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More From Campus Politics
How Political Correctness Chills Speech on Campus
Conor Friedersdorf
Grading the University of Chicago's Letter on Academic Freedom
What Should the Standard of Proof Be in Campus Rape Cases?
When 'Diversity' and 'Inclusion' Are Tenure Requirements
How Emory's Student Activists Are Fueling Trumpism
The billionaire candidate couldn't have created more perfect foils for a candidacy built on resentment.
By Conor Friedersdorf
Mpspqr / Wikimedia
Had Donald Trump's 2016 campaign for the White House somehow infiltrated the ranks of Emory's student activists and blackmailed the university's President James W. Wagner, it could scarcely have orchestrated a spectacle more helpful to Trump's prospects, or damaging to the values that protect vulnerable groups, than what they accomplished on their own this week. After someone wrote "Trump 2016" in colored chalk around campus, several dozen student demonstrators objected that the banal campaign message scared, upset, or offended them, and administrators responded by going Orwellian.
Read Follow-Up Notes
Emory students respond to their critics
The Emory Wheel reports that Wagner will review footage from campus security cameras to uncover who made the chalkings. "He added that if they're students, they will go through the conduct violation process," the newspaper stated, "while if they are from outside of the University, trespassing charges will be pressed." Ponder the precedent. An academic authority figure will use surveillance to track down and punish someone for urging support for a political candidate. If possible, he will marshal criminal law to do so. As Jesse Singal wrote at New York, that is "extremely creepy, and a sign that something has gone seriously wrong."
Can you imagine how campus progressives would have reacted if a university president threatened to have someone punished or charged with trespassing for chalking "Obama 2012" or "Bernie 2016" on campus sidewalks? But these students see no need for viewpoint-neutral standards about politicking in presidential elections.
The shortsightedness of all involved is staggering. Set aside the brazen illiberalism of their actions and briefly consider this from a consequentialist perspective.
For starters, leftist activists are far more likely than anyone else to use sidewalk chalk and should be pushing to dispense with existing, rarely enforced campus regulations. The medium is unusually suited to the powerless, too: It is cheap, easy to use, and very hard to suppress. Yet they're signing on to surveillance and punishment for chalk-wielding activism, as if it hasn't even occurred to them that their allies stand to lose the most from future crackdowns, whereas Donald Trump 2016 could foreswear sidewalk chalk forever without suffering from it at all. I don't know whether these students have an incoherent theory of how power works, or haven't thought the matter through, but future leftist activists may rue their behavior.
What's more, if the sidewalk-chalker is unmasked and punished, the effect will be to fuel the popularity of Trump 2016, not to undermine it. This is so obvious to everyone outside the bubble of campus leftism that I begin to wonder if activists at Emory don't understand that, or just don't actually care about outcomes beyond their bubble.
At ages 18 to 22, many of us were less able to see the world through the eyes of others than in earlier or later years. I find it easy to forgive college students, whether activists or otherwise, when they display that quality. It doesn't make them bad people. Still, good people can harm important causes. I wish the ideological cohort that makes privilege so central to their analysis would expend more effort reflecting on this fact: Those on track to earn degrees from prestigious universities are unusual in their ability to indulge rhetoric and actions without reflecting on how they will be perceived by fellow citizens or undermine the rights of the powerless.
Put more simply: Please stop undermining #NeverTrump and the culture of free speech that will be especially vital if the billionaire with authoritarian tendencies is elected president.
Off campus, these students have managed to generate lots of incredulous coverage—and some open mockery—from the Washington Post, ABC News, Gawker, People Magazine, the Associated Press, CBS, The Week, The Atlanta-Journal Constitution, The Daily Beast, and beyond. Has there ever been a more self-evidently counterproductive course willingly taken by activists than the one presently unfolding? Outsiders can only hope Emory's president doesn't succeed in finding whoever wrote the messages and making a martyr out of a Trump supporter in media outlets that would in almost no other circumstances regard his partisans as victims of unfair treatment.
Already, other damage has been done. Earlier this week, I noted that a black student at UC Davis suffered a hate crime near campus. Three men were later arrested for the assault. Previously, I've highlighted the horrifying affects of NYPD spying on innocent Muslim students and the UC Berkeley riot police that turned batons on students. There is sometimes good reason for college students to be concerned about their physical safety on campus, and there are incidents of racism that do not threaten physical safety but are nevertheless abhorrent and understandably upsetting. When students react like this to the mere appearance of the name of a leading candidate in the middle of a presidential-election year, treating the most commonplace political advocacy as if it makes them unsafe, they create perverse incentives for invoking victimhood and deflate the currency of claimed trauma and offense.
After much searching, the most thoughtful defense of Emory's student activists I could find came from Osita Nwanevu, a recent graduate of the University of Chicago and editor of the South Side Weekly. By way of background, he recently published a provocative Harper's essay that casts today's leftist campus protesters as intellectual inheritors of William F. Buckley and concluded that isn't actually a bad thing.
About Emory, he said this:
Yesterday: Trump supporters' violence & rhetoric re: race are scary
Today: Look at these idiot minority students afraid of Trump supporters
— Osita Nwanevu (@OsitaNwanevu) March 23, 2016
I can see, though, why this is laughable to non-minority journos who don't have to live in close quarters with potential white supremacists.
Anyway, "These fools are afraid of chalk" is a very good meme. Great job, everyone. 10/10.
"Lol, why would minority students feel 'unsafe' about people proclaiming Trump support on campus, haha" https://t.co/u6WcnYACjQ
Those Tweets gesture at a perceived contradiction: Lots of public intellectuals and journalists at outlets from Gawker to National Review regard Trump as a genuinely dangerous figure. Yet they mock students who feel frightened by support for the candidate.
For like-minded observers who perceive an inconsistency, let me try to explain why, even apart from consequentialist concerns, I don't think the widespread backlash to Emory activists is contradictory, even among those who fear a Trump administration.
It is grounded in these premises:
All Emory University students have been aware for months that they live amid lots of Donald Trump supporters. He is the leading contender for the Republican nomination. He easily won the GOP primary in the state of Georgia. The fact that one or two Trump supporters with access to chalk live close enough to Emory to write "Trump 2016" on their sidewalks is not new information. For that reason, most observers find it difficult to believe that these students are fearful or traumatized because they're newly aware of living near Trump supporters and have concluded they're not physically safe anymore.
While the students are not literally afraid of chalk, they have given most observers the impression that they are more upset by the fact that someone in their community is speaking out in favor of Trump than the underlying reality of his base. That's because they—not their critics—have made the chalking the subject of their activism. Doing so has reinforced the notion that college students are irrationally focused on policing what people say at the expense of confronting and grappling with whatever it is that people believe. As the editor of the student newspaper at Emory aptly countered, "Institutionally prohibiting an ignorant, hurtful or violent idea does not destroy it; it allows the idea to grow and worsen in the shadows, far from the moderating effects of public scrutiny. The best way to destroy an idea is to confront it."
Indeed, if it really had taken these chalk messages to awaken some Emory students to the fact that Trump may win the presidency and enjoys substantial support among Georgia residents, their appearance would have been salutary, insofar as they would've helped these students to confront an ugly reality while there is still time to organize and prevent Trump from winning.
Meanwhile, most observers—even those, like myself, who fully see the vile racism and xenophobia that have characterized Trump's campaign— understand that supporting Trump 2016 does not automatically make someone a racist or a xenophobe, never mind a threat to the safety of those around them. The seeming inability of students to understand that what it would mean for them to support Trump is not what many others mean by supporting Trump—that Americans support politicians for all sorts of complicated, irrational, contradictory, quirky, unexpected, or sui generis reasons—is a major failing on the part of the students themselves and their educators.
This failure dramatically weakens the ability of these students to understand, engage with, and persuade Trump supporters in the upcoming election, and to participate more broadly in a civic system that depends, at some level, on overcoming the typical-mind fallacy. There are surely actual Trump voters on Emory's campus. If the campus climate were different, perhaps they could be persuaded, in the course of discussion, to see the error of their ways. Do you think they'll out themselves to fellow students now?
And look at this passage in Wagner's response to this controversey: "After meeting with these students, I cannot dismiss their expression of feelings and concern as motivated only by political preference or over-sensitivity. Instead, the students with whom I spoke heard a message, not about political process or candidate choice, but instead about values regarding diversity and respect that clash with Emory's own." In his formulation, the fact that they "heard a message" about "values regarding diversity" is somehow offered as if it proves that they aren't motivated by "over-sensitivity." But if someone were acting out of "over-sensivity" wouldn't it logically be because they heard a message that wasn't, in fact, there? Wagner hasn't yet put together a coherent explanation of his own thought process.
In a subsequent Tweet, Nwanevu wrote this:
I wonder why people don't get that students do this in college precisely *because* they won't be able to afterwards. https://t.co/245CiEL1O1
Actually, the more cynical critics of progressive campus activists believe precisely that they are motivated by the relative power they now hold, not by truly feeling unsafe—in this telling, they are using their ideological clout on college campuses to punish speech they don't like from people with less power in that space, and if the same ideological cohort ever attains power outside campus, it will try to suppress speech there, too. Lots of Trump supporters are motivated precisely by the belief that, without a guy like Trump to represent their tribe, their own speech will be suppressed.
But there is an even more direct rejoinder to Nwanevu's claim: Emory activists who believe that they are being effective within the bubble of their campus are wrong. The student newspaper editor, Zak Hudak, expressed his own aversion to Trump while pointing out the obvious unacceptability of suppressing "Trump 2016" advocacy.
On Yik Yak, a social media app popular among college students in large part because it permits anonymous speech, the Emory student reaction to the chalk controversy wasn't mixed, as often happens when one views that platform during a campus controversy. It was clearly, overwhelmingly antagonistic to the student activists. Keep in mind that the content that follows, which went on for scroll after scroll, dominating the platform, was all posted within 1.5 miles of Emory's campus:
Knowing that is the reaction in an enclave wildly more progressive than America as a whole, you'd think that the activists at Emory might change their approach.
In activist circles, being "a bad ally" is a serious charge.
And right now, Emory's chalk-focused activists and its president are the worst allies imaginable for anti-Trumpism. They're not just ineffective, they're doing all harm and no good. They're focused on how Trump supporters make them feel rather than opposing his rise as effectively as possible. And their abandonment of liberal values bolsters the false belief of Trump supporters that such values are only ever invoked cynically.
That is fuel for more illiberalism. And insofar as America becomes a zero-sum game to see who can do the most to suppress the speech of whom, the campus left will not win. Why aren't more tenured faculty members who understand that speaking up?
Everyone who wants to see Trump and the pernicious trends he represents defeated in American life, or who doesn't want to see future activists identified by surveillance footage and punished, should look to Emory for a case study in what not to do.
The liberal coalition can't afford any more such self-indulgence.
This is an election season. If you live in a state that Trump could possibly win in a primary or general election, you can buy some chalk yourself. You can learn how to canvas and go door to door; volunteer at a phone bank; or pick a civil-liberties organization that protects the sorts of people that you regard as most vulnerable and see if you can volunteer on their behalf. There are dozens of things that would help weaken Trumpism. Fighting to persuade a university president to denounce and punish Trump supporters is not one of them.


Religious education is central to the life of our school community reaching out into all aspects of it, at all times. The Catholic Faith is presented to all pupils through the experience of living, working and praying together; through the Scriptures; the Liturgy and through the Doctrine.
The children are prepared for the sacraments of Reconciliation and Eucharist in year 3. Their teachers work closely with our priests, parish catechists and of course, the parents. Together, we nurture the growth of the life of Christ within our pupils and develop their ability to recognise and respect Christ in themselves and their neighbour.
Bede, also known as Saint Bede, Venerable Bede, and Bede the Venerable, was an English monk at the monastery of St. Peter and its companion monastery of St. Paul in the Kingdom of Northumbria of the Angles.


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SuperShuttle Shuts Down After More Than 30 Years Of Opperating
SuperShuttle Shuts Down
Losing a Good Friend at the Airport
After more than 30 years of picking people up at LAX and other airports SuperShuttle has shut down at the end of 2019. Prime Time and SuperShuttle have worked side by side since the beginning of shared ride shuttles at LAX. Shortly after Prime Time began operations the blue vans began rolling alongside our red ones.
However, due to increased competition and regulation changes those vans will no longer be picking people up at the airport anymore. We have continued to improve our technology and operations to stay up to date. These changes allow us to remain in business while SuperShuttle closes its doors.
Prime Time isn't Going Anywhere
Even though it saddens us to see this longtime companion of ours shutting down, we are still committed to serving customers who need a ride. To help SuperShuttle customers without a ride, throughout all of 2020, we are offering $5 off on the first ride for all new Prime Time users. Simple use the code SUPERRIDE at checkout to receive $5 off your first ride. This code is good for all our service types from Shared Vans all the way up to Private Luxury SUVs.
You can count on Prime Time picking you up at all Southern California Airports for years to come. This new change leaves Prime Time as the only remaining airport shuttle company at many airports including LAX. As the last remaining true rideshare company at LAX we are committed to providing great service.
OO Spotlight : Eric Pouncie August 1, 2011
Prime Time Shuttle to stop commercials on LA Clippers games April 28, 2014
Galaxy Giveaway March 17, 2011

redpajama_set_name: RedPajamaCommonCrawl


Dr. Charles Stillman has contributed to 3 publications.
Anterior cruciate ligament injury and bucket handle tear of the medial meniscus.
Ballas, E.R., Stillman, C.A.; J Orthop Sports Phys Ther. 2009-10-01.
Evaluation of anomalous systemic and pulmonary venous return in a young child with heterotaxy: a case study--implications for military dependent care.
Kinney, J.B., Gilman, M.D., Bolt, S.L., Zenger, D.C., Belser, C., Stillman, C.A., Sahn, D.J.; Mil Med. 2008 Mar.
Utility of hematuria testing in patients with suspected renal colic: correlation with unenhanced helical CT results.
Luchs, J.S., Katz, D.S., Lane, M.J., Mellinger, B.C., Lumerman, J.H., Stillman, C.A., Meiner, E.M., Perlmutter, S.; Urology. 2002 Jun.


ITL had a website that was built by an amateur web designer using an HTML editor similar to Dreamweaver. The website was lacking structure and content. The website offered no functionality and minimal design elements. ITL wanted a website that better represented their professional services and friendly atmosphere. They also requested that the website be easy to maintain, offer some functionality and present content that is relevant to their industry. The company was also lacking a universal, professional brand.
Web Hosting Server Setup, Domain Registry Assistance, Email Configuration, Content Building, SEO Strategy, Keyword Coordination, Analyic Reporting, Social Media Development, Social Media Integration, Photography, Stock Images, Website Maintenance and Training, Brand Development, Business Cards and Other Printed Marketing Materials.
Ponchatoula Company Gets Website With Power!


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Police Reform Resources
T he Burlington SWAT unit was formed in 2002. The purpose of the unit is to enhance the overall effectiveness of police services and to respond to unusual operational occurrences and activities. These activities can include hostage situations; barricaded subjects; high-risk search warrants; fugitive apprehension; crowd control; dignitary protection; and other related tactical circumstances. SWAT consists of tactical operators as well as snipers and negotiators who have received specialized training for the unit. The team has grown over the years to become a multi-agency team with members from the Elon Police Department, Elon Campus Police Department, and the Graham Police Department. The SWAT also trains with the Alamance County Sheriff's Department and the Mebane Police Departments Response Teams on a monthly basis.
Members of SWAT attend extensive training. A few of the courses are basic SWAT school, active shooter, chemical munitions, distraction devices, high-risk apprehension, and other tactical training. The team assists the Burlington Police Department and other Alamance County law enforcement agencies with high-risk search and arrest warrants, apprehension of known serious offenders, violent felons, and search and rescue operations. The team has also participated in operations with the Federal Bureau of Investigation (FBI) and the Drug Enforcement Agency (DEA) on federal investigations.
By partnering with other local law enforcement agencies, the team has been able to expand its manpower and territorial jurisdiction. Through these partnerships, SWAT has become well-equipped, well-trained, and capable of responding to a variety of situations within Burlington and Alamance County.
Public Body Worn Camera Videos
Strategic Planning 2022
Records Section
Evidence Control Unit
Victim/Witness Assistance
Crime Data
Offer Feedback
Burlington Police Department
267 W. Front Street


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Q: Better way to catch the state of my action in my app + react-redux +react-router I create an example to use react-redux in my app that is working and print the value of my test, my doubt here is exist other way to catch the state of the store and don't write the code login[0].user to catch the value of the reduce that i will save.
thanks to all
File:: APP
import React from 'react'
import { BrowserRouter, Route, Switch } from 'react-router-dom'
import Login from '../pages/Login'
import NotFound from '../pages/404'

const App = () => (
    <BrowserRouter>
        <Switch>
            <Route exact path="/login" name="Login Page" render={props => <Login {...props}/>}  />
            <Route component={NotFound}/>
        </Switch>
    </BrowserRouter>
)
export default App

File login
import React from 'react'
import {connect} from 'react-redux'
const Login = (...login) => {
  console.log("value before")
  console.log(login)
  const loginUser = login[0].user;
  console.log("valor after")
  console.log(loginUser)

}

const mapStateProps = (state)=>{
  return{
    user: state.loginUser,
  };

}
const wrapper = connect(mapStateProps);
const component = wrapper (Login);

export default component

File store
import { createStore, combineReducers } from 'redux'
import loginUser from './Redux/reducer/loginUser'

const reducer =combineReducers({loginUser})
const store = createStore(reducer)

export default store

File Reducer
const defautlState={username:'test',password:'test'};

function reducer(state= defautlState,{type,payload}){
    switch(type){
        case 'saveSession':{
            return {
                username:'test2',
                password:'test2'
            };
        }
        default:
            return state;
    }

}

export default reducer;

File Action creator
export const type = 'saveSession'

const saveSession = user =>{
    return {
        type,
        payload:user,
    };

};

export default saveSession;

A: The reason that you need login[0] is because of the way that you have defined Login here:
const Login = (...login) => {

The ... means that login is an array of rest parameters and that your Login component can take any number of arguments.  This isn't right because React components can only take one argument which is a object of props.
You want to define it like this:
const Login = (props) => {
  const user = props.user;
  // rest of the component
}

Or you can destructure the arguments:
const Login = ({user}) => {
  // rest of the component
}

You could also take no arguments and get the value of user from useSelector instead of connect.
import React from 'react';
import {useSelector} from 'react-redux';

const Login = () => {
  const user = useSelector( state => state.loginUser );
  // rest of the component
}

export default Login;

redpajama_set_name: RedPajamaStackExchange


Ways to Approach people (including teachers) about your book!
1. First look at your target audience or niche market. If your book targets students of any age group, schools are an excellent place to sell books. If your book doesn't target students, think about other groups of people who it might help. Many churches have small groups and age- or gender-based fellowship groups. Other community associations and service groups are often looking for speakers.
Presentations should be around 20 minutes minimum, an hour max. Think about what your book can teach, and focus on that in the presentation. Your book itself should certainly be a part of the presentation, but don't make it the entire focus.
2. Look at what your book is geared toward, then focus on that.
If your book is geared toward a certain topic such as: Self Help Topics, see what groups are in your area that cover toward this.
If your book is a health or medical book, you can attend medical conventions and offer your expertise.
If your book is geared toward teens, place your book on online teen websites.
3. Different ways to approach people. Emails are more friendly and don't seem too pushy. Schools post teacher's emails on their sites. Cold calls are more direct but can be handled in a friendly way. (Some people prefer this method.) Send letters out to teachers, libraries, businesses, bookstores etc.
3. Have a way for people to contact you. List your contact information on your website. Have a page explaining that you are available for bookings.
Now lets look at ways to reach children. Schools are full of children. Teachers have a hard job to do and sometimes need to take a break. That is where you come in. You might offer your assistance to them by offering to come do a speech to the kids. Below is an example email you could send them. Make sure you follow up with them. If they agree on you coming in to their school, then let send them a book order form that kids can buy your books before hand. You might want to bring some free pencils or stickers to those that didn't purchase a book.


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\section*{Abstract}

Iron is essential for all known life due to its redox properties, however these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases and as our understanding of iron metabolism improves the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism, however a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive.

A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease.

This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.

\section*{Author Summary}
Iron is an essential nutrient required for healthy life but, in excess, is the cause of debilitating and even fatal conditions. The most common genetic disorder in humans caused by a mutation, haemochromatosis, results in an iron overload in the liver. Indeed the liver plays a central role in the regulation of iron. Recently, an increasing amount of detail has been discovered about molecules related to iron metabolism, but an understanding of how they work together and regulate iron levels (in healthy people) or fail to do it (in disease) is still missing. We present a mathematical model of the regulation of liver iron metabolism that provides explanations of its dynamics and allows further hypotheses to be formulated and later tested in experiments. Importantly, the model reproduces accurately the healthy liver iron homeostasis and simulates haemochromatosis showing how the causative mutation leads to iron overload. We investigate how best to control iron regulation and identified reactions that can be
targets of new medicines to treat iron overload. The model provides a virtual laboratory for investigating iron metabolism and improves understanding of the method by which the liver senses and controls iron levels.

\section*{Introduction}

Iron is an essential element from archaea to complex eukaryotes and man \cite{Aisen2001Chemistry}, and is required for many processes including oxygen transport, DNA synthesis and respiration. Iron deficiency is the most common nutritional deficiency affecting a large proportion of all humans \cite{TussingHumphreys2012Review}. The redox activity which provides iron's utility also means poorly regulated iron metabolism can lead to highly toxic free radicals \cite{Kell2009Iron}. Maintaining the delicate balance of iron requires robust cellular and systemic regulation since both iron deficiency and overload can cause cell death \cite{Hentze2004Balancing}. Recent research has lead to a much greater understanding of the mechanisms controlling iron metabolism and a global view of the interactions between iron-related components is beginning to emerge \cite{Dunn2007Iron, Hower2009General}.

The liver has been proposed to play a central role in the regulation of iron homeostasis \cite{Frazer2003Orchestration} through the action of the recently discovered hormone hepcidin \cite{Park2001Hepcidin}. Hepcidin is expressed predominantly in the liver \cite{Pigeon2001New} and distributed in the serum to control systemic iron metabolism. Hepcidin acts on ferroportin to induce its degradation. Ferroportin is the sole iron exporting protein in mammalian cells \cite{VanZandt2008Iron}, therefore  hepcidin expression reduces iron export into the serum from enterocytes, and reduces iron export from the liver.  Intracellular iron metabolism is controlled by the action of iron response proteins (IRPs) \cite{Hentze1996Molecular}. IRPs post-transcriptionally regulate mRNAs encoding proteins involved in iron metabolism. IRPs combined with ferritin and the transferrin receptors (TfR) make up the center of cellular iron regulation. Ferritin is the iron-storage protein forming a hollow shell which counters
the toxic effects of free iron by storing iron atoms in a chemically less reactive ferrihydrite \cite{Harrison1977Ferritin}. Extracellular iron circulates bound to transferrin (Tf), and is imported into the cell through the action of membrane bound proteins transferrin receptors 1 and 2 (TfR1 and TfR2). Human haemochromatosis protein (HFE) competes with transferrin bound iron for binding to TfR1 and TfR2 \cite{West2001Mutational}.

Systems Biology provides an excellent methodology for elucidating understanding, through computational modelling, of the complex iron metabolic network. A quantitative model of iron metabolism allows for a careful and principled examination of the effect of the various components of the network. Modelling allows one to do ``what-if'' experiments leading to new hypotheses that can later be put to test experimentally. However, no comprehensive model of liver iron metabolism exists to date. Models have been published that cover specific molecular events only, such as the loading of iron in ferritin \cite{Salgado2010Mathematical}. A qualitative map of mammalian iron metabolism provides a detailed overview of the molecular interactions involved in iron metabolism, including in specific cell types \cite{Hower2009General}. Similarly, a detailed model of iron metabolism and oxidative stress was described but uses a Boolean approach and is specific for yeast \cite{Achcar2011}. Quantitative models of the iron network
have been recently described
\cite{Chifman2012Core,Mobilia2012}, yet these include only a few components of the iron network. The model from Chifman {\it et al.} suggests that the dynamics of this iron network is stable \cite{Chifman2012Core}. Large-scale models of the metabolism of the hepatocyte \cite{Gille2010,Krauss2012} and a generic human metabolism stoichiometric model \cite{Thiele2013} have also been published, but these contain only four reactions relating to iron metabolism. While they include iron transport, the receptors are not considered, and regulatory details are absent altogether.

Existing models are therefore at two extremes of detail: very specific and very generic --- but to address questions about hepatic iron regulation, what is desirable is a model that balances coverage and detail. This is the aim of the present work. One of the
problems of modelling iron metabolism quantitatively and in detail arises from the lack of parameter values for many interactions.
Recently, several of those parameters have been described in the literature (Table \ref{tab:reaction_parameters}), particularly using technologies like surface plasmon resonance. This has enabled us to construct a detailed mechanistic kinetic model of human hepatocyte iron metabolism. The model has been validated by being able to reproduce data from several disease conditions --- importantly, these physiological data were not used in constructing the model. This validation provides a sense of confidence that the model is indeed appropriate for understanding liver iron regulation and for predicting the response to various environmental perturbations.

\section*{Results}

Our model was constructed based on many published data on individual molecular interactions (see Methods section), and is available in Systems Biology Markup Language (SBML) and COPASI formats in supplementary data, as well as from BioModels (http://identifiers.org/biomodels.db/MODEL1302260000) \cite{LeNovere2006BioModels}. Figure \ref{bigDiagram} depicts a process diagram of the model, using the Systems Biology Graphical Notation (SBGN) standard \cite{Novere2009Systems},  where all the considered interactions are shown. It is important to highlight that while results described below are largely in agreement with observations, the model was not forced to replicate them. The extent of agreement between model and physiological data provides confidence that the model is accurate enough to carry out ``what-if'' type of experiments that can provide quantitative explanation of iron regulation in the liver.

\subsection*{Steady State}

Initial validation of the model was performed by assessing the ability to recreate experimentally-observed steady-state concentrations of metabolites and rates of reactions. Simulations were run to steady state using the parameters and initial conditions from Tables \ref{tab:tableOfParams} and \ref{tab:reaction_parameters}. Table \ref{tab:tableOfSS} compares steady-state concentrations of metabolites and reaction rates with experimental observations.

Chua {\it et al.}  \cite{Chua2010Iron} injected radio-labeled transferrin bound iron into the serum of mice and measured the total uptake of the liver after 120 minutes. The uptake rate, when expressed as mol/s, was close to that found at steady state by the computational model (Table \ref{tab:tableOfSS}).

A technical aspect of note in this steady state solution, is that it is very stiff. This originates because one section of the model is orders or magnitude faster than the rest: the cycle composed of iron binding to ferritin, internalization and release. Arguably this could be resolved by simplifying the model, but the model was left intact because this cycling is an important aspect of iron metabolism and allows the representation of ferritin saturation. Even though the stiffness is high, our software is able to cope by using an appropriate numerical method.

\subsection*{Response to Iron Challenge}
An oral dose of iron creates a fluctuation in serum transferrin saturation of approximately 10\% \cite{Girelli2011Time}. The fixed serum iron concentration in the simulation was replaced by a transient increase in concentration equivalent to a 10\% increase in transferrin saturation as a simulation of oral iron dosage on hepatocytes. The simulated hepcidin response (Figure \ref{fig:IronResponse}A) is consistent with the hepcidin response measured by Girelli {\it et al.}  \cite{Girelli2011Time} (Figure \ref{fig:IronResponse}B \& C). The time scale and dynamics of the hepcidin response to iron challenge has been accurately replicated in the simulation presented here. Although the exact dynamics of the simulated response is not validated by either experimental technique (mass spectrometry or ELISA) the simulation appears to present an approximation of the two experimental techniques reaching a peak between 4 and 8 hours and returning to around basal levels within 24 hours.

\subsection*{Cellular Iron Regulation}

The computational model supports the proposed role of HFE and TFR2 as sensors of systemic iron. Figure \ref{fig:IronChangeHFETfR}B shows that as the concentration of HFE bound to TfR2 (HFE-TfR2) increases with serum transferrin-bound iron (Tf-Fe\_intercell), at the same time the abundance of HFE bound to TfR1 (HFE-TfR1) decreases. The increase in HFE-TfR2 complex, even though of small magnitude, promotes increased expression of hepcidin (Figure \ref{fig:IronChangeHFETfR}A). It is through this mechanism that liver cells sense serum iron levels and control whole body iron metabolism through the action of hepcidin. Although the labile iron pool increases with serum transferrin-bound iron in this simulation, this is only because the model does not include the action of hepcidin in reducing duodenal export of iron. Expression and secretion of hepcidin will have a global effect of reducing the labile iron pool.

\subsection*{Hereditary Haemochromatosis Simulation}
Hereditary haemochromatosis is the most common hereditary disorder with a prevalence higher than 1 in 500 \cite{Asberg2001Screening}. Type 1 haemochromatosis is the most common and is caused by a mutation in the HFE gene leading to a misregulation of hepcidin and consequent systemic iron overload.

A virtual HFE knockdown was performed by reducing 100-fold the rate constant for HFE synthesis in the model, to create a simulation of type 1 hereditary haemochromatosis. The simulation was run to steady state and results were compared with experimental findings.

Qualitative validation showed the {\it in silico} HFE knockdown could reproduce multiple experimental findings as shown in Table \ref{table:tableHFEKO}. Quantitatively the model was unable to reproduce accurately the finding that {\it Hfe -/-} mice have 3 times higher hepatic iron levels \cite{Fleming2001Mouse}. This was due to the fixed intercellular transferrin bound iron concentration in the model, unlike in {\it Hfe -/-} mice where there is an increase in transferrin saturation as a result of increased intestinal iron absorption \cite{Fleming2001Mouse}.
Despite fixed extracellular conditions the model predicted an intracellular hepatocyte iron overload which would be further compounded by the systemic effects of the misregulation of hepcidin. The simulation recreated increased ferroportin levels despite the expression of ferroportin remaining the same as wild type which was consistent with mRNA measurements from Ludwiczek {\it {\it et al.} } \cite{Ludwiczek2005Regulatory}. mRNA based experiments can be used to validate expression rates and protein assays are able to validate steady state protein concentrations as both expression rates and steady state protein concentrations are available as results from the computational model.
The model of haemochromatosis was also able to replicate the dynamics of experimental responses to changing dietary iron conditions. An approximate 2-fold increase in hepatic ferroportin expression is caused by increased dietary iron in both haemochromatosis and healthy mice \cite{Ludwiczek2005Regulatory}. The model presented here recreated this increase with increasing intercellular iron as can be seen in Figure \ref{fig:IronChangeFPN}.

HFE knockout has been shown to impair the induction of hepcidin by iron in mouse \cite{Ludwiczek2005Regulatory}, and human \cite{Piperno2007Blunted} hepatocytes and this was seen in the computational model as increasing transferrin bound iron did not induce hepcidin as strongly in HFE knockdown.

Although an increase in transferrin receptor 2 was observed in the model ($1.77\mu M$ healthy; $2.80\mu M$ type 1 haemochromatosis), the up-regulation was slightly smaller than the change observed in vivo \cite{Robb2004Regulation}. This is due to the model having fixed extracellular transferrin bound iron concentration, in contrast to haemochromatosis where this concentration increases due to higher absorption in the intestine.

Type 3 haemochromatosis results in similar phenotype as type 1 haemochromatosis, however the mutation is found in the TfR2 gene as opposed to HFE. A virtual TfR2 knockdown mutation was performed by decreasing 100-fold the rate constant of synthesis of TfR2 from the model. Model results were then compared with the findings of Chua {\it et al.}  \cite{Chua2010Iron}. The simulation showed a steady state decrease of liver TfR1 from  $0.29\mu M$ to $0.19\mu M$ with TfR2 knockdown. This is supported by an approximate halving of TfR1 levels in TfR2 mutant mice \cite{Chua2010Iron}. An increase in hepcidin and consequent decrease in ferroportin as seen in mice was matched by the simulation.

An iron overload phenotype with increased intracellular iron is not recreated by the model of the TfR2 mutant. This is, again, due to the fixed serum transferrin-bound iron concentration, while in the whole body there would be increased iron absorption from the diet through the effect of hepcidin.

\subsubsection*{Metabolic Control Analysis}
Metabolic control analysis (MCA) is a standard technique to identify the reactions that have the largest influence on metabolite concentrations or reaction fluxes in a steady state \cite{Kacser1973Control,Heinrich1974Linear}. MCA is a special type of sensitivity analysis and thus is used to quantify the distributed control of the biochemical network. A control coefficient measures the relative change of the variable of interest caused by a small change in the reaction rate (e.g. a control coefficient can be interpreted as the percentage change of the variable given a 1\% change in the reaction rate).

The control over the concentration of the labile iron pool by each of the model reactions can be seen in Table \ref{table:MCA}. The synthesis and degradation of TfR2, TfR1, HFE and the formation of their complexes were found to have the highest control over the labile iron pool. Synthesis and degradation of IRP was also found to have some degree of control, but synthesis and degradation of hepcidin have surprisingly a very small effect on the labile iron pool.

The control over the hepcidin concentration was also measured (Table \ref{table:MCAHepc}), as the ability to control hepatic hepcidin levels could provide therapeutic opportunities to control whole system iron metabolism, due to its action on other tissues. Interestingly, in addition to the expression and degradation of hepcidin itself, the expression of HFE and degradation of HFETfR2 complex have almost as much control over hepcidin. The expression of TfR2 has a considerably lower effect, though still significant.

Flux control coefficients were also determined which indicate the control that reactions have on a chosen reaction flux. The flux control coefficients for the ferroportin mediated iron export reaction are given in Table \ref{table:MCAFlux}. This reaction is of particular interest as it is the only method of iron export, therefore controlling this reaction rate could be important in treating various iron disorders including haemochromatosis and anemia. The reactions of synthesis and degradation of TfR1, TfR2 and HFE were found to have high control, despite not having direct interactions with ferroportin. TfR1 and TfR2 may show consistently high control due to having dual roles as iron importers and iron sensors which control hepcidin expression.

A drawback of MCA, and any other local sensitivity analysis, is that it is only predictive for small changes of reaction rates. However, the changes that result in disease states are usually large, and experimental parameter estimation can result in large uncertainty. Thus a global sensitivity analysis was also performed following the method described in \cite{Sahle2008New}. This calculates the maximal and minimal values of the sensitivity coefficients within a large space of parameter values. This technique is useful, for example, if there is uncertainty about the values of the model parameters as it reveals the possible range of control of each one given the uncertainty. All parameters were allowed to vary within $\pm$ 10\% and the maximal and minimal control coefficients were  measured (Tables \ref{table:MCA}, \ref{table:MCAHepc} and \ref{table:MCAFlux}).

In terms of the control of the labile iron pool (Table \ref{table:MCA}), the reactions with highest control in the reference steady state are still the ones with highest control in the global case ({\it i.e.} when all parameters have an uncertainty of $\pm 10\%$). However TfR1 expression, TfR1 binding, TfR1 degradation, IRP expression and IRP degradation, which all have significant (but not the highest) control in the reference state, could have very low control in the global sense.
On the other hand HFETfR2 degradation, hepcidin expression, hepcidin degradation and TfR2 binding 2, have low control in the reference steady state, but could have significant control in the global sense. All other reactions have low control in any situation.

In the case of the control of hepcidin concentration (Table \ref{table:MCAHepc}) the differences between the reference state and the global are much smaller overall, and one could only identify a few reactions that have moderate control in the reference, but could have a bit less in the global sense (TfR2 expression, TfR2 binding, and TfR2 iron internalisation).

In the case of the control of the flux of iron export (Table \ref{table:MCAFlux}), we find some reactions with high control in the reference that could have low control in the global sense: TfR1 expression, TfR1 biding, TfR1 degradation, IRP expression and IRP degradation. Hepcidin expression, hepcidin degradation, and HFETfR2 degradation have almost no control in the reference, but in the global sense they could exert considerable control. This is very similar to the situation of the control of the labile iron pool.

Chifman {\it et al.}  \cite{Chifman2012Core} analysed the parameter space of their core model of iron metabolism in breast epithelial cells and concluded the system behavior is far more dependent on the network structure than the exact parameters used. The analysis presented here lends some support to that finding, since only a few reactions could have different effect on the system if the parameters are wrong.
A further scan of initial conditions for metabolites found that varying initial concentrations over 2 orders of magnitude had no affect on the steady state achieved (Table \ref{tab:tableOfSS}), indicating that the steady state found in these simulations is unique.

\subsection*{Receptor Properties}
It is known that the iron sensing by the transferrin receptors is responsive over a wide range of intercellular iron concentrations \cite{Lin2007Iron}. The present model reproduces this well (Figure \ref{fig:TfRResponse}A, $1\times$ turnover line). Becker {\it et al.} argued that a linear response of a receptor to its signal over a wide range could be achieved through a combination of: high receptor abundance, increased expression when required, recycling to the surface of internalised receptors and high receptor turnover \cite{Becker2010Covering}. This was illustrated with the behaviour of the erythropoietin (EPO) receptor \cite{Becker2010Covering}. Since the present model contains essentially the same type of reactions that can lead to such a behaviour, simulations were carried out to investigate to what extent this linearity of response is present here. In this case it is the response of the total amount of all forms of TfR1 and TfR2 bound to Tf-Fe against the amount of Tf-Fe\_intercell that
is important. A variable was created in the model to reflect the total receptor response (see Material and Methods), and this variable was followed in a time course response to an iron pulse (Figure \ref{fig:EpoIron}A). The response to the iron pulse is remarkably similar to the response of the EPO receptor to EPO \cite{Becker2010Covering}.

Becker et al. \cite{Becker2010Covering} reported that the linearity of EPO-R response, {\it i.e.} the integral of the response curve, is increased by increasing turnover rate of the receptor and this property was also observed in the simulation of TfR1 response (Figure \ref{fig:TfRResponse}). The range in which the iron response is linear is smaller than that found for EPO (Figure \ref{fig:TfRResponse}). As TfR1's half life in the model matches the experimentally determined value \cite{Chloupkova2010Stoichiometries} the non-linear receptor response seen in the simulation is expected to be accurate. This suggests that TfR1 is a poor sensor for high levels of intercellular iron. On the other hand TfR2 is more abundant than TfR1 \cite{Chloupkova2010Stoichiometries} and accordingly shows an increased linearity for a greater range of intercellular iron concentrations (Figure \ref{fig:TfR2Response}). This suggests the two transferrin receptors play different roles in sensing intercellular iron levels with TfR2
providing a wide range of
sensing and TfR1 sensing smaller perturbations. The
activation of TfR2 directly influences the expression of hepcidin and therefore it is desirable for it to sense large systemic imbalances. TfR1 does not modulate hepcidin expression itself instead it plays a primary role as an iron transporter .

\section*{Discussion}

Iron is an essential element of life, in humans it is involved in oxygen transport, respiration, biosynthesis, detoxification, and other processes. Iron regulation is essential because iron deficiency results in debilitating anemia, while iron excess leads to free radical generation and is involved in many diseases \cite{Kell2009Iron}. It is clear that healthy life depends on tight regulation of iron in the body. The mechanisms involved in iron absortion, transport, storage and regulation form a complex biochemical network \cite{Hower2009General}. The liver has a central role in the regulation of systemic iron metabolism through secretion of the peptide hormone hepcidin.

Here we analysed the hepatic biochemical network involved in iron sensing and regulation through a mathematical model and computer simulation. The model was constructed mostly based on {\it in vitro} biochemical data, such as protein complex dissociation constants. The model was then validated by comparison with experimental data from multiple physiological studies at both steady state and during dynamic responses. Where quantitative data were available the model matched these well and also qualitatively recreated many findings from clinical and experimental investigations. The simulation accurately modelled the highly prevalent iron disorder haemochromatosis. The disease state was simulated through altering a single parameter of the model and showed quantitatively how an iron overload phenotype occurs in patients with a HFE mutation.

Due to the limited availability of quantitative clinical data on human iron metabolism, various other data sources, particularly from {\it in vitro} experiments and animal models, were integrated for the parameterisation of this model.
This computational modelling effort constitutes a clinical translational approach, enabling data from multiple sources to improve our understanding of human iron metabolism. Several arguments could be raised to cast doubt on this approach, such as the the failure of {\it in vitro} conditions to mimic those {\it in vivo} or the difference between animal models and humans. This means that this type of data integration must be carefully monitored in terms of establishing the validity of the resulting model. Examining the behaviour of the model by simulating it at different values of initial conditions or other parameters (parameter scans) is important to establish the limits of utility of the model. Global sensitivity analysis is another approach that
determines the boundaries of parameter variation that the model tolerates before it becomes too distant from the actual system behaviour. Model validation is an essential step in modelling. Validation should be carried out by enquiring if the model is able to match experimental observations that were not used to calibrate it. Here the model was validated by the simulation of haemochromatosis disease, where the model behaviour matched the clinical data (Table \ref{table:tableHFEKO}).

The precise regulatory mechanism behind transferrin receptors and HFE controlling hepcidin expression remains to be validated experimentally, however the model presented here supports current understanding that the interaction of TfR2 and HFE form the signal transduction pathway that leads to the induction of hepcidin expression \cite{Gao2009Interaction}.

The global metabolic control analysis results support the identification of the transferrin receptors, particularly TfR2, and HFE as potential therapeutic targets; a result that is robust even to inaccuracies in parameter values. Although hepcidin would be an intuitive point of high control of this system (and therefore a good therapeutic target), in the present model this is not the case. It seems that targeting the promoters of hepcidin expression may be more desirable. However this conclusion has to be expressed with some reservation that stems from  the fact that the global sensitivity analysis identified the hepcidin synthesis and degradation reactions in the group of those with the largest uncertainty. By changing parameter values by no more than 10\% it would be possible to have the hepcidin expression and degradation show higher control. So it seems important that the expression of hepcidin be studied in more detail. We also predict that the control of hepcidin over the system would be
higher if the
model had included the regulation of intestinal ferroportin by hepatic ferroportin.

The global sensitivity analysis, however, allows taking strong conclusions about the reactions for which the reference steady state is not much different from the maximal and minimal values. It turns out that these are the reactions that have the largest and the smallest control over the system variables. For example, the reactions with greatest control on the labile iron pool and iron export are those of the HFE-TfR2 system. But the reactions of the HFE-TfR1 system have always low control. These two conclusions are valid {\it under a wide range of parameter values}.

Construction of this model required several assumptions to be made due to lack of measured parameter values, as described in Material and Methods. These assumptions may or may not have a large impact on the model behaviour, and it is important to identify those that have a large impact, as their measurement will improve our knowledge the most. Of all the assumptions made, the rates of expression and degradation of ferroportin are those that have a significant impact on the labile iron pool in the model (see Table \ref{table:MCA}). This means that if the values assumed for these rate parameters were to be significantly different the model prediction for labile iron pool behaviour would also be different. The model is therefore also useful by suggesting experiments that will optimally improve our knowledge about this system.

Limitations on the predictive power of the model occur due to the scope of the system chosen. Fixed serum iron conditions, which were used as boundary conditions in the model, do not successfully recreate the amplifying feedbacks that occur as a result of hepcidin expression controlling enterocyte iron export. To relieve this limitation, a more advanced model should include dietary iron uptake and the action of hepcidin on that process.

The model predicts a quasi-linear response to increasing pulses of serum iron, similar to what has been predicted for the erythropoietin system \cite{Becker2010Covering}.  Our simulations   display response of the transferrin receptors to pulses of extracellular transferrin-bound iron that is similar to the EPO-R response to EPO (Figure \ref{fig:TfRResponse}). The integral of this response {\it versus} the iron sensed deviates very little from linearity in the range of physiological iron (Figure \ref{fig:EpoIron}).

Computational models are research tools whose function is to allow for reasoning in a complex nonlinear system. The present model can be useful in terms of predicting properties of the liver iron system. These predictions form hypotheses that lead to new experiments. Their outcome will undoubtedly improve our knowledge and will also either confirm the accuracy of the model or refute it (in which case it then needs to be corrected). The present model and its results identified a number of predictions about liver iron regulation that should be investigated further:
\begin{itemize}
\item changes in activity of the hepcidin gene in the liver have little effect on the size of the labile iron pool,
\item the rate of expression of HFE has a high control over the steady state level of hepcidin,
\item the strong effect of HFE is due to its interaction with TfR2 rather than TfR1,
\item the rate of liver iron export by ferroportin has a strong dependence on the expression of TfR1, TfR2 and HFE,
\item the rate of expression of hepcidin is approximately linear with the concentration of plasma iron within the physiological range.
\end{itemize}

The present model is the most detailed quantitative mechanistic model of cellular iron metabolism to date, allowing for a comprehensive description of its regulation. It can be used to elucidate the link from genotype to phenotype, as demonstrated here with hereditary haemochromatosis. The model provides the ability to investigate scenarios for which there are currently no experimental data available --- thus making predictions about the system and aiding in experimental design.

\section*{Materials and Methods}

The model is constructed using ordinary differential equations (ODEs) to represent the rate of change of each chemical species. COPASI \cite{Hoops2006COPASIa} was used as the software framework for model construction, simulation and analysis. Cell Designer \cite{Funahashi2003CellDesigner} was used for construction of a SBGN process diagram (Figure \ref{bigDiagram}).

The model consists of 2 compartments representing the  serum and the liver.
Concentrations of haeme and transferrin bound iron in the serum were fixed to represent constant extracellular conditions. Fixed metabolites simulate a constant influx of iron through the diet as any iron absorbed by the liver is effectively replenished. A labile iron pool (LIP) consumption reaction is added to represent various uses of iron and create a flow through the system.
Some of the LIP consumption reaction would be attributed to heme biosynthesis however this process was not considered explicitly in this study to avoid unnecessary complexity and because the bone marrow is the major site of heme biosynthesis \cite{Ajioka2016}.

Initial concentrations for metabolites were set to appropriate concentrations based on a literature survey (Table \ref{tab:tableOfParams}). All metabolites formed through complex binding were set to zero initial concentrations (Table \ref{tab:tableOfParams}).
The concentration of a chemical species at a time point in the simulation is determined by integrating the system of ODEs. For some proteins a half-life was available in the literature, but sources could not be found for their synthesis rates (translation). In this occurrence, estimated steady-state concentrations were used from the literature and a synthesis rate was chosen such that at steady state the concentration of the protein would be approximately accurate, following Equation \ref{eq:synthrate}:

\begin{equation}
 \label{eq:synthrate}
\frac{d[\textrm{P]}}{dt} = +k-d[\textrm{P}] = 0.
 \end{equation}

This is solved for $k$ where $[\textrm{P}]$ is the steady-state concentration of the protein and $d$ is the degradation rate obtained from the half-life ($\lambda$) using:

\begin{equation}
 \label{eq:lambda}
d=\frac{\ln{2}}{\lambda}.
 \end{equation}

Complex formation reactions, such as binding of TfR1 to Tf-Fe for iron uptake, are modelled using the on and off binding constants as a forward and reverse mass action reaction. For example:

\begin{equation}
 \label{eq:rev}
\textrm{TfR1}  +  \textrm{Tf-Fe} \rightleftharpoons \textrm{Tf-Fe-TfR1}
\end{equation}

is modelled using two reactions:
\begin{equation}
 \label{eq:irrevf}
\textrm{TfR1}  +  \textrm{Tf-Fe} \stackrel{k_a}{\rightarrow} \textrm{Tf-Fe-TfR1}
\end{equation}

\begin{equation}
 \label{eq:irrevr}
\textrm{Tf-Fe-TfR1} \stackrel{k_d}{\rightarrow} \textrm{TfR1}  +  \textrm{Tf-Fe}
\end{equation}

There is one ODE per each chemical species. The two reactions \ref{eq:irrevf} and \ref{eq:irrevr} add the following terms to the set of ODEs:

\begin{equation}
 \label{eq:ode}
\begin{split}
\frac{d[\textrm{TfR1}]}{dt} =&  -k_a[\textrm{TfR1}][\textrm{TF-Fe}]+k_d[\textrm{Tf-Fe-TfR1}] \ldots\\
\frac{d[\textrm{Tf-Fe}]}{dt} =& -k_a[\textrm{TfR1}][\textrm{TF-Fe}]+k_d[\textrm{Tf-Fe-TfR1}] \ldots\\
\frac{d[\textrm{Tf-Fe-TfR1}]}{dt} =& +k_a[\textrm{TfR1}][\textrm{TF-Fe}]-k_d[\textrm{Tf-Fe-TfR1}] \ldots
\end{split}
\end{equation}

Intracellular haeme levels are controlled by a balance between uptake, export and oxygenation. haeme import through the action of haeme carrier protein 1 (HCP1), export by ATP-binding cassette sub-family G member 2 (ABCG2) and oxygenation by haeme oxygenase-1 (HO-1) follow Michaelis-Menten kinetics. HO-1 expression is promoted by haeme through by a Hill function (Equation \eqref{eqn:Hill}).
\begin{align}
v = [\textrm{S}] \cdot a \cdot &\left( \frac{[\textrm{M}]^{n_{H}}}  {K^{n_{H}}+[\textrm{M}]^{n_{H}}} \right),\label{eqn:Hill}\\
v = [\textrm{S}] \cdot a \cdot &\left( 1-\frac{[\textrm{M}]^{n_{H}}}{K^{n_{H}}+[\textrm{M}]^{n_{H}}} \right).\label{eqn:invHill}
\end{align}
Where $S$ is the substrate, $M$ is the modifier, $a$ is the turnover number, $K$ is the ligand concentration which produces half occupancy of the binding sites of the enzyme, and $n_{H}$ is the Hill coefficient. Values of $n_{H}$ larger than $1$ produce positive cooperativity ({\it i.e.} a sigmoidal response); when $n_{H}=1$ the response is the same as Michaelis-Menten kinetics.  A Hill coefficient of $n_{H}=1$ was assumed unless there is literature evidence for a different value. Where $K$ is not known it has been estimated to be of the order of magnitude of experimentally observed concentrations for the ligand.

IRP/Iron-responsive elements (IRE) regulation is represented by Hill kinetics using Equation \eqref{eqn:Hill} to simulate the 3' binding of IRP promoting the translation rate, and Equation \eqref{eqn:invHill} to represent the 5' binding of IRP reducing the translation rate.
Ferroportin degradation is modelled using 2 reactions: one representing the standard half-life and the other representing the hepcidin-induced degradation. A Hill equation (Equation \ref{eqn:Hill}) is used to simulate the hepcidin-induced degradation of ferroportin.

Hepcidin expression is the only reaction modelled using a Hill coefficient greater than 1. Due to the small dynamic range of HFE-TfR2 concentrations a Hill coefficient of 5 was chosen to provide the sensitivity required to produce the expected range of hepcidin concentrations. The mechanism by which HFE-TfR2 interactions induce hepcidin expression is not well understood, but is thought to involve the mitogen-activated protein kinase (MAPK) signalling pathway \cite{Wallace2009Combined}. The stimulus/response curve of the MAPK cascade has been found to be equivalent to a cooperative enzyme with a Hill coefficient of 4-5 \cite{Huang1996Ultrasensitivity}, making the steep Hill function appropriate to model hepcidin expression.

Ferritin modelling follows the work of Salgado {\it et al.} \cite{Salgado2010Mathematical}. Iron from the LIP binds to, and is internalised in, ferritin with mass action kinetics. Internalised iron release from ferritin occurs through 2 reactions (intact ferritin release and release due to ferritin degradation). The average amount of iron internalised per ferritin affects the iron release rate and this is modelled using Equation \ref{eq:salgado} (adapted from \cite{Salgado2010Mathematical}):

\begin{equation}
 \label{eq:salgado}
v = [\textrm{S}] \cdot k_\textrm{loss} \cdot \left(1+\frac{0.048 \cdot \frac{[\textrm{FT1}]}{[\textrm{FT}]}}{1+\frac{[\textrm{FT1}]}{[\textrm{FT}]}}\right).
\end{equation}

Where $S$ is internalised iron, $k_\textrm{loss}$ is the rate constant and $[\textrm{FT1}]/ [\textrm{FT}]$ is the ratio of iron internalised in ferritin to total ferritin available. The value 0.0048 was obtained by dividing the value given in Salgado {\it et al.} \cite{Salgado2010Mathematical} by 50 as that simulation was scaled for 50 iron atom packages.

Iron is also released from ferritin when the entire ferritin cage is degraded. The kinetics of ferritin degradation are mass action, however the amount of iron released when a ferritin cage is degraded is an average based on ferritin levels and total iron internalised in ferritin. Incorporating mass action and ferritin saturation ratio gives the following rate law for $\textrm{FT1}~\rightarrow~\textrm{LIP}$:

\begin{equation}
v = [\textrm{S}] \cdot k \cdot \frac{[\textrm{FT1}]}{[\textrm{FT}]}.
\end{equation}

Iron export rate was modelled using Equation \ref{eqn:Hill} with ferroportin as the modifier and a Hill coefficient of 1. $K$ was assumed to be around the steady state concentration of IRP ($1\mu M$). A rate (V) of $40\textrm{pm} \cdot (10^6 cells \cdot 5\textrm{min})^{-1}$ was used from Sarkar {\it et al.} \cite{Sarkar2003} and these values were substituted into the equation and solved for $a$.

Ferroportin expression rates and degradation rates are poorly understood. Ferroportin abundance data \cite{Wang2012PaxDb} lead to an estimate of ferroportin concentration around $0.16 \mu M$. The hepcidin induced degradation of ferroportin is represented in the model by a rate law in the form of Equation \ref{eqn:Hill} with a Hill coefficient $n_{H} = 5$ (see above) and a $K^{n_{H}}$ equal to the measured concentration of hepcidin \cite{Zaritsky2010Reduction} (see Table \ref{tab:tableOfParams}). We then assume a maximal rate of degradation to be 1 $nM s^{-1}$, and using the steady state concentration of ferroportin, the rate constant can be estimated as 0.0002315 $s^{-1}$. The ferroportin synthesis rate was then calculated to produce the required steady-state concentration of ferroportin at the nominal hepcidin concentration.

The HFE-TfR2 binding and dissociation constants were also not available and so it was assumed that they were the same as those of TfR1-HFE. Finally, the HFE-TfR and HFE-TfR2 degradation rates are also not known; we used a value that is an order of magnitude lower than the half life for unbound TfR (i.e. we assume the complex to be more stable than the free form of TfR).

Although DMT1 may contribute towards transferrin bound iron uptake in hepatocytes this contribution has been found to be minor and DMT1 knockout has little affect on iron metabolism \cite{Wang2013Hepatocyte}, therefore DMT1 was not included in the model.

The two iron response proteins (IRP1 and IRP2) which are responsible for cellular iron regulation were modelled as a single metabolite in this study as the mechanistic differences in their regulatory roles is poorly understood. Equivalent regulation by both IRPs has been found in multiple studies \cite{Kim1995Translational, Ke1998Loops, Erlitzki2002Multiple}.

Global sensitivity analysis was performed using the method proposed by Sahle {\it et al.} \cite{Sahle2008New}, where all parameter values were allowed to vary within $\pm 10\%$ of their nominal value in the model and we search for the maximum and minimum value that concentration- or flux-control coefficients of interest are able to reach within that parameter space. The searches were carried out with the particle swarm optimisation algorithm \cite{494215}. In order to process these optimisations in a reasonable time  a HTCondor \cite{condor-hunter} distributed computing system was used, managed through the Condor-COPASI package \cite{22834945}.

To perform analysis of receptor response in a similar manner to the EPO system studied by Becker {\it et al.} \cite{Becker2010Covering} initial conditions were adjusted to recreate a similar virtual experiment. Haeme concentration was fixed at zero to isolate transferrin bound iron uptake. The rate constant of the labile iron pool depletion reaction was reduced to balance the reduced iron uptake (which results in iron having a similar half-life to EPO in \cite{Becker2010Covering}). Initial concentrations for all metabolites were set to steady-state concentrations with the exception of the labile iron pool and iron bound to all receptors which were set to zero. Extracellular transferrin bound iron was allowed to vary and set at increasing concentrations to determine receptor response. Time courses were calculated for Tf-Fe-TfR1, 2(Tf-Fe)-TfR1, Tf-Fe-TfR2 and 2(Tf-Fe)-TfR2 as iron binds its two receptors in a two-staged process. Two new variables were defined in COPASI which integrated the results of the time
courses corresponding to the two receptors (in their different ligand states):

\begin{equation}
\textrm{Int\_TfR1\_binding} = \int [\textrm{Tf\-Fe\-TfR1}] \cdot dt + \int [\textrm{2(Tf\-Fe)\-TfR1}] \cdot dt ,
\end{equation}

\begin{equation}
\textrm{Int\_TfR2\_binding} = \int [\textrm{Tf\-Fe\-TfR2}] \cdot dt + \int [\textrm{2(Tf\-Fe)\-TfR2}] \cdot dt .
\end{equation}

\section*{Acknowledgments}

We thank Steve Ackman, Douglas Kell, Reinhard Laubenbacher, Frank Torti and Suzy Torti for many discussions. We thank Ed Kent and the EPS IT Research Services staff for help with running the HTCondor pool. We also thank Anthony West for sharing binding data for HFE, TfR1 and TfR2. SM is grateful to the Virginia Bioinformatics Institute and the Wake Forest University Department of Cancer Biology for hosting visits.

redpajama_set_name: RedPajamaArXiv


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Seeking to put God's love into action, Habitat for Humanity brings people together to build homes, communities and hope.
About Habitat for Humanity International
Habitat for Humanity International (HFHI) is a global, non-profit housing organization operated on Christian principles that seeks to put God's love into action by building homes, communities and hope. HFHI is dedicated to eliminating sub-standard housing locally and worldwide through constructing, rehabilitating and preserving homes; by advocating for fair and just housing policies; and by providing training and access to resources to help families improve their shelter conditions. HFHI was founded on the conviction that every man, woman and child should have a simple, durable place to live in dignity and safety, and that decent shelter in decent communities should be a matter of conscience and action for all.
Founded in Americus, Georgia, USA, in 1976, Habitat for Humanity International today operates around the globe and has helped build, renovate and repair more than 1,000,000 decent, affordable houses sheltering more than 22 million people worldwide.
Habitat for Humanity International and its affiliates have an open-door policy: All who believe that everyone needs a decent, affordable place to live are welcome to help with the work, regardless of race, religion, age, gender, political views or any of the other distinctions that too often divide people. In short, Habitat welcomes volunteers and supporters from all backgrounds and also serves people in need of decent housing regardless of race or religion.
Non-proselytizing Policy
Habitat for Humanity and its affiliate organizations will not proselytize. Nor will Habitat work with entities or individuals who insist on proselytizing as part of their work with Habitat. This means that Habitat will not offer assistance on the expressed or implied condition that people must adhere to or convert to a particular faith or listen and respond to messaging designed to induce conversion to a particular faith.


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Happy To Read Tuesday! Here we're highlighting the 10 titles that our editors are most excited to add to their TBR shelves. For even more hot new releases, check out our Spring Previews for the best books coming out this season.
No, not Wall Street. Sarajevo. In this thriller by Matthew Palmer (who has experience as a diplomat), readers will embark on a gripping adventure in the Balkans. Eric Petrosian lost a lot in the Srebrenica massacre during the Bosnian War, including his friend, Meho Alimerović. He still thinks about the massacre all the time, and has struggled to move forward with his life. Now, with conflict threatening the region again, Petrosian will learn secrets with the power to send shockwaves through the country and its political scene. Fans of thrillers are sure to love this intricate and tense story, and fans of history will appreciate Palmer's careful plotting.
The unthinkable has already happened to Kelsey's mother: She was kidnapped years ago, and escaped. Now that she and Kelsey are safe, she's not going to let anything happen to them ever again. As a result, she has stayed inside for the last 17 years. This situation is unusual, but workable until Kesley slips out one night to see her crush, Ryan, and returns home to find her mother missing. Now, Kelsey must work to find her mother and stay safe herself. Readers who love a little bit of romance with their thrills and chills will love this new young adult novel from Megan Miranda.
Kirkus said it best: "This may be the only book about grief to feel like a vacation." In This Too Shall Pass by Milena Busquets, Blanca is facing a personal tragedy: the death of her mother. In the wake of this loss, Blanca decides to travel to Cadaqués on the coast of Spain to spend some time in her family's old home—now hers. There, she will work on healing and understanding her loss, and also reconnect with exes and old friends. Busquets writes about grief in a way that feels authentic, and Blanca's inner life is vibrant and alive on the page. We think readers will find this book inviting and moving at the same time.
If you're a dog person, you might be surprised to learn how excited people get about pet fish like the Asian arowana, or the dragon fish. Unlike that labradoodle you've been wanting to dognap, the arowana isn't particularly cute, and it definitely isn't cuddly (in fact, they're known for being aggressive). We also hear it isn't great at playing fetch. Still, some enthusiasts will pay more than quarter of a million dollars for just one. Emily Voigt delves into this fascinating subculture, and helps readers understand why people are so fascinated by the dragon fish. We are happy to report that this book about the dragon fish is far less expensive than one of the fish themselves.
Vera's parents go way back—as far as boarding school, in fact, where the two met and decided to procreate before going their separate ways. By the time Vera turns 17, however, both parents—Lucas and Katya—are trying harder to co-parent. Around this time, Vera suffers an episode of psychosis, which prompts Lucas to whisk her away to Lithuania, in order to see if the change of pace and scenery will help Vera to feel better. Meanwhile, Vera grapples with her health, and ponders her changing relationship with her father. Those who enjoy reading about mental health issues and complicated family dynamics won't want to miss this one.
Dan Vyleta's fantasy novel transports readers to Victorian England. It's a world that readers will find unfamiliar, a place where black Smoke emanates from the bodies of sinners, marking them as unclean to the world. Charlie Cooper and Thomas Argyle, students at an elite boarding school, have never questioned the way of the world—only focused on keeping their thoughts clean and their actions kind. When they both meet and fall for Livia, she reveals her laboratory to them and shares the findings of her research: Everything they're told is true is a lie. Unable to trust anyone with this knowledge, the three set out on a mission to uncover the truth about Smoke.
Mary Burton's romantic suspense novel will send chills down your spine. Virginia state trooper Riley Tatum was left unconscious on the streets as a teenager after being kidnapped. She has no memories of her time in captivity other than two men playing cards. Clay Bowman, a former FBI agent and Riley's ex, believes that she was taken by a man known as the Shark—a serial killer who uses girls like chips in a twisted poker game where the loser must commit murder. Riley's the only girl to escape from the Shark alive, and the recent murder of yet another girl indicates that he hasn't forgotten about her. Clay and Riley have to work together to catch the Shark before he strikes.
Mercy Wong is a girl with big dreams and enough moxie to chase after them. With the hope of getting herself and her sick brother out of Chinatown, she bribes her way into an elite boarding school and poses as a wealthy Chinese heiress. Mercy sticks out in the mostly white school, but soon starts to find friends and make a place for herself. Readers familiar with San Francisco's history will know that Mercy's school days are limited. It's 1906 and a historic earthquake is about to strike, leaving the city in chaos. Stacey Lee's second young adult novel is ideal for fans of historical fiction and gutsy heroines.
Fantasy and history mix in this engaging middle grade novel by Rebecca Behrens. When her mom drags her to Roanoke Island for the summer, Nell Dare is certain that she'll be bored to tears. But once she arrives she connects with Ambrose, a colonial re-enactor, and starts to help him look into the mysterious disappearance of the citizens of Roanoke's Lost Colony. Readers are sure to leave this novel and head straight for the stacks at their local library in search of more unsolved historical mysteries.
Little conductors-in-training will eagerly look forward to going to sleep with this picture book as their bedtime reading. Author Brianna Caplan Sayres and illustrator Christian Slade team up to create a sweet rhyming tale that explores what different trains (from freights to trolleys) do when the sun goes down and their work is done. Observant readers will particularly love the train engineer mouse who is present on each and every page, taking as much joy in the story as the readers will.


If you are thinking of starting an email marketing newsletter, you might be wondering how quickly this will start working for you in terms of producing new clients for your business. After all, if you are going to put the time, effort and energy into an email marketing newsletter, you want to know that it will produce for you, yes?
The good news is that in many cases an email marketing newsletter works instantly. As soon as the first email is sent, it produces new clients and puts money into the business bank.
On the flip side, some email marketing newsletters can take a few weeks or even months to start working in terms of producing new business, but if that puts you off, you are missing the main point.
An email marketing newsletter does so much more for you than just bring you new clients, but it will always do that too.
It allows them to print out your newsletter and put it on their wall, seeing your name and your business name every day (yes this does happen).
Amazon send me about three emails every day. I don't always open them, but they send them. When I want to buy something, I remember that they exist.
Your email marketing newsletter gives you a chance of your clients and prospects remembering that you still exist.
For example, in my business, all of my best clients have come from my email marketing newsletter, many of them two years after they first signed up to my email list. Does this disappoint me? No, because when they come to me after two years of receiving my email marketing tips, they are only asking me (no other marketing consultants), they are not concerned about price (within reason – because they want to buy me as the expert not any old marketing expert) and they are ready to get going and make huge changes to their income by winning new clients on a consistent basis, month after month after month.
So an email marketing newsletter can indeed work instantly, and frequently does, but if it does not work instantly for you, let me assure you that stopping it would be the worst possible idea for your business. When it comes to email marketing, persistence and consistency (perconstance I call it) is crucial.
So many people I speak with start an email marketing newsletter for a few weeks, and then because their world hasn't changed overnight, they give in, just before it would have started to work for them.
Look, you are old enough and wise enough to know now that when it comes to growing your business, the 'instant, overnight, no effort route to getting rich quick' does not exist, despite what so many people will tell you.
However, the sure fire, guaranteed way to make your business very profitable method of choosing several core marketing activities as part of your overall marketing plan, particularly when one of those is email marketing, and then consistently doing them is a really smart thing to do.


Optimal extension services can be more easily and effectively provided to stakeholders when frontline agricultural officers – who came into direct contact with our nation's farmers – are trained and equipped in current, best practices. This, according to Agricultural Entomologist (Ag.) in the Ministry of Agriculture, Land and Fisheries (MALF), Ms. Roshni Ramsingh, was the thinking behind an in-house training programme on Pest and Disease Identification and Management, embarked upon by Ministry staff last week.
The three (3)-day training course – which took place at the Packing House of the National Marketing Development Corporation (NAMDEVCO) in Piarco and the Farmers Training Centre in Centeno from March 6, 8-9, 2018 – was facilitated by both Ms. Ramsingh and Agricultural Officer (MALF), Mr. Rishi Mohansingh – both of the Extension Training and Information Services (ETIS) Division. The sessions were aimed at impacting those frontline Extension Officers of both the Regional Administration North (RAN) and Regional Administration South (RAS) Divisions of MALF, by building on their existing knowledge of pests and diseases whilst honing skills in areas of diagnosis and management so as to enable them to successfully carry out field diagnosis as well as prognosis. They comprised a review of the main causes of plant health problems, concentrating mainly on current and potential pests and diseases (including giant African snail; sweet potato weevil; citrus greening and frosty pod) as well as environmental disorders and nutrition.
Mr. Mohansingh's presentation on the Red Palm Mite and Ms. Ramsingh's presentation on the Tomato Midge, wrapped up the training's theoretical discourse on Friday 9th March, 2018, paving the way for the practical exercise which ensued. "We asked the trainees to bring samples of plants which they feel are diseased or have pest problems. So, based on the samples submitted we will now embark on a practical examination of them to determine just how well the trainees have learnt from the theory over the last two (2) days and whether or not they are currently in a position to give and / or administer sound management options," Ms. Ramsingh said.


Annugas Compression Consulting Ltd. is improving oil and gas production with a beam gas compressor. Once installed on the walking beam of a pumpjack, the 'ANNUGAS PRODUCTION ENHANCER®' removes gas that can accumulate during oil production. By drawing off the gas and discharging it into the flowline, back pressure downhole is reduced allowing more fluid to flow out from the formation. The results can be increased production and smoother well operation.
The 'ANNUGAS PRODUCTION ENHANCER®' also allows recovery of vapors from on site processing and storage equipment, assists in decreasing gas locking situations and compress methane gas from surface casing vents into the flowline.
If casing pressure is high in relation to formation pressure, some of the free gas enters into the pump barrel causing gas locks and reducing the pump volumetric efficiency. By reducing the casing pressure on wells with low formation pressures, gas volumes entering the pump barrel are minimized and gas lock problems are reduced. The free gas is diverted into the annulus and produced with the assistance of the 'ANNUGAS PRODUCTION ENHANCER®'.
While compressors for controlling casing pressure are not new, they have not nearly reached their capabilities and potential in the field. Some models have caused problems, typically by being misapplied or installed incorrectly. When properly applied, the 'ANNUGAS PRODUCTION ENHANCER®' can typically improve oil production by about 85%. One application improved production from 6 cubic meters a day to 36 cubic meters a day - overnight.
With a totally non-lube design, there is absolutely no daily maintenance and no environmental cleanup. If a unit has operated for one year, we recommend having an ANNUGAS Service Technician come onsite to inspect and service the compressor package.
Applications for 'ANNUGAS PRODUCTION ENHANCER®' include wells with low formation pressure and low solution gas.


75 of preschool children had at least one friend. Let every nation know, whether it wishes us well or ill, that we shall pay any price, bear any burden, meet any hardship, support any friend, oppose any foe, to assure the survival and the success of liberty. "Most adults have 'only two close friends. A b Newman,. They experience a language delay causing them to have a harder time playing with other children. Finally, to those nations who would make themselves our adversary, we offer not a pledge but a request: that both sides begin anew the quest for peace, before the dark powers of destruction unleashed by science engulf all humanity in planned or accidental self-destruction. Sparks, Glenn (August 7, 2007). 22 :55 In animals edit See also: Ethology, Altruism in animals, and Sociobiology A man with a squirrel Friendship is also found among animals of higher intelligence, such as higher mammals and some birds. (2004) Holism, contextual variability, and the study of friendships in adolescent development. 3 :250 Potential benefits of friendship include the opportunity to learn about empathy and problem solving.
All this will not be finished in the first one hundred days. 3 :248 Demographics edit Friends tend to be more similar to one another in terms of age, gender, behavior, substance abuse, personal disposition, and academic performance. "Children with Autism and Their Friends: A Multidimensional Study of Friendship in High-Functioning Autism Spectrum Disorder". Bauminger, Nirit; Solomon, Marjorie; Aviezer, Anat; Heung, Kelly; Gazit, Lilach; Brown, John; Rogers, Sally.
Most children with Down syndrome may prefer to watch other students and play alongside a friend but not with them, mostly because they understand more than they can outwardly express. Let both sides seek to invoke the wonders of science instead of its terrors. 15 Adulthood edit Friendships in adulthood Friendship in adulthood provides companionship, affection, as well as emotional support, and contributes positively to mental well-being and improved physical health. Romans 12:12 (King James Version of the Holy Bible). Retrieved Further reading edit External links edit. 20 Older adults edit Older adults continue to report high levels of personal satisfaction in their friendships as they age, and even as the overall number of friends tends to decline.


Liberal crank David Goodfriend and The Gateway Pundit's Jim Hoft joined Steve Malzberg on Newsmax TV to discuss News of the Day, specifically: Clinton supporters, money news, Clinton canceling her fundraiser, and Charlotte protests.
"Hillary is in free fall. Everybody knows it. The campaign knows it. She canceled her appearance yesterday. She had a fundraiser in North Carolina. They didn't even give an excuse for it. They just canceled. They are rumors now that she's going to cancel the debate on Monday. Some top conservative wrote me today… And she's really going in the wrong direction. She spent $50 million last month and dropped 10 points. So it's a free fall for Hillary. She's collapsing like she did on 9-11.
Liberal Goodfriend lost it after that.
Poor Democrats are freaking out.


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The Iraq-Vietnam Comparison
by Joseph Carroll
An ongoing subtext in the war with Iraq is whether the situation will turn into "another Vietnam" for the United States -- that is, a war with high U.S. casualties and little obvious progress toward its stated goals.
While it is too early to say whether Iraq will be similar to Vietnam in this regard, we can compare public opinion about Iraq to see how closely it mirrors the trend in public opinion about Vietnam. While Americans initially supported President Lyndon Johnson and generally supported Richard Nixon as they conducted the war, eventually the public came to view the war as a mistake. The public has not reached that stage in its view of the Iraq war, but there are some parallels to the decline in support for Vietnam.
During both conflicts, Gallup asked the public to evaluate how the presidents were handling the war situations, and to assess whether the United States made a "mistake" in sending troops. So far, the data indicate that Americans have generally been more positive about George W. Bush's handling of the war in Iraq than about Johnson's handling of Vietnam, until Bush's Iraq approval ratings recently dipped into the lower 40% range. Public opinion has held steady that it was not a mistake to send troops to Iraq.
War Approval
After roughly 184,000 troops were deployed to South Vietnam by the end of 1965, Gallup found majority approval for Johnson's handling of the situation in four separate polls. The period from December 1965 to late March 1966 would be the only time that a majority supported Johnson's handling of Vietnam. Gallup initially found 56% of adults nationwide approving in December 1965. In January 1966, 57% approved -- the pinnacle of Johnson's approval on Vietnam. Johnson's approval dipped to 50% in February but rebounded to the mid-50% range in March.
By mid-April 1966, less than half of all Americans, 47%, approved of Johnson's handling of Vietnam. From May to December 1966, Johnson's Vietnam approval showed a slight dip, averaging 42% in that period. In May and June 1966, for the first time, more Americans disapproved than approved.
Approval declined further in 1967, with approval averaging 37% for the year and falling as low as 27% in August -- the low point in Johnson's administration. After that, his approval ratings began to improve, reaching 40% in November 1967. However, the improvement was short-lived and his ratings soon fell in early 1968 to 32% by late February, after the Tet Offensive. By the spring of 1968, after Johnson dropped out of the race for president, his ratings on Vietnam improved to the low 40% range.
Nixon was elected in part because of his "secret plan" to end the war in Vietnam. Early in his administration (March and April 1969), 44% of Americans approved of Nixon's handling of Vietnam. Following Nixon's announcement of a peace offer in mid-May, his approval edged up to 52% from 47% earlier in the month. (It is important to note that during the first four months of Nixon's presidency, between a quarter and a third of Americans had no opinion about how Nixon was dealing with Vietnam.)
Polls conducted from July 1969 through November 1969, when the United States began to withdraw troops, show an average Vietnam approval rating of 54% for Nixon. Nixon's Vietnam ratings averaged 54% again in 1970, then 41% in a single poll in 1971, and finally 52% in 1972.
On Jan. 15, 1973, Nixon suspended military action in Vietnam. A Gallup Poll conducted before this announcement found 43% of Americans approving of Nixon. After this announcement and during the signing of the peace accord in Paris, 75% of Americans approved of Nixon.
Bush's Iraq approval was quite steady, with an average of 54%, before the war started in March 2003. Immediately after military action in Iraq began, Bush's approval on Iraq spiked to 71%. It increased to 76% after the fall of Baghdad in mid-April. Roughly a month after Bush announced the end of major combat fighting in Iraq, his approval rating decreased to 63%.
Bush's Iraq approval remained steady in July and August 2003, ranging between 57% and 60%. The ratings began to decline last fall, from 51% in September, to 47% in October, and to 45% in November. In early December, Bush's Iraq rating was 50%. It increased to 61% in an early January 2004 poll, the first Gallup Poll conducted after Saddam Hussein's capture.
Bush's approval ratings on Iraq in 2004 have been marked by a slow, consistent decline. After the 61% rating after Hussein's capture, Bush's Iraq approval dropped to 46% in late January/early February. These ratings increased slightly to 51% in March, before dropping to 48% in April, amid reports describing numerous attacks against U.S. soldiers in Iraq. After reports surfaced in early May about the abuse of Iraqi prisoners, Bush's Iraq approval dropped to 41% -- the low point of his administration. The latest Gallup survey, taken in early June, shows no change in that rating.
Bush's average approval ratings on Iraq are just slightly higher than Nixon's on Vietnam, but both presidents rate substantially higher than Johnson did. Bush now averages a 55% approval rating on Iraq across 24 polls conducted October 2002 through early June 2004. This compares with Nixon, who averaged 52% across 21 surveys from March 1969 until January 1973, and Johnson, who only averaged 41% over 38 polls from December 1965 to May 1968.
Mistake Sending Troops?
So far, the American public is not convinced that it was a mistake to send troops to Iraq. Since January 2004, between 41% and 44% tell Gallup that it was a mistake to send troops. A majority of Americans across these polls (between 54% and 58%) say it was not a mistake.
Once the government deployed a large number of troops to Vietnam, Gallup found just 24% of Americans saying it was a mistake to send troops, with 60% saying it was not a mistake. At least half of all Americans continued to say it was not a mistake until July 1967. In July 1967, a plurality still supported the notion that it was not a mistake to send troops to Vietnam, by a 48% to 41% margin.
The tide began to turn by October 1967, when more Americans said it was a mistake to send troops (47%) than said it was not (44%). This pattern persisted for nearly a year, until August 1968, when a majority of Americans (53%) said it was a mistake to send troops. This sentiment grew, as the percentage of Americans who said it was a mistake averaged 55% in 1969 and 1970, then increased to 60% in 1971 and 1973.
Even now in retrospect, Americans feel it was a mistake to send troops to Vietnam. Three polls conducted from 1990-2000 found about 7 in 10 Americans saying it was a mistake.
What do the comparisons between Vietnam and the current war in Iraq mean for Bush? On the plus side, the public, on average, has rated Bush more positively on Iraq than it did Nixon or Johnson on Vietnam, and a majority still do not think the country erred in sending troops to Iraq. However, Bush's Iraq ratings now sit at the lowest level of his administration -- not a good sign in an election year, or as the June 30 transition of power in Iraq approaches. That event looms large and will be key in helping determine whether Iraq will have the same effect on Bush that Vietnam had on Johnson.
Foreign Trade: Opportunity or Threat to the U.S. Economy?
Seventy-four percent of U.S. adults say trade represents "an opportunity for economic growth through increased U.S. exports."
Almost All Americans Consider World War II a "Just" War
Sunday marks the 60th anniversary of D-Day, and a new Gallup Poll finds that 9 in 10 Americans consider World War II a "just war," significantly higher than the percentages of Americans who feel that way about wars conducted in the years since. A little more than a third of Americans don't know specific details about D-Day, including the country against whom the Allies were fighting or the geographic location of the D-Day landing. Younger Americans (aged 18 to 29) are least likely to be able to recall these specifics.
Is War Still Necessary in the 21st Century?
Amid recurring questions about whether the war in Iraq was justified, how many Americans currently feel that no war is justified? Over the last 30 years, Gallup has occasionally asked Americans for their opinions on the need for war as a means to resolve conflicts between nations.
From Vietnam to Iraq: How Americans Have Rated the President
Public approval of the way President Bush is handling the situation in Iraq has diminished considerably since his peak rating of 76% in mid-April. Following months of decline, only 47% of Americans in early October approved of Bush's handling of Iraq, and, for the first time, more of them disapproved than approved.
The People's Priorities, Examined
by Frank Newport
Healthcare, the economy and immigration are A-list issues in the 2020 election, while other issues are broadly important but not top of mind.
Gallup https://news.gallup.com/poll/11998/IraqVietnam-Comparison.aspx


With oversized grommets laced with white ribbons, this short sleeve knit dress has a appealing nautical vibe. Wear it with flat sandals, wedges, espadrilles—even sneakers. It has a go-anywhere attitude, just as all good sailors should.