychosocial needs into the care pathway. Use of a mixed methods design across the two studies will generate a holistic patient and healthcare professional perspective that is more likely to identify viable solutions to enable implementation of timely and integrated care. Based on the research outputs, appropriate support interventions will be developed, implemented and evaluated in a linked follow-on study.

Reconstruction and Evaluation of the Synthetic Bacterial MEP Pathway in Saccharomyces cerevisiae

PubMed Central

Partow, Siavash; Siewers, Verena; Daviet, Laurent; Schalk, Michel; Nielsen, Jens

2012-01-01

Isoprenoids, which are a large group of natural and chemical compounds with a variety of applications as e.g. fragrances, pharmaceuticals and potential biofuels, are produced via two different metabolic pathways, the mevalonate (MVA) pathway and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. Here, we attempted to replace the endogenous MVA pathway in Saccharomyces cerevisiae by a synthetic bacterial MEP pathway integrated into the genome to benefit from its superior properties in terms of energy consumption and productivity at defined growth conditions. It was shown that the growth of a MVA pathway deficient S. cerevisiae strain could not be restored by the heterologous MEP pathway even when accompanied by the co-expression of genes erpA, hISCA1 and CpIscA involved in the Fe-S trafficking routes leading to maturation of IspG and IspH and E. coli genes fldA and fpr encoding flavodoxin and flavodoxin reductase believed to be responsible for electron transfer to IspG and IspH. PMID:23285068

Mediating Relationship of Differential Products in Understanding Integration in Introductory Physics

ERIC Educational Resources Information Center

Amos, Nathaniel; Heckler, Andrew F.

2018-01-01

In the context of introductory physics, we study student conceptual understanding of differentials, differential products, and integrals and possible pathways to understanding these quantities. We developed a multiple choice conceptual assessment employing a variety of physical contexts probing physical understanding of these three quantities and…

Defining Integrated Student Supports for Linked Learning Pathways. Knowledge Brief

ERIC Educational Resources Information Center

John W. Gardner Center for Youth and Their Communities, 2016

2016-01-01

This document outlines how effectively integrated student supports build or scaffold student competencies in five broad domains of learning for college, career, and civic readiness. Relevant supports are not limited to "services" or "programs" but extend to enabling resources and social conditions, including, for example,…

Integrated Model of Chemical Perturbations of a Biological PathwayUsing 18 In Vitro High Throughput Screening Assays for the Estrogen Receptor

EPA Science Inventory

We demonstrate a computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation and ER-dependent cell proliferation. The network model uses activity pa...

Systems Proteomics for Translational Network Medicine

PubMed Central

Arrell, D. Kent; Terzic, Andre

2012-01-01

Universal principles underlying network science, and their ever-increasing applications in biomedicine, underscore the unprecedented capacity of systems biology based strategies to synthesize and resolve massive high throughput generated datasets. Enabling previously unattainable comprehension of biological complexity, systems approaches have accelerated progress in elucidating disease prediction, progression, and outcome. Applied to the spectrum of states spanning health and disease, network proteomics establishes a collation, integration, and prioritization algorithm to guide mapping and decoding of proteome landscapes from large-scale raw data. Providing unparalleled deconvolution of protein lists into global interactomes, integrative systems proteomics enables objective, multi-modal interpretation at molecular, pathway, and network scales, merging individual molecular components, their plurality of interactions, and functional contributions for systems comprehension. As such, network systems approaches are increasingly exploited for objective interpretation of cardiovascular proteomics studies. Here, we highlight network systems proteomic analysis pipelines for integration and biological interpretation through protein cartography, ontological categorization, pathway and functional enrichment and complex network analysis. PMID:22896016

Autophagy and genomic integrity

PubMed Central

Vessoni, A T; Filippi-Chiela, E C; Menck, C FM; Lenz, G

2013-01-01

DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress. PMID:23933813

A novel method to identify hub pathways of rheumatoid arthritis based on differential pathway networks.

PubMed

Wei, Shi-Tong; Sun, Yong-Hua; Zong, Shi-Hua

2017-09-01

The aim of the current study was to identify hub pathways of rheumatoid arthritis (RA) using a novel method based on differential pathway network (DPN) analysis. The present study proposed a DPN where protein‑protein interaction (PPI) network was integrated with pathway‑pathway interactions. Pathway data was obtained from background PPI network and the Reactome pathway database. Subsequently, pathway interactions were extracted from the pathway data by building randomized gene‑gene interactions and a weight value was assigned to each pathway interaction using Spearman correlation coefficient (SCC) to identify differential pathway interactions. Differential pathway interactions were visualized using Cytoscape to construct a DPN. Topological analysis was conducted to identify hub pathways that possessed the top 5% degree distribution of DPN. Modules of DPN were mined according to ClusterONE. A total of 855 pathways were selected to build pathway interactions. By filtrating pathway interactions of weight values >0.7, a DPN with 312 nodes and 791 edges was obtained. Topological degree analysis revealed 15 hub pathways, such as heparan sulfate/heparin‑glycosaminoglycan (HS‑GAG) degradation, HS‑GAG metabolism and keratan sulfate degradation for RA based on DPN. Furthermore, hub pathways were also important in modules, which validated the significance of hub pathways. In conclusion, the proposed method is a computationally efficient way to identify hub pathways of RA, which identified 15 hub pathways that may be potential biomarkers and provide insight to future investigation and treatment of RA.

ChlamyCyc: an integrative systems biology database and web-portal for Chlamydomonas reinhardtii.

PubMed

May, Patrick; Christian, Jan-Ole; Kempa, Stefan; Walther, Dirk

2009-05-04

The unicellular green alga Chlamydomonas reinhardtii is an important eukaryotic model organism for the study of photosynthesis and plant growth. In the era of modern high-throughput technologies there is an imperative need to integrate large-scale data sets from high-throughput experimental techniques using computational methods and database resources to provide comprehensive information about the molecular and cellular organization of a single organism. In the framework of the German Systems Biology initiative GoFORSYS, a pathway database and web-portal for Chlamydomonas (ChlamyCyc) was established, which currently features about 250 metabolic pathways with associated genes, enzymes, and compound information. ChlamyCyc was assembled using an integrative approach combining the recently published genome sequence, bioinformatics methods, and experimental data from metabolomics and proteomics experiments. We analyzed and integrated a combination of primary and secondary database resources, such as existing genome annotations from JGI, EST collections, orthology information, and MapMan classification. ChlamyCyc provides a curated and integrated systems biology repository that will enable and assist in systematic studies of fundamental cellular processes in Chlamydomonas. The ChlamyCyc database and web-portal is freely available under http://chlamycyc.mpimp-golm.mpg.de.

Integrating Disciplinary Core Ideas, the Agriculture, Food and Natural Resources Career Pathways and Next Generation Science Standards

ERIC Educational Resources Information Center

Kirby, Barrick R.; Heinert, Seth B.; Myers, Brian E.; Thoron, Andrew C.; Stofer, Kathryn

2018-01-01

The purpose of this study was to identify disciplinary core ideas that should be included in secondary school agriscience programs using a panel of experts in agricultural education, and to create a matrix of disciplinary core ideas, Agriculture, Food and Natural Resources career pathways performance indicators, and the Next Generation Science…

Differential genomic effects on canonical signaling pathways by two different CeO2 nanoparticles in HepG2 cells

EPA Science Inventory

Differential genomic effects on signaling pathways by two different CeO2 nanoparticles in HepG2 cells. Sheau-Fung Thai1, Kathleen A. Wallace1, Carlton P. Jones1, Hongzu Ren2, Benjamin T. Castellon1, James Crooks2, Kirk T. Kitchin1. 1Integrated Systems Toxicology Divison, 2Resea...

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants.

PubMed

Samanta, Subhasis; Thakur, Jitendra K

2015-01-01

Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes.

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants

PubMed Central

Samanta, Subhasis; Thakur, Jitendra K.

2015-01-01

Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes. PMID:26442070

PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3.

PubMed

Remy, Ingrid; Montmarquette, Annie; Michnick, Stephen W

2004-04-01

Transforming growth factor beta (TGF-beta) has a major role in cell proliferation, differentiation and apoptosis in many cell types. Integration of the TGF-beta pathway with other signalling cascades that control the same cellular processes may modulate TGF-beta responses. Here we report the discovery of a new functional link between TGF-beta and growth factor signalling pathways, mediated by a physical interaction between the serine-threonine kinase PKB (protein kinase B)/Akt and the transcriptional activator Smad3. Formation of the complex is induced by insulin, but inhibited by TGF-beta stimulation, placing PKB-Smad3 at a point of convergence between these two pathways. PKB inhibits Smad3 by preventing its phosphorylation, binding to Smad4 and nuclear translocation. In contrast, Smad3 does not inhibit PKB. Inhibition of Smad3 by PKB occurs through a kinase-activity-independent mechanism, resulting in a decrease in Smad3-mediated transcription and protection of cells against TGF-beta-induced apoptosis. Consistently, knockdown of the endogenous PKB gene with small-interfering RNA (siRNA) has the opposite effect. Our results suggest a very simple mechanism for the integration of signals arising from growth-factor- and TGF-beta-mediated pathways.

Radiogenomics: a systems biology approach to understanding genetic risk factors for radiotherapy toxicity ?

PubMed Central

Herskind, Carsten; Talbot, Christopher J.; Kerns, Sarah L.; Veldwijk, Marlon R.; Rosenstein, Barry S.; West, Catharine M. L.

2016-01-01

Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review ‘omics’ approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different ‘omics’ approaches may be more efficient in identifying critical pathways than pathway analysis based on single ‘omics’ data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterized by different mechanisms. Thus ‘omics’ and functional approaches may synergize if they are integrated into radiogenomics ‘systems biology’ to facilitate the goal of individualised radiotherapy. PMID:26944314

Integrated palliative care is about professional networking rather than standardisation of care: A qualitative study with healthcare professionals in 19 integrated palliative care initiatives in five European countries

PubMed Central

den Herder-van der Eerden, Marlieke; van Wijngaarden, Jeroen; Preston, Nancy; Linge-Dahl, Lisa; Radbruch, Lukas; Van Beek, Karen; Menten, Johan; Busa, Csilla; Csikos, Agnes; Vissers, Kris; van Gurp, Jelle; Hasselaar, Jeroen

2018-01-01

Background: Integrated palliative care aims at improving coordination of palliative care services around patients’ anticipated needs. However, international comparisons of how integrated palliative care is implemented across four key domains of integrated care (content of care, patient flow, information logistics and availability of (human) resources and material) are lacking. Aim: To examine how integrated palliative care takes shape in practice across abovementioned key domains within several integrated palliative care initiatives in Europe. Design: Qualitative group interview design. Setting/participants: A total of 19 group interviews were conducted (2 in Belgium, 4 in the Netherlands, 4 in the United Kingdom, 4 in Germany and 5 in Hungary) with 142 healthcare professionals from several integrated palliative care initiatives in five European countries. The majority were nurses (n = 66; 46%) and physicians (n = 50; 35%). Results: The dominant strategy for fostering integrated palliative care is building core teams of palliative care specialists and extended professional networks based on personal relationships, shared norms, values and mutual trust, rather than developing standardised information exchange and referral pathways. Providing integrated palliative care with healthcare professionals in the wider professional community appears difficult, as a shared proactive multidisciplinary palliative care approach is lacking, and healthcare professionals often do not know palliative care professionals or services. Conclusion: Achieving better palliative care integration into regular healthcare and convincing the wider professional community is a difficult task that will take time and effort. Enhancing standardisation of palliative care into education, referral pathways and guidelines and standardised information exchange may be necessary. External authority (policy makers, insurance companies and professional bodies) may be needed to support integrated palliative care practices across settings. PMID:29436279

Host factors that promote retrotransposon integration are similar in distantly related eukaryotes

PubMed Central

Rai, Sudhir Kumar; Sangesland, Maya; Lee, Michael; Esnault, Caroline; Cui, Yujin; Chatterjee, Atreyi Ghatak

2017-01-01

Retroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the selection of integration sites associated with promoters. The LTR-retrotransposon Tf1 of Schizosaccharomyces pombe is studied as a model for oncogenic retroviruses because it integrates into the promoters of stress response genes. Although integrases (INs) encoded by retroviruses and LTR-retrotransposons are responsible for catalyzing the insertion of cDNA into the host genome, it is thought that distinct host factors are required for the efficiency and specificity of integration. We tested this hypothesis with a genome-wide screen of host factors that promote Tf1 integration. By combining an assay for transposition with a genetic assay that measures cDNA recombination we could identify factors that contribute differentially to integration. We utilized this assay to test a collection of 3,004 S. pombe strains with single gene deletions. Using these screens and immunoblot measures of Tf1 proteins, we identified a total of 61 genes that promote integration. The candidate integration factors participate in a range of processes including nuclear transport, transcription, mRNA processing, vesicle transport, chromatin structure and DNA repair. Two candidates, Rhp18 and the NineTeen complex were tested in two-hybrid assays and were found to interact with Tf1 IN. Surprisingly, a number of pathways we identified were found previously to promote integration of the LTR-retrotransposons Ty1 and Ty3 in Saccharomyces cerevisiae, indicating the contribution of host factors to integration are common in distantly related organisms. The DNA repair factors are of particular interest because they may identify the pathways that repair the single stranded gaps flanking the sites of strand transfer following integration of LTR retroelements. PMID:29232693

Host factors that promote retrotransposon integration are similar in distantly related eukaryotes.

PubMed

Rai, Sudhir Kumar; Sangesland, Maya; Lee, Michael; Esnault, Caroline; Cui, Yujin; Chatterjee, Atreyi Ghatak; Levin, Henry L

2017-12-01

Retroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the selection of integration sites associated with promoters. The LTR-retrotransposon Tf1 of Schizosaccharomyces pombe is studied as a model for oncogenic retroviruses because it integrates into the promoters of stress response genes. Although integrases (INs) encoded by retroviruses and LTR-retrotransposons are responsible for catalyzing the insertion of cDNA into the host genome, it is thought that distinct host factors are required for the efficiency and specificity of integration. We tested this hypothesis with a genome-wide screen of host factors that promote Tf1 integration. By combining an assay for transposition with a genetic assay that measures cDNA recombination we could identify factors that contribute differentially to integration. We utilized this assay to test a collection of 3,004 S. pombe strains with single gene deletions. Using these screens and immunoblot measures of Tf1 proteins, we identified a total of 61 genes that promote integration. The candidate integration factors participate in a range of processes including nuclear transport, transcription, mRNA processing, vesicle transport, chromatin structure and DNA repair. Two candidates, Rhp18 and the NineTeen complex were tested in two-hybrid assays and were found to interact with Tf1 IN. Surprisingly, a number of pathways we identified were found previously to promote integration of the LTR-retrotransposons Ty1 and Ty3 in Saccharomyces cerevisiae, indicating the contribution of host factors to integration are common in distantly related organisms. The DNA repair factors are of particular interest because they may identify the pathways that repair the single stranded gaps flanking the sites of strand transfer following integration of LTR retroelements.

Integrated palliative care is about professional networking rather than standardisation of care: A qualitative study with healthcare professionals in 19 integrated palliative care initiatives in five European countries.

PubMed

den Herder-van der Eerden, Marlieke; van Wijngaarden, Jeroen; Payne, Sheila; Preston, Nancy; Linge-Dahl, Lisa; Radbruch, Lukas; Van Beek, Karen; Menten, Johan; Busa, Csilla; Csikos, Agnes; Vissers, Kris; van Gurp, Jelle; Hasselaar, Jeroen

2018-06-01

Integrated palliative care aims at improving coordination of palliative care services around patients' anticipated needs. However, international comparisons of how integrated palliative care is implemented across four key domains of integrated care (content of care, patient flow, information logistics and availability of (human) resources and material) are lacking. To examine how integrated palliative care takes shape in practice across abovementioned key domains within several integrated palliative care initiatives in Europe. Qualitative group interview design. A total of 19 group interviews were conducted (2 in Belgium, 4 in the Netherlands, 4 in the United Kingdom, 4 in Germany and 5 in Hungary) with 142 healthcare professionals from several integrated palliative care initiatives in five European countries. The majority were nurses ( n = 66; 46%) and physicians ( n = 50; 35%). The dominant strategy for fostering integrated palliative care is building core teams of palliative care specialists and extended professional networks based on personal relationships, shared norms, values and mutual trust, rather than developing standardised information exchange and referral pathways. Providing integrated palliative care with healthcare professionals in the wider professional community appears difficult, as a shared proactive multidisciplinary palliative care approach is lacking, and healthcare professionals often do not know palliative care professionals or services. Achieving better palliative care integration into regular healthcare and convincing the wider professional community is a difficult task that will take time and effort. Enhancing standardisation of palliative care into education, referral pathways and guidelines and standardised information exchange may be necessary. External authority (policy makers, insurance companies and professional bodies) may be needed to support integrated palliative care practices across settings.

Common genetic variants related to genomic integrity and risk of papillary thyroid cancer

PubMed Central

Neta, Gila; Brenner, Alina V.; Sturgis, Erich M.; Pfeiffer, Ruth M.; Hutchinson, Amy A.; Aschebrook-Kilfoy, Briseis; Yeager, Meredith; Xu, Li; Wheeler, William; Abend, Michael; Ron, Elaine; Tucker, Margaret A.; Chanock, Stephen J.; Sigurdson, Alice J.

2011-01-01

DNA damage is an important mechanism in carcinogenesis, so genes related to maintaining genomic integrity may influence papillary thyroid cancer (PTC) risk. Candidate gene studies targeting some of these genes have identified only a few polymorphisms associated with risk of PTC. Here, we expanded the scope of previous candidate studies by increasing the number and coverage of genes related to maintenance of genomic integrity. We evaluated 5077 tag single-nucleotide polymorphisms (SNPs) from 340 candidate gene regions hypothesized to be involved in DNA repair, epigenetics, tumor suppression, apoptosis, telomere function and cell cycle control and signaling pathways in a case–control study of 344 PTC cases and 452 matched controls. We estimated odds ratios for associations of single SNPs with PTC risk and combined P values for SNPs in the same gene region or pathway to obtain gene region-specific or pathway-specific P values using adaptive rank-truncated product methods. Nine SNPs had P values <0.0005, three of which were in HDAC4 and were inversely related to PTC risk. After multiple comparisons adjustment, no SNPs remained associated with PTC risk. Seven gene regions were associated with PTC risk at P < 0.01, including HUS1, ALKBH3, HDAC4, BAK1, FAF1_CDKN2C, DACT3 and FZD6. Our results suggest a possible role of genes involved in maintenance of genomic integrity in relation to risk of PTC. PMID:21642358

Destruction of white matter integrity in patients with mild cognitive impairment and Alzheimer disease.

PubMed

Sun, Xiaoyan; Salat, David; Upchurch, Kristen; Deason, Rebecca; Kowall, Neil; Budson, Andrew

2014-10-01

Accumulating evidence shows that gradual loss of white matter integrity plays an important role in the development of Alzheimer disease (AD). The aim of this research was to study the microstructural integrity of white matter in AD in vivo. Global fractional anisotropy, global axial diffusivity (AxD), and global radial diffusivity (RD) were analyzed in subjects with normal controls (NC), mild cognitive impairment (MCI), and AD using Alzheimer's Disease Neuroimaging Initiative data (total N = 210). We further compared specific white matter tracts among the 3 groups. Compared with the NC group, the MCI group had significantly increased global AxD and global RD. Compared with the NC and MCI groups, the AD group had significantly decreased global fractional anisotropy, increased global AxD, and increased global RD. With regard to specific white matter tracts, in the MCI group, we found increased AxD and increased RD in the external capsule, part of the lateral cholinergic pathway, in addition to the tracts connecting the limbic regions, predominantly in the left hemisphere. In the AD group, white matter abnormalities were widespread, including in the external capsule (cholinergic pathway) and limbic region tracts as well as tracts connecting anterior to posterior regions bilaterally. The radiographic manifestation of damaged white matter microstructural integrity in the cholinergic pathway in MCI patients may provide a rational basis for the use of cholinesterase inhibitor drugs in the MCI stage of AD.

An integrated bioinformatics approach to improve two-color microarray quality-control: impact on biological conclusions.

PubMed

van Haaften, Rachel I M; Luceri, Cristina; van Erk, Arie; Evelo, Chris T A

2009-06-01

Omics technology used for large-scale measurements of gene expression is rapidly evolving. This work pointed out the need of an extensive bioinformatics analyses for array quality assessment before and after gene expression clustering and pathway analysis. A study focused on the effect of red wine polyphenols on rat colon mucosa was used to test the impact of quality control and normalisation steps on the biological conclusions. The integration of data visualization, pathway analysis and clustering revealed an artifact problem that was solved with an adapted normalisation. We propose a possible point to point standard analysis procedure, based on a combination of clustering and data visualization for the analysis of microarray data.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

PubMed

Juraeva, Dilafruz; Haenisch, Britta; Zapatka, Marc; Frank, Josef; Witt, Stephanie H; Mühleisen, Thomas W; Treutlein, Jens; Strohmaier, Jana; Meier, Sandra; Degenhardt, Franziska; Giegling, Ina; Ripke, Stephan; Leber, Markus; Lange, Christoph; Schulze, Thomas G; Mössner, Rainald; Nenadic, Igor; Sauer, Heinrich; Rujescu, Dan; Maier, Wolfgang; Børglum, Anders; Ophoff, Roel; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Mattheisen, Manuel; Brors, Benedikt

2014-06-01

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

FREQUENT SUBGRAPH MINING OF PERSONALIZED SIGNALING PATHWAY NETWORKS GROUPS PATIENTS WITH FREQUENTLY DYSREGULATED DISEASE PATHWAYS AND PREDICTS PROGNOSIS.

PubMed

Durmaz, Arda; Henderson, Tim A D; Brubaker, Douglas; Bebek, Gurkan

2017-01-01

Large scale genomics studies have generated comprehensive molecular characterization of numerous cancer types. Subtypes for many tumor types have been established; however, these classifications are based on molecular characteristics of a small gene sets with limited power to detect dysregulation at the patient level. We hypothesize that frequent graph mining of pathways to gather pathways functionally relevant to tumors can characterize tumor types and provide opportunities for personalized therapies. In this study we present an integrative omics approach to group patients based on their altered pathway characteristics and show prognostic differences within breast cancer (p < 9:57E - 10) and glioblastoma multiforme (p < 0:05) patients. We were able validate this approach in secondary RNA-Seq datasets with p < 0:05 and p < 0:01 respectively. We also performed pathway enrichment analysis to further investigate the biological relevance of dysregulated pathways. We compared our approach with network-based classifier algorithms and showed that our unsupervised approach generates more robust and biologically relevant clustering whereas previous approaches failed to report specific functions for similar patient groups or classify patients into prognostic groups. These results could serve as a means to improve prognosis for future cancer patients, and to provide opportunities for improved treatment options and personalized interventions. The proposed novel graph mining approach is able to integrate PPI networks with gene expression in a biologically sound approach and cluster patients in to clinically distinct groups. We have utilized breast cancer and glioblastoma multiforme datasets from microarray and RNA-Seq platforms and identified disease mechanisms differentiating samples. Supplementary methods, figures, tables and code are available at https://github.com/bebeklab/dysprog.

Representative Agricultural Pathways and Scenarios for Regional Integrated Assessment of Climate Change Impacts, Vulnerability, and Adaptation. 5; Chapter

NASA Technical Reports Server (NTRS)

Valdivia, Roberto O.; Antle, John M.; Rosenzweig, Cynthia; Ruane, Alexander C.; Vervoort, Joost; Ashfaq, Muhammad; Hathie, Ibrahima; Tui, Sabine Homann-Kee; Mulwa, Richard; Nhemachena, Charles;

MESSI: metabolic engineering target selection and best strain identification tool.

PubMed

Kang, Kang; Li, Jun; Lim, Boon Leong; Panagiotou, Gianni

2015-01-01

Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. © The Author(s) 2015. Published by Oxford University Press.

C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling.

PubMed

Reiner, David J; Ailion, Michael; Thomas, James H; Meyer, Barbara J

2008-08-05

Different environmental stimuli, including exposure to dauer pheromone, food deprivation, and high temperature, can induce C. elegans larvae to enter the dauer stage, a developmentally arrested diapause state. Although molecular and cellular pathways responsible for detecting dauer pheromone and temperature have been defined in part, other sensory inputs are poorly understood, as are the mechanisms by which these diverse sensory inputs are integrated to achieve a consistent developmental outcome. In this paper, we analyze a wild C. elegans strain isolated from a desert oasis. Unlike wild-type laboratory strains, the desert strain fails to respond to dauer pheromone at 25 degrees C, but it does respond at higher temperatures, suggesting a unique adaptation to the hot desert environment. We map this defect in dauer response to a mutation in the scd-2 gene, which, we show, encodes the nematode anaplastic lymphoma kinase (ALK) homolog, a proto-oncogene receptor tyrosine kinase. scd-2 acts in a genetic pathway shown here to include the HEN-1 ligand, the RTK adaptor SOC-1, and the MAP kinase SMA-5. The SCD-2 pathway modulates TGF-beta signaling, which mediates the response to dauer pheromone, but SCD-2 might mediate a nonpheromone sensory input, such as food. Our studies identify a new sensory pathway controlling dauer formation and shed light on ALK signaling, integration of signaling pathways, and adaptation to extreme environmental conditions.

The Nuclear Dbf2-Related Kinase COT1 and the Mitogen-Activated Protein Kinases MAK1 and MAK2 Genetically Interact to Regulate Filamentous Growth, Hyphal Fusion and Sexual Development in Neurospora crassa

PubMed Central

Maerz, Sabine; Ziv, Carmit; Vogt, Nico; Helmstaedt, Kerstin; Cohen, Nourit; Gorovits, Rena; Yarden, Oded; Seiler, Stephan

2008-01-01

Ndr kinases, such as Neurospora crassa COT1, are important for cell differentiation and polar morphogenesis, yet their input signals as well as their integration into a cellular signaling context are still elusive. Here, we identify the cot-1 suppressor gul-4 as mak-2 and show that mutants of the gul-4/mak-2 mitogen-activated protein (MAP) kinase pathway suppress cot-1 phenotypes along with a concomitant reduction in protein kinase A (PKA) activity. Furthermore, mak-2 pathway defects are partially overcome in a cot-1 background and are associated with increased MAK1 MAPK signaling. A comparative characterization of N. crassa MAPKs revealed that they act as three distinct modules during vegetative growth and asexual development. In addition, common functions of MAK1 and MAK2 signaling during maintenance of cell-wall integrity distinguished the two ERK-type pathways from the p38-type OS2 osmosensing pathway. In contrast to separate functions during vegetative growth, the concerted activity of the three MAPK pathways is essential for cell fusion and for the subsequent formation of multicellular structures that are required for sexual development. Taken together, our data indicate a functional link between COT1 and MAPK signaling in regulating filamentous growth, hyphal fusion, and sexual development. PMID:18562669

Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus

PubMed Central

Teixeira, Catia M.; Kron, Michelle M.; Masachs, Nuria; Zhang, Helen; Lagace, Diane C.; Martinez, Albert; Reillo, Isabel; Duan, Xin; Bosch, Carles; Pujadas, Lluis; Brunso, Lucas; Song, Hongjun; Eisch, Amelia J.; Borrell, Victor; Howell, Brian W.; Parent, Jack M.; Soriano, Eduardo

2012-01-01

Adult hippocampal neurogenesis is thought to be essential for learning and memory and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of disabled-1 (Dab1), an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain- and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. PMID:22933789

Pheromone-Induced Morphogenesis Improves Osmoadaptation Capacity by Activating the HOG MAPK Pathway**

PubMed Central

Baltanás, Rodrigo; Bush, Alan; Couto, Alicia; Durrieu, Lucía; Hohmann, Stefan; Colman-Lerner, Alejandro

2013-01-01

Environmental and internal conditions expose cells to a multiplicity of stimuli whose consequences are difficult to predict. Here, we investigate the response to mating pheromone of yeast cells adapted to high osmolarity. Events downstream of pheromone binding involve two mitogen-activated protein kinase (MAPK) cascades: the pheromone response (PR) and the cell-wall integrity response (CWI). Although these MAPK pathways share components with each and a third MAPK pathway, the high osmolarity response (HOG), they are normally only activated by distinct stimuli, a phenomenon called insulation. We found that in cells adapted to high osmolarity, PR activated the HOG pathway in a pheromone- and osmolarity- dependent manner. Activation of HOG by the PR was not due to loss of insulation, but rather a response to a reduction in internal osmolarity, which resulted from an increase in glycerol release caused by the PR. By analyzing single-cell time courses, we found that stimulation of HOG occurred in discrete bursts that coincided with the “shmooing” morphogenetic process. Activation required the polarisome, the cell wall integrity MAPK Slt2, and the aquaglyceroporin Fps1. HOG activation resulted in high glycerol turnover that improved adaptability to rapid changes in osmolarity. Our work shows how a differentiation signal can recruit a second, unrelated sensory pathway to enable responses to yeast to multiple stimuli. PMID:23612707

The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence.

PubMed

de Dios, Carmen Herrero; Román, Elvira; Monge, Rebeca Alonso; Pla, Jesús

2010-12-01

In recent years, Mitogen-Activated Protein Kinase (MAPK) pathways have emerged as major regulators of cellular physiology. In the fungal pathogen Candida albicans, three different MAPK pathways have been characterized in the last years. The HOG pathway is mainly a stress response pathway that is activated in response to osmotic and oxidative stress and also participates regulating other pathways. The SVG pathway (or mediated by the Cek1 MAPK) is involved in cell wall formation under vegetative and filamentous growth, while the Mkc1-mediated pathway is involved in cell wall integrity. Oxidative stress is one of the types of stress that every fungal cell has to face during colonization of the host, where the cell encounters both hypoxia niches (i.e. gut) and high concentrations of reactive oxygen species (upon challenge with immune cells). Two pathways have been shown to be activated in response to oxidative stress: the HOG pathway and the MKC1-mediated pathway while the third, the Cek1 pathway is deactivated. The timing, kinetics, stimuli and functional responses generated upon oxidative stress differ among them; however, they have essential functional consequences that severely influence pathogenesis. MAPK pathways are, therefore, valuable targets to be explored in antifungal research.

atBioNet--an integrated network analysis tool for genomics and biomarker discovery.

PubMed

Ding, Yijun; Chen, Minjun; Liu, Zhichao; Ding, Don; Ye, Yanbin; Zhang, Min; Kelly, Reagan; Guo, Li; Su, Zhenqiang; Harris, Stephen C; Qian, Feng; Ge, Weigong; Fang, Hong; Xu, Xiaowei; Tong, Weida

2012-07-20

Large amounts of mammalian protein-protein interaction (PPI) data have been generated and are available for public use. From a systems biology perspective, Proteins/genes interactions encode the key mechanisms distinguishing disease and health, and such mechanisms can be uncovered through network analysis. An effective network analysis tool should integrate different content-specific PPI databases into a comprehensive network format with a user-friendly platform to identify key functional modules/pathways and the underlying mechanisms of disease and toxicity. atBioNet integrates seven publicly available PPI databases into a network-specific knowledge base. Knowledge expansion is achieved by expanding a user supplied proteins/genes list with interactions from its integrated PPI network. The statistically significant functional modules are determined by applying a fast network-clustering algorithm (SCAN: a Structural Clustering Algorithm for Networks). The functional modules can be visualized either separately or together in the context of the whole network. Integration of pathway information enables enrichment analysis and assessment of the biological function of modules. Three case studies are presented using publicly available disease gene signatures as a basis to discover new biomarkers for acute leukemia, systemic lupus erythematosus, and breast cancer. The results demonstrated that atBioNet can not only identify functional modules and pathways related to the studied diseases, but this information can also be used to hypothesize novel biomarkers for future analysis. atBioNet is a free web-based network analysis tool that provides a systematic insight into proteins/genes interactions through examining significant functional modules. The identified functional modules are useful for determining underlying mechanisms of disease and biomarker discovery. It can be accessed at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm.

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study

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

Cochran, Jaquelin M.; Palchak, Joseph D; McBennett, Brendan

The higher-spatial-resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.' The Regional Study validates the relative value of mitigation strategies demonstrated in the National Study - namely, coordinatedmore » operations among states reduce production costs, and reducing coal minimum generation levels reduces RE curtailment. Significantly, the Regional Study also highlights a potential barrier to realizing the value of these mitigation strategies: when locations of RE development are planned independently of state-level transmission, intrastate congestion can result in undesirable levels of RE curtailment. Therefore a key objective of this study is to illustrate to state-level power system planners and operators, in particular, how a higher-resolution model, inclusive of intrastate granularity, can be used as a planning tool for two primary purposes: -To better anticipate, understand, and mitigate system constraints that could affect RE integration; and - To provide a modeling framework that can be used as part of future transmission studies and planning efforts. The Regional Study is not intended to predict precisely how RE will affect state-level operations. There is considerable uncertainty regarding the locations of the RE development, as well as how contract terms can affect access to the inherent physical flexibility of the system. But the scenarios analyzed identify the types of issues that can arise under various RE and transmission expansion pathways. The model developed for this study provides a rigorous framework for future work and can be updated with the characteristics of new capacity as more information on the future power system is known.« less

Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum

PubMed Central

2012-01-01

Background Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurable metabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. Conclusions The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner. PMID:22713133

Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum.

PubMed

Beisser, Daniela; Grohme, Markus A; Kopka, Joachim; Frohme, Marcus; Schill, Ralph O; Hengherr, Steffen; Dandekar, Thomas; Klau, Gunnar W; Dittrich, Marcus; Müller, Tobias

2012-06-19

Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurable metabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner.

Revealing pathways from payments for ecosystem services to socioeconomic outcomes

PubMed Central

Zhang, Jindong

2018-01-01

Payments for ecosystem services (PES) programs have been widely implemented as a promising tool to conserve ecosystems while facilitating socioeconomic development. However, the underlying pathways (or processes) through which PES programs affect socioeconomic outcomes remain elusive, and existing literature provides little guidance to quantify them. By integrating linkages among PES programs, livelihood activities, and socioeconomic outcomes, we develop a framework to reveal pathways from PES programs to socioeconomic outcomes. We empirically demonstrate the framework’s operationalization and uncover the pathways that lead to unexpected negative effects of two important PES programs on participating households’ income. With improved understanding of the pathways (for example, the programs decreased income through reducing crop production), we provide recommendations to enhance the PES programs’ outcomes in our demonstration site and beyond. Our study highlights the finding that elucidating the pathways from PES programs to their outcomes can help identify specific strategies to achieve ecosystem conservation and socioeconomic development simultaneously. PMID:29750187

Psychological Perspectives on Pathways Linking Socioeconomic Status and Physical Health

PubMed Central

Matthews, Karen A.; Gallo, Linda C.

2011-01-01

Low socioeconomic status (SES) is a reliable correlate of poor physical health. Rather than treat SES as a covariate, health psychology has increasingly focused on the psychobiological pathways that inform understanding why SES is related to physical health. This review assesses the status of research that has examined stress and its associated distress, and social and personal resources as pathways. It highlights work on biomarkers and biological pathways related to SES that can serve as intermediate outcomes in future studies. Recent emphasis on the accumulation of psychobiological risks across the life course is summarized and represents an important direction for future research. Studies that test pathways from SES to candidate psychosocial pathways to health outcomes are few in number but promising. Future research should test integrated models rather than taking piecemeal approaches to evidence. Much work remains to be done, but the questions are of great health significance. PMID:20636127

Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

PubMed Central

Le Sage, Valerie; Cinti, Alessandro; Amorim, Raquel; Mouland, Andrew J.

2016-01-01

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs. PMID:27231932

CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea

PubMed Central

Marraffini, Luciano A.; Sontheimer, Erik J.

2010-01-01

Sequence-directed genetic interference pathways control gene expression and preserve genome integrity in all kingdoms of life. The importance of such pathways is highlighted by the extensive study of RNA interference (RNAi) and related processes in eukaryotes. In many bacteria and most archaea, clustered, regularly interspaced short palindromic repeats (CRISPRs) are involved in a more recently discovered interference pathway that protects cells from bacteriophages and conjugative plasmids. CRISPR sequences provide an adaptive, heritable record of past infections and express CRISPR RNAs — small RNAs that target invasive nucleic acids. Here, we review the mechanisms of CRISPR interference and its roles in microbial physiology and evolution. We also discuss potential applications of this novel interference pathway. PMID:20125085

Anatomical Pathways Involved in Generating and Sensing Rhythmic Whisker Movements

PubMed Central

Bosman, Laurens W. J.; Houweling, Arthur R.; Owens, Cullen B.; Tanke, Nouk; Shevchouk, Olesya T.; Rahmati, Negah; Teunissen, Wouter H. T.; Ju, Chiheng; Gong, Wei; Koekkoek, Sebastiaan K. E.; De Zeeuw, Chris I.

2011-01-01

The rodent whisker system is widely used as a model system for investigating sensorimotor integration, neural mechanisms of complex cognitive tasks, neural development, and robotics. The whisker pathways to the barrel cortex have received considerable attention. However, many subcortical structures are paramount to the whisker system. They contribute to important processes, like filtering out salient features, integration with other senses, and adaptation of the whisker system to the general behavioral state of the animal. We present here an overview of the brain regions and their connections involved in the whisker system. We do not only describe the anatomy and functional roles of the cerebral cortex, but also those of subcortical structures like the striatum, superior colliculus, cerebellum, pontomedullary reticular formation, zona incerta, and anterior pretectal nucleus as well as those of level setting systems like the cholinergic, histaminergic, serotonergic, and noradrenergic pathways. We conclude by discussing how these brain regions may affect each other and how they together may control the precise timing of whisker movements and coordinate whisker perception. PMID:22065951

Quantifying ubiquitin signaling.

PubMed

Ordureau, Alban; Münch, Christian; Harper, J Wade

2015-05-21

Ubiquitin (UB)-driven signaling systems permeate biology, and are often integrated with other types of post-translational modifications (PTMs), including phosphorylation. Flux through such pathways is dictated by the fractional stoichiometry of distinct modifications and protein assemblies as well as the spatial organization of pathway components. Yet, we rarely understand the dynamics and stoichiometry of rate-limiting intermediates along a reaction trajectory. Here, we review how quantitative proteomic tools and enrichment strategies are being used to quantify UB-dependent signaling systems, and to integrate UB signaling with regulatory phosphorylation events, illustrated with the PINK1/PARKIN pathway. A key feature of ubiquitylation is that the identity of UB chain linkage types can control downstream processes. We also describe how proteomic and enzymological tools can be used to identify and quantify UB chain synthesis and linkage preferences. The emergence of sophisticated quantitative proteomic approaches will set a new standard for elucidating biochemical mechanisms of UB-driven signaling systems. Copyright © 2015 Elsevier Inc. All rights reserved.

Intracortical pathways mediate nonlinear fast oscillation (>200 Hz) interactions within rat barrel cortex.

PubMed

Staba, Richard J; Ard, Tyler D; Benison, Alexander M; Barth, Daniel S

2005-05-01

Whisker evoked fast oscillations (FOs; >200 Hz) within the rodent posteromedial barrel subfield are thought to reflect very rapid integration of multiwhisker stimuli, yet the pathways mediating FO interactions remain unclear and may involve interactions within thalamus and/or cortex. In the present study using anesthetized rats, a cortical incision was made between sites representing the stimulated whiskers to determine how intracortical networks contributed to patterns of FOs. With cortex intact, simultaneous stimulation of a pair of whiskers aligned in a row evoked supralinear responses between sites separated by several millimeters. In contrast, stimulation of a nonadjacent pair of whiskers within an arc evoked FOs with no evidence for nonlinear interactions. However, stimulation of an adjacent pair of whiskers in an arc did evoke supralinear responses. After a cortical cut, supralinear interactions associated with FOs within a row were lost. These data indicate a distinct bias for stronger long-range connectivity that extends along barrel rows and that horizontal intracortical pathways exclusively mediate FO-related integration of tactile information.

Managing care pathways combining SNOMED CT, archetypes and an electronic guideline system.

PubMed

Bernstein, Knut; Andersen, Ulrich

2008-01-01

Today electronic clinical guideline systems exist, but they are not well integrated with electronic health records. This paper thus proposes that the patient's "position" in the pathway during the patient journey should be made visible to all involved healthcare parties and the patient. This requires that the generic knowledge, which is represented in the guidelines, is combined with the patient specific information - and then made accessible for all relevant parties. In addition to the decision support provided by the guideline system documentation support can be provided by templates based on archetypes. This paper provides a proposal for how the guideline system and the EHR can be integrated by the use of archetypes and SNOMED CT. SNOMED CT provides the common reference terminology and the semantic links between the systems. The proposal also includes the use of a National Patient Index for storing data about the patient's position in the pathway and for sharing this information by all involved parties.

Electronic Implementation of Integrated End-of-life Care: A Local Approach

PubMed Central

Schlieper, Daniel; Altreuther, Christiane; Schallenburger, Manuela; Neukirchen, Martin; Schmitz, Andrea

2017-01-01

Introduction: The Liverpool Care Pathway for the Dying Patient is an instrument to deliver integrated care for patients in their last hours of life. Originally a paper-based system, this study investigates the feasibility of an electronic version. Methods: An electronic Liverpool Care Pathway was implemented in a specialized palliative care unit of a German university hospital. Its use is exemplified by means of auditing and analysis of the proportion of recorded items. Results: In the years 2013 and 2014 the electronic Liverpool Care Pathway was used for the care of 159 patients. The uptake of the instrument was high (67%). Most items were recorded. Apart from a high usability, the fast data retrieval allows fast analysis for auditing and research. Conclusions and discussion: The electronic instrument is feasible in a computerized ward and has strong advantages for retrospective analysis. Trial registration: Internal Clinical Trial Register of the Medical Faculty, Heinrich Heine University Düsseldorf, No. 2015124683 (7 December 2015). PMID:28970746

New strategy for drug discovery by large-scale association analysis of molecular networks of different species.

PubMed

Zhang, Bo; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Wu, Ziyin; Zhang, Wenjuan; Yang, Xiaoyan; Gong, Fukai; Li, Yuerong; Chen, Xiaoyu; Gao, Shuo; Chen, Xuetong; Li, Yan; Lu, Aiping; Wang, Yonghua

2016-02-25

The development of modern omics technology has not significantly improved the efficiency of drug development. Rather precise and targeted drug discovery remains unsolved. Here a large-scale cross-species molecular network association (CSMNA) approach for targeted drug screening from natural sources is presented. The algorithm integrates molecular network omics data from humans and 267 plants and microbes, establishing the biological relationships between them and extracting evolutionarily convergent chemicals. This technique allows the researcher to assess targeted drugs for specific human diseases based on specific plant or microbe pathways. In a perspective validation, connections between the plant Halliwell-Asada (HA) cycle and the human Nrf2-ARE pathway were verified and the manner by which the HA cycle molecules act on the human Nrf2-ARE pathway as antioxidants was determined. This shows the potential applicability of this approach in drug discovery. The current method integrates disparate evolutionary species into chemico-biologically coherent circuits, suggesting a new cross-species omics analysis strategy for rational drug development.

The first president's pathway into ESTSS: memories and ideas for future issue. Patients as partners.

PubMed

Van der Schrieck-De Loos, Erica M

2013-01-01

This article addresses Wolter De Loos' pathway into ESTSS that ended on 6th January 2004. His footsteps are still printed in the field of psychotraumatology as he showed the field how a physician was trying to integrate his working field with that of psychiatry, with a great passion for his patients. Erica M. Van der Schrieck-De Loos outlines the perspectives of her father as funding president of the ESTSS by using his Opening Address of the Fourth ESTSS Conference in 1995. This address emphasized that the mixture of righteousness and offence in warfare is ubiquitious and everlasting. The perspective of the first president's pathway has been integrated with the current vision of the author to show that the patient can be a partner of the healthcare team. A suggestion for ESTSS main objective number (8), contained within the ESTSS mission statement, is to involve patients as partners of the traumatic stress care team into accelerating traumatic stress care across Europe and beyond.

Genetic and environmental pathways to complex diseases.

PubMed

Gohlke, Julia M; Thomas, Reuben; Zhang, Yonqing; Rosenstein, Michael C; Davis, Allan P; Murphy, Cynthia; Becker, Kevin G; Mattingly, Carolyn J; Portier, Christopher J

2009-05-05

Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches. Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes. Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

PubMed Central

Chiappelli, Joshua; Postolache, Teodor T; Kochunov, Peter; Rowland, Laura M; Wijtenburg, S Andrea; Shukla, Dinesh K; Tagamets, Malle; Du, Xiaoming; Savransky, Anya; Lowry, Christopher A; Can, Adem; Fuchs, Dietmar; Hong, L Elliot

2016-01-01

Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and 1H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (p<0.001), and kynurenine/tryptophan ratios were correspondingly higher (p=0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r=0.347, p=0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r=−0.391 and −0.350 respectively, p=0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia. PMID:27143602

A tiered approach for integrating exposure and dosimetry with ...

EPA Pesticide Factsheets

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The chemical-agnostic Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which pathway-based data can be arranged to aid in the understanding of in vitro toxicity testing results. In addition, risk estimation also requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with concentrations that trigger a molecular initiating event (MIE) at the relevant biological target in vivo. Such target site exposures (TSEs) can be estimated using computational models to integrate exposure information with a chemical’s absorption, distribution, metabolism, and elimination (ADME) processes. In this presentation, the utility of a tiered approach for integrating exposure, ADME, and hazard into risk-based decision making will be demonstrated using several case studies, along with the investigation of how uncertainties in exposure and ADME might impact risk estimates. These case studies involve 1) identifying and prioritizing chemicals capable of altering biological pathways based on their potential to reach an in vivo target; 2) evaluating the infl

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis.

PubMed

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-07-14

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis.

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis

PubMed Central

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-01-01

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis. PMID:27411928

The Cost-Effectiveness of the Integration of Nalmefene within the UK Healthcare System Treatment Pathway for Alcohol Dependence.

PubMed

Laramée, Philippe; Bell, Melissa; Irving, Adam; Brodtkorb, Thor-Henrik

2016-05-01

To assess the cost-effectiveness of integrating nalmefene within the treatment pathway for alcohol dependence recommended by the National Institute for Health and Care Excellence in the UK. A Markov model, taking a UK NHS perspective, followed a cohort with alcohol dependence and high/very high drinking risk levels (HVHDRLs), who do not require immediate detoxification and who continue at HVHDRLs after initial assessment, for 5 years. Costs and quality-adjusted life years (QALYs) from treatment with nalmefene plus psychosocial support versus psychosocial support alone were modelled. The consequent incidence of alcohol-attributable harmful events and disease progression, with the possibility of requiring other options or recurrent treatment, were captured. Nalmefene plus psychosocial support dominated psychosocial support alone, with lower costs and increased QALYs after 5 years. Savings are driven by the higher response to nalmefene, and the subsequent lower cost accumulation for alternatives. Nalmefene represents a highly cost-effective treatment option in this population. The analysis shows that integrating nalmefene within the current UK clinical treatment pathway for alcohol dependence could reduce the economic burden on the NHS by limiting harmful events and disease progression. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics.

PubMed

Wilmes, Anja; Bielow, Chris; Ranninger, Christina; Bellwon, Patricia; Aschauer, Lydia; Limonciel, Alice; Chassaigne, Hubert; Kristl, Theresa; Aiche, Stephan; Huber, Christian G; Guillou, Claude; Hewitt, Philipp; Leonard, Martin O; Dekant, Wolfgang; Bois, Frederic; Jennings, Paul

2015-12-25

Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 μM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation Mining: Integrating Text Mining and Bibliometrics for Research User Profiling.

ERIC Educational Resources Information Center

Kostoff, Ronald N.; del Rio, J. Antonio; Humenik, James A.; Garcia, Esther Ofilia; Ramirez, Ana Maria

2001-01-01

Discusses the importance of identifying the users and impact of research, and describes an approach for identifying the pathways through which research can impact other research, technology development, and applications. Describes a study that used citation mining, an integration of citation bibliometrics and text mining, on articles from the…

Integrative Metabolism: An Interactive Learning Tool for Nutrition, Biochemistry, and Physiology

ERIC Educational Resources Information Center

Carey, Gale

2010-01-01

Metabolism is a dynamic, simultaneous, and integrative science that cuts across nutrition, biochemistry, and physiology. Teaching this science can be a challenge. The use of a scenario-based, visually appealing, interactive, computer-animated CD may overcome the limitations of learning "one pathway at a time" and engage two- and…

Temperamental, Parental, and Contextual Contributors to Early-Emerging Internalizing Problems: A New Integrative Analysis Approach

ERIC Educational Resources Information Center

Mills, Rosemary S. L.; Hastings, Paul D.; Helm, Jonathan; Serbin, Lisa A.; Etezadi, Jamshid; Stack, Dale M.; Schwartzman, Alex E.; Li, Hai Hong

2012-01-01

This study evaluated a comprehensive model of factors associated with internalizing problems (IP) in early childhood, hypothesizing direct, mediated, and moderated pathways linking child temperamental inhibition, maternal overcontrol and rejection, and contextual stressors to IP. In a novel approach, three samples were integrated to form a large…

Pathways of Knowing: Integrating Citizen Science and Critical Thinking in the Adult ELL Classroom

ERIC Educational Resources Information Center

Basham, Melody

2012-01-01

This action research study examines what common perceptions and constructs currently exist in educating adult immigrants in Arizona and considers how might the integration of citizen science with the current English curriculum promote higher order thinking and educational equity in this population. A citizen science project called the Mastodon…

Role for ribosome-associated complex and stress-seventy subfamily B (RAC-Ssb) in integral membrane protein translation.

PubMed

Acosta-Sampson, Ligia; Döring, Kristina; Lin, Yuping; Yu, Vivian Y; Bukau, Bernd; Kramer, Günter; Cate, Jamie H D

2017-12-01

Targeting of most integral membrane proteins to the endoplasmic reticulum is controlled by the signal recognition particle, which recognizes a hydrophobic signal sequence near the protein N terminus. Proper folding of these proteins is monitored by the unfolded protein response and involves protein degradation pathways to ensure quality control. Here, we identify a new pathway for quality control of major facilitator superfamily transporters that occurs before the first transmembrane helix, the signal sequence recognized by the signal recognition particle, is made by the ribosome. Increased rates of translation elongation of the N-terminal sequence of these integral membrane proteins can divert the nascent protein chains to the ribosome-associated complex and stress-seventy subfamily B chaperones. We also show that quality control of integral membrane proteins by ribosome-associated complex-stress-seventy subfamily B couples translation rate to the unfolded protein response, which has implications for understanding mechanisms underlying human disease and protein production in biotechnology. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

A qualitative study of the perspectives of key stakeholders on the delivery of clinical academic training in the East Midlands

PubMed Central

Evans, Val; MacLeod, Sheona

2018-01-01

Objective Major changes in the design and delivery of clinical academic training in the United Kingdom have occurred yet there has been little exploration of the perceptions of integrated clinic academic trainees or educators. We obtained the views of a range of key stakeholders involved in clinical academic training in the East Midlands. Design A qualitative study with inductive iterative thematic content analysis of findings from trainee surveys and facilitated focus groups. Setting The East Midlands School of Clinical Academic Training. Participants Integrated Clinical Academic Trainees, clinical and academic educators involved in clinical academic training. Main outcome measures The experience, opinions and beliefs of key stakeholders about barriers and enablers in the delivery of clinical academic training. Results We identified key themes many shared by both trainees and educators. These highlighted issues in the systems and process of the integrated academic pathways, career pathways, supervision and support, the assessment process and the balance between clinical and academic training. Conclusions Our findings help inform the future development of integrated academic training programmes. PMID:29487745

Network analyses based on comprehensive molecular interaction maps reveal robust control structures in yeast stress response pathways

PubMed Central

Kawakami, Eiryo; Singh, Vivek K; Matsubara, Kazuko; Ishii, Takashi; Matsuoka, Yukiko; Hase, Takeshi; Kulkarni, Priya; Siddiqui, Kenaz; Kodilkar, Janhavi; Danve, Nitisha; Subramanian, Indhupriya; Katoh, Manami; Shimizu-Yoshida, Yuki; Ghosh, Samik; Jere, Abhay; Kitano, Hiroaki

2016-01-01

Cellular stress responses require exquisite coordination between intracellular signaling molecules to integrate multiple stimuli and actuate specific cellular behaviors. Deciphering the web of complex interactions underlying stress responses is a key challenge in understanding robust biological systems and has the potential to lead to the discovery of targeted therapeutics for diseases triggered by dysregulation of stress response pathways. We constructed large-scale molecular interaction maps of six major stress response pathways in Saccharomyces cerevisiae (baker’s or budding yeast). Biological findings from over 900 publications were converted into standardized graphical formats and integrated into a common framework. The maps are posted at http://www.yeast-maps.org/yeast-stress-response/ for browse and curation by the research community. On the basis of these maps, we undertook systematic analyses to unravel the underlying architecture of the networks. A series of network analyses revealed that yeast stress response pathways are organized in bow–tie structures, which have been proposed as universal sub-systems for robust biological regulation. Furthermore, we demonstrated a potential role for complexes in stabilizing the conserved core molecules of bow–tie structures. Specifically, complex-mediated reversible reactions, identified by network motif analyses, appeared to have an important role in buffering the concentration and activity of these core molecules. We propose complex-mediated reactions as a key mechanism mediating robust regulation of the yeast stress response. Thus, our comprehensive molecular interaction maps provide not only an integrated knowledge base, but also a platform for systematic network analyses to elucidate the underlying architecture in complex biological systems. PMID:28725465

Concentrating Solar Power Gen3 Demonstration Roadmap

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

Mehos, Mark; Turchi, Craig; Vidal, Judith

Today's power-tower concentrating solar power (CSP) technology exists in large part as a result of Department of Energy (DOE) and utility industry funding of demonstration systems in the 1980s and 1990s. Today's most advanced towers are integrated with molten-salt thermal energy storage, delivering thermal energy at 565 degrees C for integration with conventional steam-Rankine cycles. The supercritical carbon dioxide power cycle has been identified as a likely successor to the steam-Rankine power cycle due to its potential for high efficiency when operating at elevated temperatures of 700 degrees C or greater. Over the course of the SunShot Initiative, DOE hasmore » supported a number of technology pathways that can operate efficiently at these temperatures and that hold promise to be reliable and cost effective. Three pathways - molten salt, particle, and gaseous - were selected for further investigation based on a two-day workshop held in August of 2016. The information contained in this roadmap identifies research and development challenges and lays out recommended research activities for each of the three pathways. DOE foresees that by successfully addressing the challenges identified in this roadmap, one or more technology pathways will be positioned for demonstration and subsequent commercialization within the next ten years. Based on current knowledge of the three power tower technologies, all three have the potential to achieve the SunShot goal of 6 cents/kilowatt-hour. Further development, modeling, and testing are now required to bring one or more of the technologies to a stage where integrated system tests and pilot demonstrations are feasible.« less

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

PubMed

Kusko, Rebecca L; Brothers, John F; Tedrow, John; Pandit, Kusum; Huleihel, Luai; Perdomo, Catalina; Liu, Gang; Juan-Guardela, Brenda; Kass, Daniel; Zhang, Sherry; Lenburg, Marc; Martinez, Fernando; Quackenbush, John; Sciurba, Frank; Limper, Andrew; Geraci, Mark; Yang, Ivana; Schwartz, David A; Beane, Jennifer; Spira, Avrum; Kaminski, Naftali

2016-10-15

Despite shared environmental exposures, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease are usually studied in isolation, and the presence of shared molecular mechanisms is unknown. We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and IPF. We defined the transcriptional repertoire of chronic obstructive pulmonary disease, IPF, or normal histology lungs using RNA-seq (n = 87). Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n = 193). Immunohistochemistry confirmed overexpression of HIF1A, MDM2, and NFKBIB members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/hypoxia pathway-associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared with control and validated these findings by quantitative polymerase chain reaction and the nCounter Analysis System on an independent sample set (n = 193). Finally, by integrating parallel microRNA and mRNA-Seq data on the same samples, we identified MIR96 as a key novel regulatory hub in the p53/hypoxia gene-expression network and confirmed that modulation of MIR96 in vitro recapitulates the disease-associated gene-expression network. Our results suggest convergent transcriptional regulatory hubs in diseases as varied phenotypically as chronic obstructive pulmonary disease and IPF and suggest that these hubs may represent shared key responses of the lung to environmental stresses.

Modeling Signaling Networks to Advance New Cancer Therapies.

PubMed

Saez-Rodriguez, Julio; MacNamara, Aidan; Cook, Simon

2015-01-01

Cell signaling pathways control cells' responses to their environment through an intricate network of proteins and small molecules partitioned by intracellular structures, such as the cytoskeleton and nucleus. Our understanding of these pathways has been revised recently with the advent of more advanced experimental techniques; no longer are signaling pathways viewed as linear cascades of information flowing from membrane-bound receptors to the nucleus. Instead, such pathways must be understood in the context of networks, and studying such networks requires an integration of computational and experimental approaches. This understanding is becoming more important in designing novel therapies for diseases such as cancer. Using the MAPK (mitogen-activated protein kinase) and PI3K (class I phosphoinositide-3' kinase) pathways as case studies of cellular signaling, we give an overview of these pathways and their functions. We then describe, using a number of case studies, how computational modeling has aided in understanding these pathways' deregulation in cancer, and how such understanding can be used to optimally tailor current therapies or help design new therapies against cancer.

Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.

PubMed

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre F R; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2015-07-01

Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. © 2015 American Heart Association, Inc.

1-CMDb: A Curated Database of Genomic Variations of the One-Carbon Metabolism Pathway.

PubMed

Bhat, Manoj K; Gadekar, Veerendra P; Jain, Aditya; Paul, Bobby; Rai, Padmalatha S; Satyamoorthy, Kapaettu

2017-01-01

The one-carbon metabolism pathway is vital in maintaining tissue homeostasis by driving the critical reactions of folate and methionine cycles. A myriad of genetic and epigenetic events mark the rate of reactions in a tissue-specific manner. Integration of these to predict and provide personalized health management requires robust computational tools that can process multiomics data. The DNA sequences that may determine the chain of biological events and the endpoint reactions within one-carbon metabolism genes remain to be comprehensively recorded. Hence, we designed the one-carbon metabolism database (1-CMDb) as a platform to interrogate its association with a host of human disorders. DNA sequence and network information of a total of 48 genes were extracted from a literature survey and KEGG pathway that are involved in the one-carbon folate-mediated pathway. The information generated, collected, and compiled for all these genes from the UCSC genome browser included the single nucleotide polymorphisms (SNPs), CpGs, copy number variations (CNVs), and miRNAs, and a comprehensive database was created. Furthermore, a significant correlation analysis was performed for SNPs in the pathway genes. Detailed data of SNPs, CNVs, CpG islands, and miRNAs for 48 folate pathway genes were compiled. The SNPs in CNVs (9670), CpGs (984), and miRNAs (14) were also compiled for all pathway genes. The SIFT score, the prediction and PolyPhen score, as well as the prediction for each of the SNPs were tabulated and represented for folate pathway genes. Also included in the database for folate pathway genes were the links to 124 various phenotypes and disease associations as reported in the literature and from publicly available information. A comprehensive database was generated consisting of genomic elements within and among SNPs, CNVs, CpGs, and miRNAs of one-carbon metabolism pathways to facilitate (a) single source of information and (b) integration into large-genome scale network analysis to be developed in the future by the scientific community. The database can be accessed at http://slsdb.manipal.edu/ocm/. © 2017 S. Karger AG, Basel.

Representative Agricultural Pathways: A Trans-Disciplinary Approach to Agricultural Model Inter-comparison, Improvement, Climate Impact Assessment and Stakeholder Engagement

NASA Astrophysics Data System (ADS)

Antle, J. M.; Valdivia, R. O.; Claessens, L.; Nelson, G. C.; Rosenzweig, C.; Ruane, A. C.; Vervoort, J.

2013-12-01

The global change research community has recognized that new pathway and scenario concepts are needed to implement impact and vulnerability assessment that is logically consistent across local, regional and global scales. For impact and vulnerability assessment, new socio-economic pathway and scenario concepts are being developed. Representative Agricultural Pathways (RAPs) are designed to extend global pathways to provide the detail needed for global and regional assessment of agricultural systems. In addition, research by the Agricultural Model Inter-comparison and Improvement Project (AgMIP) shows that RAPs provide a powerful way to engage stakeholders in climate-related research throughout the research process and in communication of research results. RAPs are based on the integrated assessment framework developed by AgMIP. This framework shows that both bio-physical and socio-economic drivers are essential components of agricultural pathways and logically precede the definition of adaptation and mitigation scenarios that embody associated capabilities and challenges. This approach is based on a trans-disciplinary process for designing pathways and then translating them into parameter sets for bio-physical and economic models that are components of agricultural integrated assessments of climate impact, adaptation and mitigation. RAPs must be designed to be part of a logically consistent set of drivers and outcomes from global to regional and local. Global RAPs are designed to be consistent with higher-level global socio-economic pathways, but add key agricultural drivers such as agricultural growth trends that are not specified in more general pathways, as illustrated in a recent inter-comparison of global agricultural models. To create pathways at regional or local scales, further detail is needed. At this level, teams of scientists and other experts with knowledge of the agricultural systems and regions work together through a step-wise process. Experiences from AgMIP Regional Teams, and from the project on Regional Approaches to Climate Change in the Pacific Northwest, are used to discuss how the RAPs procedures can be further developed and improved, and how RAPs can help engage stakeholders in climate-related research throughout the research process and in communication of research results.

The role of alcohol in identity construction among LGBT people: a qualitative study.

PubMed

Emslie, Carol; Lennox, Jemma; Ireland, Lana

2017-11-01

Research suggests that alcohol use and misuse are higher among lesbian, gay and bisexual than heterosexual populations, yet the social context of drinking in sexual minority communities has rarely been examined. To explore lesbian, gay, bisexual and transgender (LGBT) people's relationship with alcohol, we conducted seven focus groups (N = 33) with pre-existing groups of friends and work colleagues (18 to 52 years) in Scotland, UK. We identified and analysed patterns in our data using thematic analysis. Respondents perceived heavy drinking as central to the commercial gay scene. Choice of drink and drinking vessel was an important part of identity construction. Respondents discussed the perception that gay men would drink alcopops and cocktails while lesbians would drink pints of beer. Even when stereotypes were dismissed as inaccurate, they were still thought to pressure people to drink 'appropriately'. Respondents who did not identify as male or female, and those who used drag, were particularly aware of their choice of drink as a means to express identity or to challenge people's preconceptions about gender. Researchers developing interventions to reduce alcohol-related harm in sexual minority populations need to take account of the central role of identity construction in LGBT drinking practices. © 2017 Foundation for the Sociology of Health & Illness.

The impact of second language learning on semantic and nonsemantic first language reading.

PubMed

Nosarti, Chiara; Mechelli, Andrea; Green, David W; Price, Cathy J

2010-02-01

The relationship between orthography (spelling) and phonology (speech sounds) varies across alphabetic languages. Consequently, learning to read a second alphabetic language, that uses the same letters as the first, increases the phonological associations that can be linked to the same orthographic units. In subjects with English as their first language, previous functional imaging studies have reported increased left ventral prefrontal activation for reading words with spellings that are inconsistent with their orthographic neighbors (e.g., PINT) compared with words that are consistent with their orthographic neighbors (e.g., SHIP). Here, using functional magnetic resonance imaging (fMRI) in 17 Italian-English and 13 English-Italian bilinguals, we demonstrate that left ventral prefrontal activation for first language reading increases with second language vocabulary knowledge. This suggests that learning a second alphabetic language changes the way that words are read in the first alphabetic language. Specifically, first language reading is more reliant on both lexical/semantic and nonlexical processing when new orthographic to phonological mappings are introduced by second language learning. Our observations were in a context that required participants to switch between languages. They motivate future fMRI studies to test whether first language reading is also altered in contexts when the second language is not in use.

Multi-pathway Kinase Signatures of Multipotent Stromal Cells are Predictive for Osteogenic Differentiation

PubMed Central

Platt, Manu O.; Wilder, Catera L.; Wells, Alan; Griffith, Linda G.; Lauffenburger, Douglas A.

2010-01-01

Bone marrow-derived multi-potent stromal cells (MSCs) offer great promise for regenerating tissue. While certain transcription factors have been identified in association with tendency toward particular MSC differentiation phenotypes, the regulatory network of key receptor-mediated signaling pathways activated by extracellular ligands that induce various differentiation responses remain poorly understood. Attempts to predict differentiation fate tendencies from individual pathways in isolation are problematic due to the complex pathway interactions inherent in signaling networks. Accordingly, we have undertaken a multi-variate systems approach integrating experimental measurement of multiple kinase pathway activities and osteogenic differentiation in MSCs, together with computational analysis to elucidate quantitative combinations of kinase signals predictive of cell behavior across diverse contexts. In particular, for culture on polymeric biomaterials surfaces presenting tethered epidermal growth factor (tEGF), type-I collagen, neither, or both, we have found that a partial least-squares regression model yields successful prediction of phenotypic behavior on the basis of two principal components comprising the weighted sums of 8 intracellular phosphoproteins: p-EGFR, p-Akt, p-ERK1/2, p-Hsp27, p-c-jun, p-GSK3α/β, p-p38, and p-STAT3. This combination provides strongest predictive capability for 21-day differentiated phenotype status when calculated from day-7 signal measurements (99%); day-4 (88%) and day-14 (89%) signal measurements are also significantly predictive, indicating a broad time-frame during MSC osteogenesis wherein multiple pathways and states of the kinase signaling network are quantitatively integrated to regulate gene expression, cell processes, and ultimately, cell fate. PMID:19750537

Shared molecular pathways and gene networks for cardiovascular disease and type 2 diabetes mellitus in women across diverse ethnicities.

PubMed

Chan, Kei Hang K; Huang, Yen-Tsung; Meng, Qingying; Wu, Chunyuan; Reiner, Alexander; Sobel, Eric M; Tinker, Lesley; Lusis, Aldons J; Yang, Xia; Liu, Simin

2014-12-01

Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D. © 2014 American Heart Association, Inc.

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways.

PubMed

Liu, Guiyou; Zhang, Fang; Jiang, Yongshuai; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

2017-02-01

Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date. We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets. Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets. In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2. We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Learning cellular sorting pathways using protein interactions and sequence motifs.

PubMed

Lin, Tien-Ho; Bar-Joseph, Ziv; Murphy, Robert F

2011-11-01

Proper subcellular localization is critical for proteins to perform their roles in cellular functions. Proteins are transported by different cellular sorting pathways, some of which take a protein through several intermediate locations until reaching its final destination. The pathway a protein is transported through is determined by carrier proteins that bind to specific sequence motifs. In this article, we present a new method that integrates protein interaction and sequence motif data to model how proteins are sorted through these sorting pathways. We use a hidden Markov model (HMM) to represent protein sorting pathways. The model is able to determine intermediate sorting states and to assign carrier proteins and motifs to the sorting pathways. In simulation studies, we show that the method can accurately recover an underlying sorting model. Using data for yeast, we show that our model leads to accurate prediction of subcellular localization. We also show that the pathways learned by our model recover many known sorting pathways and correctly assign proteins to the path they utilize. The learned model identified new pathways and their putative carriers and motifs and these may represent novel protein sorting mechanisms. Supplementary results and software implementation are available from http://murphylab.web.cmu.edu/software/2010_RECOMB_pathways/.

The care pathway: concepts and theories: an introduction.

PubMed

Schrijvers, Guus; van Hoorn, Arjan; Huiskes, Nicolette

2012-01-01

This article addresses first the definition of a (care) pathway, and then follows a description of theories since the 1950s. It ends with a discussion of theoretical advantages and disadvantages of care pathways for patients and professionals. The objective of this paper is to provide a theoretical base for empirical studies on care pathways. The knowledge for this chapter is based on several books on pathways, which we found by searching in the digital encyclopedia Wikipedia. Although this is not usual in scientific publications, this method was used because books are not searchable by databases as Pubmed. From 2005, we performed a literature search on Pubmed and other literature databases, and with the keywords integrated care pathway, clinical pathway, critical pathway, theory, research, and evaluation. One of the inspirational sources was the website of the European Pathway Association (EPA) and its journal International Journal of Care Pathways. The authors visited several sites for this paper. These are mentioned as illustration of a concept or theory. Most of them have English websites with more information. The URLs of these websites are not mentioned in this paper as a reference, because the content of them changes fast, sometimes every day.

The care pathway: concepts and theories: an introduction

PubMed Central

Schrijvers, Guus; van Hoorn, Arjan; Huiskes, Nicolette

2012-01-01

This article addresses first the definition of a (care) pathway, and then follows a description of theories since the 1950s. It ends with a discussion of theoretical advantages and disadvantages of care pathways for patients and professionals. The objective of this paper is to provide a theoretical base for empirical studies on care pathways. The knowledge for this chapter is based on several books on pathways, which we found by searching in the digital encyclopedia Wikipedia. Although this is not usual in scientific publications, this method was used because books are not searchable by databases as Pubmed. From 2005, we performed a literature search on Pubmed and other literature databases, and with the keywords integrated care pathway, clinical pathway, critical pathway, theory, research, and evaluation. One of the inspirational sources was the website of the European Pathway Association (EPA) and its journal International Journal of Care Pathways. The authors visited several sites for this paper. These are mentioned as illustration of a concept or theory. Most of them have English websites with more information. The URLs of these websites are not mentioned in this paper as a reference, because the content of them changes fast, sometimes every day. PMID:23593066

VisANT 3.0: new modules for pathway visualization, editing, prediction and construction.

PubMed

Hu, Zhenjun; Ng, David M; Yamada, Takuji; Chen, Chunnuan; Kawashima, Shuichi; Mellor, Joe; Linghu, Bolan; Kanehisa, Minoru; Stuart, Joshua M; DeLisi, Charles

2007-07-01

With the integration of the KEGG and Predictome databases as well as two search engines for coexpressed genes/proteins using data sets obtained from the Stanford Microarray Database (SMD) and Gene Expression Omnibus (GEO) database, VisANT 3.0 supports exploratory pathway analysis, which includes multi-scale visualization of multiple pathways, editing and annotating pathways using a KEGG compatible visual notation and visualization of expression data in the context of pathways. Expression levels are represented either by color intensity or by nodes with an embedded expression profile. Multiple experiments can be navigated or animated. Known KEGG pathways can be enriched by querying either coexpressed components of known pathway members or proteins with known physical interactions. Predicted pathways for genes/proteins with unknown functions can be inferred from coexpression or physical interaction data. Pathways produced in VisANT can be saved as computer-readable XML format (VisML), graphic images or high-resolution Scalable Vector Graphics (SVG). Pathways in the format of VisML can be securely shared within an interested group or published online using a simple Web link. VisANT is freely available at http://visant.bu.edu.

Evaluation of additional biogeochemical impacts on mitigation pathways in an energy sytem integrated assessment model.

NASA Astrophysics Data System (ADS)

Dessens, O.

2017-12-01

Within the last IPCC AR5 a large and systematic sensitivity study around available technologies and timing of policies applied in IAMs to achieve the 2°C target has been conducted. However the simple climate representations included in IAMs are generally tuned to the results of ensemble means. This may result in hiding within the ensemble mean results possible challenging mitigation pathways for the economy or the technology future scenarios. This work provides new insights on the sensitivity of the socio-economic response to different climate factors under a 2°C climate change target in order to help guide future efforts to reduce uncertainty in the climate mitigation decisions. The main objective is to understand and bring new insights on how future global warming will affect the natural biochemical feedbacks on the climate system and what could be the consequences of these feedbacks on the anthropogenic emission pathways with a specific focus on the energy-economy system. It specifically focuses on three issues of the climate representation affecting the energy system transformation and GHG emissions pathways: 1- Impacts of the climate sensitivity (or TCR); 2- Impacts of warming on the radiative forcing (cloudiness,...); 3- Impacts of warming on the carbon cycle (carbon cycle feedback). We use the integrated assessment model TIAM-UCL to examine the mitigation pathways compatible with the 2C target depending on assumptions regarding the 3 issues of the climate representation introduced above. The following key conclusions drawn from this study are that mitigation to 2°C is still possible under strong climate sensitivity (TCR), strong carbon cycle amplification or positive radiative forcing feedback. However, this level of climate mitigation will require a significant transformation in the way we produce and consume energy. Carbon capture and sequestration on electricity generation, industry and biomass is part of the technology pool needed to achieve this level of decarbonisation. In extreme condition (positive correlation between the 3 issues discussed) the integrated assessment model TIAM-UCL creates pathways requiring additional negative emission technologies at the end of this century to keep temperature change well below 2°C.

Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo.

PubMed

Yang, Wei; Kim, Yongsoo; Kim, Taek-Kyun; Keay, Susan K; Kim, Kwang Pyo; Steen, Hanno; Freeman, Michael R; Hwang, Daehee; Kim, Jayoung

2012-12-01

What's known on the subject? and What does the study add? Interstitial cystitis (IC) is a prevalent and debilitating pelvic disorder generally accompanied by chronic pain combined with chronic urinating problems. Over one million Americans are affected, especially middle-aged women. However, its aetiology or mechanism remains unclear. No efficient drug has been provided to patients. Several urinary biomarker candidates have been identified for IC; among the most promising is antiproliferative factor (APF), whose biological activity is detectable in urine specimens from >94% of patients with both ulcerative and non-ulcerative IC. The present study identified several important mediators of the effect of APF on bladder cell physiology, suggesting several candidate drug targets against IC. In an attempt to identify potential proteins and genes regulated by APF in vivo, and to possibly expand the APF-regulated network identified by stable isotope labelling by amino acids in cell culture (SILAC), we performed an integration analysis of our own SILAC data and the microarray data of Gamper et al. (2009) BMC Genomics 10: 199. Notably, two of the proteins (i.e. MAPKSP1 and GSPT1) that are down-regulated by APF are involved in the activation of mTORC1, suggesting that the mammalian target of rapamycin (mTOR) pathway is potentially a critical pathway regulated by APF in vivo. Several components of the mTOR pathway are currently being studied as potential therapeutic targets in other diseases. Our analysis suggests that this pathway might also be relevant in the design of diagnostic tools and medications targeting IC. • To enhance our understanding of the interstitial cystitis urine biomarker antiproliferative factor (APF), as well as interstitial cystitis biology more generally at the systems level, we reanalyzed recently published large-scale quantitative proteomics and in vivo transcriptomics data sets using an integration analysis tool that we have developed. • To identify more differentially expressed genes with a lower false discovery rate from a previously published microarray data set, an integrative hypothesis-testing statistical approach was applied. • For validation experiments, expression and phosphorylation levels of select proteins were evaluated by western blotting. • Integration analysis of this transcriptomics data set with our own quantitative proteomics data set identified 10 genes that are potentially regulated by APF in vivo from 4140 differentially expressed genes identified with a false discovery rate of 1%. • Of these, five (i.e. JUP, MAPKSP1, GSPT1, PTGS2/COX-2 and XPOT) were found to be prominent after network modelling of the common genes identified in the proteomics and microarray studies. • This molecular signature reflects the biological processes of cell adhesion, cell proliferation and inflammation, which is consistent with the known physiological effects of APF. • Lastly, we found the mammalian target of rapamycin pathway was down-regulated in response to APF. • This unbiased integration analysis of in vitro quantitative proteomics data with in vivo quantitative transcriptomics data led to the identification of potential downstream mediators of the APF signal transduction pathway. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.

Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

PubMed

Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

2017-11-20

Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Characterization of the role of Fhit in maintenance of genomic integrity following low dose radiation, in vivo and in vitro

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

Ya Wang

2010-05-31

The major goal of this study is to determine the effects of the Fhit pathway on low dose ({le} 0.1 Gy) ionizing radiation (IR)-induced genetic instability. Reduction of Fhit protein expression is observed in most solid tumors particularly in those tumors resulting from exposure to environmental carcinogens. Therefore, characterization of the role of the Fhit-dependent pathway in preventing low dose IR-induced genetic instability will provide useful parameters for evaluating the low dose IR-induced risk of mutagenesis and carcinogenesis. We pursued 3 specific aims to study our hypothesis that the Fhit-dependent pathways maintain genomic integrity through adjusting checkpoint response and repairmore » genes expression following low dose IR. Aim 1: Determine whether Fhit interaction with RPA is necessary for Fhit to affect the cellular response to low dose IR. We combined the approaches of in vitro (GST pull-down and site-directed mutagenesis) and in vivo (observing the co-localization and immunoprecipitation of Fhit and RPA in Fhit knock out mouse cells transfected with mutant Fhit which has lost ability to interact with RPA in vitro). Aim 2: Determine the role of genes whose expression is affected by Fhit in low dose irradiated cells. We analyzed the distinct signature of gene expression in low dose irradiated Fhit-/- cells compared with Fhit+/+ cells by combining microarray, gene transfection and siRNA approaches. Aim 3: Determine the role of Fhit in genetic susceptibility to low dose IR in vivo. We compared the gene mutation frequency and the fragile site stability in the cells isolated from the Fhit+/+ and Fhit-/- mice at 1.5 years following low dose IR. These results determine the role of the Fhit-dependent pathway in maintaining genomic integrity in vitro and in vivo, which provide a basis for choosing surrogate markers in the Fhit-dependent pathway to evaluate low dose IR-induced risk of mutagenesis and carcinogenesis.« less

Duration of U.S. stay and body mass index among Latino and Asian immigrants: A test of theoretical pathways.

PubMed

Ro, Annie; Bostean, Georgiana

2015-11-01

Studies find that longer-term immigrants have higher body mass index (BMI) than their more recently arrived counterparts. Most interpretations of these health patterns by duration of U.S. residence rely on theories of immigrant integration; they posit that with increasing time in the United States, immigrants incorporate economically, socially, and culturally into aspects of U.S. society, and that these changes impact health. Few studies empirically examine whether these aspects of integration are indeed mediators of the association between duration of U.S. stay and BMI, and if their patterns differ across immigrant subgroups. This study examines data from the National Latino and Asian American Survey, using path analytic methods to simultaneously test six hypothesized mediators between duration and BMI: household income, English language ability, ethnic identity, family cohesion, acculturative stress and discrimination for both Latino and Asian immigrants, stratified by gender. We find little evidence for an association between duration and BMI for either Latino or Asian men. For women, duration and BMI have a significant and positive relationship, although the pathways differ between the two ethnic groups. For Latina women, household income and acculturative stress are significant indirect pathways, although they work in opposing directions. For Asian women, English proficiency and discrimination are significant indirect pathways. Our findings reveal complex pathways between duration and BMI that vary by ethnicity and gender and highlight limitations in the negative acculturation theory, which suggests that exposure to the United States should have a net negative impact on health. In contrast, our findings suggest that not all groups show declining health with longer duration, as measured by BMI, and that integration processes do not always translate into health differences in the expected directions. Future research on duration patterns may need to consider alternative explanations beyond incorporation-based processes, such as cross-national health theories or age, period, cohort effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells

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

Lee, Kiwon; Lee, Ah-Young; Kwon, Yunhee Kim

Highlights: {yields} Integration of HPV into host genome critical for activation of E6 and E7 oncogenes. {yields} BAF53 is essential for higher-order chromatin structure. {yields} BAF53 knockdown suppresses E6 and E7 from HPV integrants, but not from episomal HPVs. {yields} BAF53 knockdown decreases H3K9Ac and H4K12Ac on P105 promoter of integrated HPV 18. {yields} BAF53 knockdown restores the p53-dependent signaling pathway in HeLa and SiHa cells. -- Abstract: Deregulation of the expression of human papillomavirus (HPV) oncogenes E6 and E7 plays a pivotal role in cervical carcinogenesis because the E6 and E7 proteins neutralize p53 and Rb tumor suppressor pathways,more » respectively. In approximately 90% of all cervical carcinomas, HPVs are found to be integrated into the host genome. Following integration, the core-enhancer element and P105 promoter that control expression of E6 and E7 adopt a chromatin structure that is different from that of episomal HPV, and this has been proposed to contribute to activation of E6 and E7 expression. However, the molecular basis underlying this chromatin structural change remains unknown. Previously, BAF53 has been shown to be essential for the integrity of higher-order chromatin structure and interchromosomal interactions. Here, we examined whether BAF53 is required for activated expression of E6 and E7 genes. We found that BAF53 knockdown led to suppression of expression of E6 and E7 genes from HPV integrants in cervical carcinoma cell lines HeLa and SiHa. Conversely, expression of transiently transfected HPV18-LCR-Luciferase was not suppressed by BAF53 knockdown. The level of the active histone marks H3K9Ac and H4K12Ac on the P105 promoter of integrated HPV 18 was decreased in BAF53 knockdown cells. BAF53 knockdown restored the p53-dependent signaling pathway in HeLa and SiHa cells. These results suggest that activated expression of the E6 and E7 genes of integrated HPV is dependent on BAF53-dependent higher-order chromatin structure or nuclear motor activity.« less

Neurological and biological foundations of children's social and emotional development: an integrated literature review.

PubMed

Nelson, Helen Jean; Kendall, Garth Edward; Shields, Linda

2014-08-01

This article provides an integrated review of the expert literature on developmental processes that combine social, biological, and neurological pathways, and the mechanisms through which these pathways may influence school success and health. It begins with a historical overview of the current understanding of how attachment relationships and social environments influence brain development and plasticity and are, therefore, central to the physical and mental health of individuals and populations. It then expands on the effect of plasticity in relation to behavior and learning at school. This article concludes with a discussion of the role the school nurse may play in supporting health and learning by recognizing signs of relational stress and by advocating for prevention strategies. © The Author(s) 2013.

The Peroxide Pathway

NASA Technical Reports Server (NTRS)

McNeal, Curtis I., Jr.; Anderson, William

1999-01-01

NASA's current focus on technology roadmaps as a tool for guiding investment decisions leads naturally to a discussion of NASA's roadmap for peroxide propulsion system development. NASA's new Second Generation Space Transportation System roadmap calls for an integrated Reusable Upper-Stage (RUS) engine technology demonstration in the FY03/FY04 time period. Preceding this integrated demonstration are several years of component developments and subsystem technology demonstrations. NASA and the Air Force took the first steps at developing focused upper stage technologies with the initiation of the Upper Stage Flight Experiment with Orbital Sciences in December 1997. A review of this program's peroxide propulsion development is a useful first step in establishing the peroxide propulsion pathway that could lead to a RUS demonstration in 2004.

Metabolic engineering with plants for a sustainable biobased economy.

PubMed

Yoon, Jong Moon; Zhao, Le; Shanks, Jacqueline V

2013-01-01

Plants are bona fide sustainable organisms because they accumulate carbon and synthesize beneficial metabolites from photosynthesis. To meet the challenges to food security and health threatened by increasing population growth and depletion of nonrenewable natural resources, recent metabolic engineering efforts have shifted from single pathways to holistic approaches with multiple genes owing to integration of omics technologies. Successful engineering of plants results in the high yield of biomass components for primary food sources and biofuel feedstocks, pharmaceuticals, and platform chemicals through synthetic biology and systems biology strategies. Further discovery of undefined biosynthesis pathways in plants, integrative analysis of discrete omics data, and diversified process developments for production of platform chemicals are essential to overcome the hurdles for sustainable production of value-added biomolecules from plants.

Understanding and exploiting autophagy signaling in plants

PubMed Central

Batoko, Henri; Dagdas, Yasin; Baluska, Frantisek; Sirko, Agnieszka

2017-01-01

Autophagy is an essential catabolic pathway and is activated by various endogenous and exogenous stimuli. In particular, autophagy is required to allow sessile organisms such as plants to cope with biotic or abiotic stress conditions. It is thought that these various environmental signaling pathways are somehow integrated with autophagy signaling. However, the molecular mechanisms of plant autophagy signaling are not well understood, leaving a big gap of knowledge as a barrier to being able to manipulate this important pathway to improve plant growth and development. In this review, we discuss possible regulatory mechanisms at the core of plant autophagy signaling. PMID:29233877

Middle Level Preservice Teachers Experience a Natural History Arts-Integrated Interdisciplinary Thematic Unit

ERIC Educational Resources Information Center

Weber, Carolyn A.; Rule, Audrey C.

2017-01-01

Curricular demands and best practices for middle school require interdisciplinary units. Arts integration can provide motivation and a new pathway to learning. This unit focused on inquiry into the natural history of artifacts and rocks recovered from the exposed subsoil of an area near Cedar Falls, Iowa that had been bulldozed as part of…

Advancing Prostate Cancer Research by Providing Summer Research Opportunities for HBCU Students at the Cancer Center at UTHSCSA

DTIC Science & Technology

2017-08-01

Health is to determine the most effective ways to integrate , interpret, and apply biological, social, psychological , and clinical determinants of...MED 238A Nucleic Acids Concentration and Integrity Room MED 5.573C Methods Overview – Nucleic Acids Room MED 238A Critical Thinking...response evoked in the medial prefrontal cortex by stimulating in the hippocampus, a measure of the integrity of this important pathway that is 11

Integrated microRNA and mRNA signatures in peripheral blood lymphocytes of familial epithelial ovarian cancer.

PubMed

Dou, Yun-De; Huang, Tao; Wang, Qun; Shu, Xin; Zhao, Shi-Gang; Li, Lei; Liu, Tao; Lu, Gang; Chan, Wai-Yee; Liu, Hong-Bin

2018-01-29

Characterization of the genetic landscapes of familial ovarian cancer through integrated analysis of microRNA and mRNA by partial least squares (PLS) and Monte Carlo technique based on genome-wide association studies (GWAS). The miRNA and mRNA transcriptional data in familial ovarian cancer were characterized from the Gene Expression Omnibus (GEO) database. The miRNA and mRNA expression profiles in peripheral blood lymphocytes (PBLs) of 74 familial ovarian cancer patients and 47 control subjects were analyzed with the integration of partial least squares (PLS) and Monte Carlo techniques. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also performed. Total of 16 miRNA-mRNA pairs were identified with the target gene prediction results of miRNAs and mRNAs. An innovated miRNA-mRNA integrated network was constructed in which 6 downregulated miRNAs and 1 upregulated miRNAs were included. KEGG and GO pathway enrichment analysis revealed over-representation of dysregulated miRNAs in various biological processes especially in cancer pathology. Hsa-miR-34b played a pivotal role in this network and interacted with other miRNAs. Hsa-miR-136 and hsa-miR-335 were associated with p53 and Erk1/2 pathways and tumor suppressors, such as PTEN. The results from this research provide insights on miRNA-mRNA networks and offer new tools for studying transcriptional variants in familial ovarian cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata.

PubMed

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata , identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata , with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata , as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature.

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata

PubMed Central

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata, identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata, with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata, as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature. PMID:29719546

Integrated care through disease-oriented clinical care pathways: experience from Japan’s regional health planning initiatives

PubMed Central

Okamoto, Etsuji; Miyamoto, Masaki; Hara, Kazuhiro; Yoshida, Jun; Muto, Masaki; Hirai, Aizan; Tatsumi, Haruyuki; Mizuno, Masaaki; Nagata, Hiroshi; Yamakata, Daisuke; Tanaka, Hiroshi

2011-01-01

Introduction In April 2008, Japan launched a radical reform in regional health planning that emphasized the development of disease-oriented clinical care pathways. These ‘inter-provider critical paths’ have sought to ensure effective integration of various providers ranging among primary care practitioners, acute care hospitals, rehabilitation hospitals, long-term care facilities and home care. Description of policy practice All 47 prefectures in Japan developed their Regional Health Plans pursuant to the guideline requiring that these should include at least four diseases: diabetes, acute myocardial infarction, cerebrovascular accident and cancer. To illustrate the care pathways developed, this paper describes the guideline referring to strokes and provides examples of the new Regional Health Plans as well as examples of disease-oriented inter-provider clinical paths. In particular, the paper examines the development of information sharing through electronic health records (EHR) to enhance effective integration among providers is discussed. Discussion and conclusion Japan’s reform in 2008 is unique in that the concept of ‘disease-oriented regional inter-provider critical paths’ was adopted as a national policy and all 47 prefectures developed their Regional Health Plans simultaneously. How much the new regional health planning policy has improved the quality and outcome of care remains to be seen and will be evaluated in 2013 after the five-year planned period of implementation has concluded. Whilst electronic health records appear to be a useful tool in supporting care integration they do not guarantee success in the application of an inter-provider critical path. PMID:22128281

Network specific change in white matter integrity in mesial temporal lobe epilepsy.

PubMed

Imamura, Hisaji; Matsumoto, Riki; Takaya, Shigetoshi; Nakagawa, Tomokazu; Shimotake, Akihiro; Kikuchi, Takayuki; Sawamoto, Nobukatsu; Kunieda, Takeharu; Mikuni, Nobuhiro; Miyamoto, Susumu; Fukuyama, Hidenao; Takahashi, Ryosuke; Ikeda, Akio

2016-02-01

To identify the specific change of white matter integrity that occurs in the brain network related to epileptic activity in patients with mesial temporal lobe epilepsy (MTLE). We recruited 18 patients with MTLE and 18 healthy subjects. In MTLE patients, the remote functional-deficit zone was delineated using fluorodeoxyglucose positron emission tomography as an extratemporal region showing glucose hypometabolism. Using diffusion magnetic resonance imaging tractography, we defined a seizure propagation tract (PT) as a white matter pathway that connects the focus with a remote functional deficit zone. We also used the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF) as control tracts in the hemisphere ipsilateral to the focus. Fractional anisotropy (FA), mean diffusivity (MD), and volume of the tracts were compared among PT, CST, and ILF. Tractographic analysis identified the uncinate fasciculus, arcuate fasciculus, and fornix as PTs. A decrease in FA was found in MTLE patients compared with healthy subjects in all tracts, but PTs showed a more significant decrease in FA than did the two control tracts. Although the change in MD was also found in MTLE patients compared with healthy controls, a tract-specific change was not observed. Although white-matter damage was observed in all candidate tracts examined, the integrity of white matter was most significantly decreased in PTs in MTLE. The change in white matter integrity occurs specifically in the pathways that connect the focus and remote functional deficit zones in patients with MTLE, i.e., the pathways that are assume to be associated with seizure propagation. Copyright © 2015 Elsevier B.V. All rights reserved.

VitaPad: visualization tools for the analysis of pathway data.

PubMed

Holford, Matthew; Li, Naixin; Nadkarni, Prakash; Zhao, Hongyu

2005-04-15

Packages that support the creation of pathway diagrams are limited by their inability to be readily extended to new classes of pathway-related data. VitaPad is a cross-platform application that enables users to create and modify biological pathway diagrams and incorporate microarray data with them. It improves on existing software in the following areas: (i) It can create diagrams dynamically through graph layout algorithms. (ii) It is open-source and uses an open XML format to store data, allowing for easy extension or integration with other tools. (iii) It features a cutting-edge user interface with intuitive controls, high-resolution graphics and fully customizable appearance. http://bioinformatics.med.yale.edu matthew.holford@yale.edu; hongyu.zhao@yale.edu.

Detecting Disease Specific Pathway Substructures through an Integrated Systems Biology Approach

PubMed Central

Alaimo, Salvatore; Marceca, Gioacchino Paolo; Ferro, Alfredo; Pulvirenti, Alfredo

2017-01-01

In the era of network medicine, pathway analysis methods play a central role in the prediction of phenotype from high throughput experiments. In this paper, we present a network-based systems biology approach capable of extracting disease-perturbed subpathways within pathway networks in connection with expression data taken from The Cancer Genome Atlas (TCGA). Our system extends pathways with missing regulatory elements, such as microRNAs, and their interactions with genes. The framework enables the extraction, visualization, and analysis of statistically significant disease-specific subpathways through an easy to use web interface. Our analysis shows that the methodology is able to fill the gap in current techniques, allowing a more comprehensive analysis of the phenomena underlying disease states. PMID:29657291

Metabolic pathway reconstruction of eugenol to vanillin bioconversion in Aspergillus niger

PubMed Central

Srivastava, Suchita; Luqman, Suaib; Khan, Feroz; Chanotiya, Chandan S; Darokar, Mahendra P

2010-01-01

Identification of missing genes or proteins participating in the metabolic pathways as enzymes are of great interest. One such class of pathway is involved in the eugenol to vanillin bioconversion. Our goal is to develop an integral approach for identifying the topology of a reference or known pathway in other organism. We successfully identify the missing enzymes and then reconstruct the vanillin biosynthetic pathway in Aspergillus niger. The procedure combines enzyme sequence similarity searched through BLAST homology search and orthologs detection through COG & KEGG databases. Conservation of protein domains and motifs was searched through CDD, PFAM & PROSITE databases. Predictions regarding how proteins act in pathway were validated experimentally and also compared with reported data. The bioconversion of vanillin was screened on UV-TLC plates and later confirmed through GC and GC-MS techniques. We applied a procedure for identifying missing enzymes on the basis of conserved functional motifs and later reconstruct the metabolic pathway in target organism. Using the vanillin biosynthetic pathway of Pseudomonas fluorescens as a case study, we indicate how this approach can be used to reconstruct the reference pathway in A. niger and later results were experimentally validated through chromatography and spectroscopy techniques. PMID:20978605

Integrative data mining of high-throughput in vitro screens, in vivo data, and disease information to identify Adverse Outcome Pathway (AOP) signatures:ToxCast high-throughput screening data and Comparative Toxicogenomics Database (CTD) as a case study.

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework provides a systematic way to describe linkages between molecular and cellular processes and organism or population level effects. The current AOP assembly methods however, are inefficient. Our goal is to generate computationally-pr...

Application of Adverse Outcome Pathways (AOPs) in Human ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making. Because many fundamental molecular and cellular pathways are conserved across taxa, data from assays that screen chemicals for their ability to interact with specific biomolecular targets can often be credibly applied to a broad range of species, even if the apical outcomes of those perturbations may differ. Information concerning the different trajectories of adversity that molecular initiating events may take in different taxa, life stages, and sexes of organisms can be captured in the form of an AOP network. As an example, AOPs documenting divergent consequences of thyroid peroxidase (TPO) and deiodinase (DIO) inhibition in mammals, amphibians, and fish have been developed. These AOPs provide the foundation for using data from common in vitro assays for TPO or DIO activity to inform both human health and ecological risk assessments. They also provide the foundation for an integrated approach to testing and assessment, where available information and biological understanding can be integrated in order to formulate plausible and testable hypotheses which can be used to target in vivo testing on the endpoints of greatest concern. Application of this AOP knowledge in several different r

Integrating publicly-available data to generate computationally ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity is limited. Methods are needed to assimilate large amounts of available molecular data and quickly generate putative AOPs for further testing and use in hazard assessment. A graph-based workflow was used to facilitate the integration of multiple data types to generate computationally-predicted (cp) AOPs. Edges between graph entities were identified through direct experimental or literature information or computationally inferred using frequent itemset mining. Data from the TG-GATEs and ToxCast programs were used to channel large-scale toxicogenomics information into a cpAOP network (cpAOPnet) of over 20,000 relationships describing connections between chemical treatments, phenotypes, and perturbed pathways measured by differential gene expression and high-throughput screening targets. Sub-networks of cpAOPs for a reference chemical (carbon tetrachloride, CCl4) and outcome (hepatic steatosis) were extracted using the network topology. Comparison of the cpAOP subnetworks to published mechanistic descriptions for both CCl4 toxicity and hepatic steatosis demonstrate that computational approaches can be used to replicate manually curated AOPs and identify pathway targets that lack genomic mar

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

PubMed

Bousquet, J; Addis, A; Adcock, I; Agache, I; Agusti, A; Alonso, A; Annesi-Maesano, I; Anto, J M; Bachert, C; Baena-Cagnani, C E; Bai, C; Baigenzhin, A; Barbara, C; Barnes, P J; Bateman, E D; Beck, L; Bedbrook, A; Bel, E H; Benezet, O; Bennoor, K S; Benson, M; Bernabeu-Wittel, M; Bewick, M; Bindslev-Jensen, C; Blain, H; Blasi, F; Bonini, M; Bonini, S; Boulet, L P; Bourdin, A; Bourret, R; Bousquet, P J; Brightling, C E; Briggs, A; Brozek, J; Buhl, R; Bush, A; Caimmi, D; Calderon, M; Calverley, P; Camargos, P A; Camuzat, T; Canonica, G W; Carlsen, K H; Casale, T B; Cazzola, M; Cepeda Sarabia, A M; Cesario, A; Chen, Y Z; Chkhartishvili, E; Chavannes, N H; Chiron, R; Chuchalin, A; Chung, K F; Cox, L; Crooks, G; Crooks, M G; Cruz, A A; Custovic, A; Dahl, R; Dahlen, S E; De Blay, F; Dedeu, T; Deleanu, D; Demoly, P; Devillier, P; Didier, A; Dinh-Xuan, A T; Djukanovic, R; Dokic, D; Douagui, H; Dubakiene, R; Eglin, S; Elliot, F; Emuzyte, R; Fabbri, L; Fink Wagner, A; Fletcher, M; Fokkens, W J; Fonseca, J; Franco, A; Frith, P; Furber, A; Gaga, M; Garcés, J; Garcia-Aymerich, J; Gamkrelidze, A; Gonzales-Diaz, S; Gouzi, F; Guzmán, M A; Haahtela, T; Harrison, D; Hayot, M; Heaney, L G; Heinrich, J; Hellings, P W; Hooper, J; Humbert, M; Hyland, M; Iaccarino, G; Jakovenko, D; Jardim, J R; Jeandel, C; Jenkins, C; Johnston, S L; Jonquet, O; Joos, G; Jung, K S; Kalayci, O; Karunanithi, S; Keil, T; Khaltaev, N; Kolek, V; Kowalski, M L; Kull, I; Kuna, P; Kvedariene, V; Le, L T; Lodrup Carlsen, K C; Louis, R; MacNee, W; Mair, A; Majer, I; Manning, P; de Manuel Keenoy, E; Masjedi, M R; Melen, E; Melo-Gomes, E; Menzies-Gow, A; Mercier, G; Mercier, J; Michel, J P; Miculinic, N; Mihaltan, F; Milenkovic, B; Molimard, M; Momas, I; Montilla-Santana, A; Morais-Almeida, M; Morgan, M; N'Diaye, M; Nafti, S; Nekam, K; Neou, A; Nicod, L; O'Hehir, R; Ohta, K; Paggiaro, P; Palkonen, S; Palmer, S; Papadopoulos, N G; Papi, A; Passalacqua, G; Pavord, I; Pigearias, B; Plavec, D; Postma, D S; Price, D; Rabe, K F; Radier Pontal, F; Redon, J; Rennard, S; Roberts, J; Robine, J M; Roca, J; Roche, N; Rodenas, F; Roggeri, A; Rolland, C; Rosado-Pinto, J; Ryan, D; Samolinski, B; Sanchez-Borges, M; Schünemann, H J; Sheikh, A; Shields, M; Siafakas, N; Sibille, Y; Similowski, T; Small, I; Sola-Morales, O; Sooronbaev, T; Stelmach, R; Sterk, P J; Stiris, T; Sud, P; Tellier, V; To, T; Todo-Bom, A; Triggiani, M; Valenta, R; Valero, A L; Valiulis, A; Valovirta, E; Van Ganse, E; Vandenplas, O; Vasankari, T; Vestbo, J; Vezzani, G; Viegi, G; Visier, L; Vogelmeier, C; Vontetsianos, T; Wagstaff, R; Wahn, U; Wallaert, B; Whalley, B; Wickman, M; Williams, D M; Wilson, N; Yawn, B P; Yiallouros, P K; Yorgancioglu, A; Yusuf, O M; Zar, H J; Zhong, N; Zidarn, M; Zuberbier, T

2014-08-01

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Application of adverse outcome pathways (AOPs) in human ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making. Because many fundamental molecular and cellular pathways are conserved across taxa, data from assays that screen chemicals for their ability to interact with specific biomolecular targets can often be credibly applied to a broad range of species, even if the apical outcomes of those perturbations may differ. Information concerning the different trajectories of adversity that molecular initiating events may take in different taxa, life stages, and sexes of organisms can be captured in the form of an AOP network. As an example, AOPs documenting divergent consequences of thyroid peroxidase (TPO) and deiodinase (DIO) inhibition in mammals, amphibians, and fish have been developed. These AOPs provide the foundation for using data from common in vitro assays for TPO or DIO activity to inform both human health and ecological risk assessments. They also provide the foundation for an integrated approach to testing and assessment, where available information and biological understanding can be integrated in order to formulate plausible and testable hypotheses which can be used to target in vivo testing on the endpoints of greatest concern. Application of this AOP knowledge in several different r

The role of human ventral visual cortex in motion perception

PubMed Central

Saygin, Ayse P.; Lorenzi, Lauren J.; Egan, Ryan; Rees, Geraint; Behrmann, Marlene

2013-01-01

Visual motion perception is fundamental to many aspects of visual perception. Visual motion perception has long been associated with the dorsal (parietal) pathway and the involvement of the ventral ‘form’ (temporal) visual pathway has not been considered critical for normal motion perception. Here, we evaluated this view by examining whether circumscribed damage to ventral visual cortex impaired motion perception. The perception of motion in basic, non-form tasks (motion coherence and motion detection) and complex structure-from-motion, for a wide range of motion speeds, all centrally displayed, was assessed in five patients with a circumscribed lesion to either the right or left ventral visual pathway. Patients with a right, but not with a left, ventral visual lesion displayed widespread impairments in central motion perception even for non-form motion, for both slow and for fast speeds, and this held true independent of the integrity of areas MT/V5, V3A or parietal regions. In contrast with the traditional view in which only the dorsal visual stream is critical for motion perception, these novel findings implicate a more distributed circuit in which the integrity of the right ventral visual pathway is also necessary even for the perception of non-form motion. PMID:23983030

A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Sheng-ma-bie-jia-tang Acting on Systemic Lupus Erythematosus by Multi-Level Data Integration.

PubMed

Huang, Lin; Lv, Qi; Liu, Fenfen; Shi, Tieliu; Wen, Chengping

2015-11-12

Sheng-ma-bie-jia-tang (SMBJT) is a Traditional Chinese Medicine (TCM) formula that is widely used for the treatment of Systemic Lupus Erythematosus (SLE) in China. However, molecular mechanism behind this formula remains unknown. Here, we systematically analyzed targets of the ingredients in SMBJT to evaluate its potential molecular mechanism. First, we collected 1,267 targets from our previously published database, the Traditional Chinese Medicine Integrated Database (TCMID). Next, we conducted gene ontology and pathway enrichment analyses for these targets and determined that they were enriched in metabolism (amino acids, fatty acids, etc.) and signaling pathways (chemokines, Toll-like receptors, adipocytokines, etc.). 96 targets, which are known SLE disease proteins, were identified as essential targets and the rest 1,171 targets were defined as common targets of this formula. The essential targets directly interacted with SLE disease proteins. Besides, some common targets also had essential connections to both key targets and SLE disease proteins in enriched signaling pathway, e.g. toll-like receptor signaling pathway. We also found distinct function of essential and common targets in immune system processes. This multi-level approach to deciphering the underlying mechanism of SMBJT treatment of SLE details a new perspective that will further our understanding of TCM formulas.

GEOGLE: context mining tool for the correlation between gene expression and the phenotypic distinction.

PubMed

Yu, Yao; Tu, Kang; Zheng, Siyuan; Li, Yun; Ding, Guohui; Ping, Jie; Hao, Pei; Li, Yixue

2009-08-25

In the post-genomic era, the development of high-throughput gene expression detection technology provides huge amounts of experimental data, which challenges the traditional pipelines for data processing and analyzing in scientific researches. In our work, we integrated gene expression information from Gene Expression Omnibus (GEO), biomedical ontology from Medical Subject Headings (MeSH) and signaling pathway knowledge from sigPathway entries to develop a context mining tool for gene expression analysis - GEOGLE. GEOGLE offers a rapid and convenient way for searching relevant experimental datasets, pathways and biological terms according to multiple types of queries: including biomedical vocabularies, GDS IDs, gene IDs, pathway names and signature list. Moreover, GEOGLE summarizes the signature genes from a subset of GDSes and estimates the correlation between gene expression and the phenotypic distinction with an integrated p value. This approach performing global searching of expression data may expand the traditional way of collecting heterogeneous gene expression experiment data. GEOGLE is a novel tool that provides researchers a quantitative way to understand the correlation between gene expression and phenotypic distinction through meta-analysis of gene expression datasets from different experiments, as well as the biological meaning behind. The web site and user guide of GEOGLE are available at: http://omics.biosino.org:14000/kweb/workflow.jsp?id=00020.

Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways.

PubMed

Mur, Luis A J; Prats, Elena; Pierre, Sandra; Hall, Michael A; Hebelstrup, Kim H

2013-01-01

Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used.