text:
Rohan March 1, 2017 CONSPIRACY THEORIES2017-03-10T15:12:24+00:00 EDITORIALS, PODCAST No Comment
STOP SPREADING CONSPIRACY THEORIES
WORRY ABOUT BEYONCÉ INSTEAD
BY Angelo Fernando
I've always wondered who invents conspiracy theories. Most people I meet – with a few exceptions from Facebook, of course – aren't loonies. So I'm beginning to suspect there must be a secret network out there. Perhaps a sweatshop of disgruntled comedy sketch writers, retired copywriters and tabloid journalists who hang out on weekends.
But do these storytellers really fill our bizarre need for entertainment?
Like the aunty next door who whispers salacious stories about the tuk-tuk driver who sports a Bob Marley T-shirt perhaps?
Some conspiracy theories of the 'Elvis-is-alive' variety are so delightful that we ought to simply leave them alone. One which you may not have heard involves the Beatles, which goes like this: 'They never existed!'
But that's not the most preposterous part…
The theory is substantiated by (and I kid you not) 'research' into the anatomy of the fab four – the visible parts, at least. Someone meticulously documented the different shapes of the Liverpool lads' earlobes and teeth.
I'm willing to admit that John, Paul, George and Ringo could have been easily swapped by a cover band with good lip-syncing skills and wigs. Or even by the Gypsies as long as they didn't attempt to sing Eleanor Rigby to the tune of Uncle Johnson.
But let's not go down that rabbit hole. The point is conspiracy theories prove that the world still has a sense of humour. Rather than be annoyed at the onslaught, we could simply grin and bear it!
Having said that, it really ticked me off when I discovered from a 'reliable source' (also known as the internet) that the moon landing never took place. The theory is that the take-off and landing were faked by the US merely to stick it to the Soviet Union, which was killing the Americans in the space race.
Stanley Kubrick has been unfortunately implicated in this bizarre theory; but at the time of writing this column, he didn't respond to a request for an interview – because he is dead!
Ever since such conspiracy theories flooded my inbox, I've taken them as seriously as the case of Barack Obama's birth certificate and to be as reliable as news on Facebook – which, in case you haven't heard, is itself bathed in conspiracy theories about being a front for a spy agency. Julian Assange, who evidently has plenty of free time in London, certainly stays off Facebook, which he calls a 'spy machine.'
Some theories are too radioactive to even question. Like the one about the lost Malaysia Airlines aircraft that was supposedly diverted to a secret Indian Ocean base. They fall under the banner of 'false flag operations' – meaning that if you click on these stories, you risk seeing black helicopters landing on your front lawn.
Now whatever you do while reading this, don't google 'black helicopters.' And yes, there's a conspiracy theory about this too, which is even more frightening than the bogey man although I will not go into that since impressionable young children (besides my mother) read this column.
And then there's the Illuminati. Word on the street (and by 'street' I refer to questions I'm asked by students who also believe that pop icons like Beyoncé are secret Illuminati operatives) is that they are everywhere.
For the uninitiated, the Illuminati was a secret society begun around 1776 by a Bavarian fellow who was hell-bent on creating a 'new world order.' Its members are said to be prominent businessmen, politicians and pop culture figures who supposedly use cryptic symbols. And its plan is to control everyone and take over the world with the help of the IMF, NATO and Beyoncé's backup singers wearing next to nothing.
What places it squarely in 'wing-nut' conspiracy territory are suggestions – well, theories – that the Illuminati probably had a hand in the French Revolution and even JFK's assassination. Give it a few months and it may also be held responsible for Trump-ism.
For 'evidence,' believers point to an Illuminati symbol hidden in plain sight on the back of the US Dollar bill. If you want to creep someone out, fish out a dollar bill and point to the triangular eye hovering over a pyramid. Does the 'all-seeing eye' portend we're being watched? Placed exactly on the reverse is the seal of the Department of Treasury, which carries the date 1789.
Put on your conspiracy hat and think hard about it: that's 13 years since the creation of the Bavarian Illuminati. Is that why the pyramid below has 13 layers? Are you terrified? Do you still have a sense of humour left? Is the aunty next door watching?
Now if you'll excuse me, I need to step outside and check why there's a black helicopter hovering above our murunga tree….
« TALKING POINT
LEADERSHIP CONUNDRUMS »


text:
Q: My grails project facing error"TransactionRequiredException:no transaction" using domain.save(flush:true).save() it can is saving but updating package com.fhjony.ocbt

import grails.web.servlet.mvc.GrailsParameterMap

class MemberService {

def save(GrailsParameterMap params) {
    Member member = new Member(params)
    def response = AppUtil.saveResponse(false, member)
    if (member.validate()) {
        member.save(true)
        if (!member.hasErrors()){
            response.isSuccess = true
        }
    }
    return response
}

def update(Member member, GrailsParameterMap params) {

    member.properties = params
    def response = AppUtil.saveResponse(false, member)
    if (member.validate()) {
        member.save(flush: true)
        if (!member.hasErrors()){
            response.isSuccess = true
        }
    }
    return response
}

def getById(Serializable id) {
    return Member.get(id)
}

def list(GrailsParameterMap params) {
    params.max = params.max ?: GlobalConfig.itemPerPage()
    List<Member> memberList = Member.createCriteria().list(params) {
        if (params?.colName && params?.colValue) {
            like(params.colName, "%" + params.colValue + "%")
        }
        if (!params.sort) {
            order("id", "desc")
        }
    }
    return [list: memberList, count: memberList.totalCount]
}

def delete(Member member) {
    try {

        member.delete(flush: true,failOnError:true)
    } catch (Exception e) {
        println(e.getMessage())
        return false
    }
    return true
}
}

Error message:
URI /member/update Class
javax.persistence.TransactionRequiredException Message null Caused by
no transaction is in progress
     Line | Method
 ->>  211 | invoke           in org.grails.core.DefaultGrailsControllerClass$ReflectionInvoker
 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  |    188 | invoke           in org.grails.core.DefaultGrailsControllerClass |     90 | handle . . . .
 . in org.grails.web.mapping.mvc.UrlMappingsInfoHandlerAdapter |   1039
 | doDispatch       in
 org.springframework.web.servlet.DispatcherServlet |    942 | doService
 . . .  in     '' |   1005 | processRequest   in
 org.springframework.web.servlet.FrameworkServlet |    908 | doPost . .
 . . . in     '' |    882 | service          in     '' |     77 |
 doFilterInternal in

A: You want your database interactions to be happening in a transactional context.  One simple piece of that is you can mark your service class with @grails.gorm.transactions.Transactional.
Separate from that, and this isn't really related to your question, but passing GrailsParameterMap map around as a method argument is an unusual thing to do.  What the right thing to do is depends on some factors in your app and you may want to pass values into your service rather than the whole map but if you really want the whole map in the service, one way to get there is by way of WebAttributes.
import grails.gorm.transactions.Transactional
import grails.web.api.WebAttributes

@Transactional
class MemberService implements WebAttributes {

    def serviceMethod() {
        // you can access params here because
        // WebAttributes provides access to it
        Member member = new Member(params)

        // ...
    }
}

redpajama_set_name: RedPajamaStackExchange


Rajasthan University Student Union Election 2015 may be organizing in the month of August. Many students are looking for the RU Union Election Voter list 2015. For this year many candidates from NSUI and ABVP are planning for filling of the nominations for RUSU Election 2015. Students from the Maharaja College & Maharani College also a part in the RUSU. It is good news for the Candidates who participating for RU Student Union Election 2015 very soon the RU Student Union Election Voter list 2015 will be announce and the schedule for the Election will be decided by the organization.
If we talking about last the number of candidates are increases and the nominations for the election also increase. Mainly there are two important parties which are NSUI and ABVP play main roles in RU Student Union Election.
In Year 2011 first time a women candidate Prabha Choudhary from Maharani College fight down Rajasthan University Student Union Election by 224 votes against Mahender Singh Shekhawat.
In year 2014, the Result of RUSU Election was delayed due to some issued and the issue was solved by the court. Finally the result was declared and for this time ABVP lost the Rajasthan University Student Union Election by 700 votes and the Anil Chopra candidate of NSUI was declared the President of RUSU against rival ABVP candidate Akhil Vidhyarthi.
Now in 2015 Many Candidates from NSUI and ABVP have filled their nominations for the Raj University Student Union Election 2015 and started their planning and strategies for winning the RU Student Union Election 2015.
RU Student Union Election 2015 will be organized in all most colleges affiliated to Rajasthan University. For this year the schedule and dates of RUSU Election not decided yet by the organization but on the basis of previous year Uniraj Student Union Election will be organize in the month of August 2015.


Pet owners might not know it but animal fur is not the main cause of your allergies, it is the tiny flakes of dead skin we call pet dander. We love our pets but for so many people the unfortunate side effect of keeping them inside, letting them lay in our bed and scoot around on the carpet comes from the discomfort of allergies. You can mange your allergies and pet dander in many different ways. Filters Fast is an air and water filtration company so we know these issues come up a lot. Which is why we want to look at the issue of pet allergies and provide some suggestions that might help in managing any discomfort.
The reason for why we have allergies is an ongoing debate. Studies like the one over at Discovery Magazine point to the body's response of releasing antibodies to attack foreign substances as being an evolutionary advantage against venomous reptiles and flying insects like bees or wasps, cancers and other diseases. If true, then it suggests that while our immune system has made our bodies more resilient against many unique forces, at the same time it has caused us to be hyper-sensitive to particles like dust, pollen, and dander from our pets.
When it comes to allergic reactions we expect the normal symptoms of an itchy throat, congestion, and water eyes, but for some people being anywhere near pet dander can cause aggressive asthma symptoms. So bad in fact that you might have to avoid some people's homes entirely, carry an inhaler, or regularly visit your doctor for allergy shots.
Still, with the unconditional love our pets give us it is super easy to make accommodation by managing our allergies through cleaning more often and taking the appropriate medication. We'll leave the doctoring to doctors and instead focus on reducing the amount of pet dander, dust, pollen and other allergy causing particle around your home.
You have a few options when it comes to home filtration. The first one we want you to get in the habit of thinking about is your air conditioning system. If you didn't know there is a filter in there. If you haven't checked your air filter in the past 3 months we urge you to use our guide to sizing air filters and pick up a replacement from filtersfast.com immediately!
The reason isn't because we just want to sell more products, it is for your general health and the amount of money you will save on heating and cooling bills. Our filters are made up of a tightly packed synthetic fibers that, you guessed it, capture particles like pet dander, mites, mold, and more ranging from 0.3 microns (a very small size) to 100 microns (thickness of human hair).
Every filter has what is called dirt holding capacity. This is the amount of airborne contaminants the filter media can trap before air flow becomes restricted. When this happens you run your air conditioning systems for longer just to change the room temperature a few degrees. So your bills goes up and your expensive air conditioning system wears out faster.
If we look at a chart comparing MERV 8, MERV 11, and MERV 13 filters, we see that the higher the MERV rating the more particles are captured because the filter media has fewer air gaps. For residential applications we do not recommend going below a MERV 8 or higher than 13.
On our chart we see pet dander falls between a MERV 8 and 11. You will notice that MERV 8 filters tend to start cheaper than higher ratings but they will allow some smaller particle to evade capture. If your allergies are less severe or you are already taking a doctor recommended medication then a MERV 8 filter might meet your needs. Keeping in mind that friends and family might thank you for choosing a MERV 11 filter so they can breathe a little easier.
Pricing of filters subject to change.
The Honeywell HHT-011 HEPAClean Compact Air Purifier fits on your desk while cleaning the air around you.
We mentioned a few paragraphs up that you should check your filter at least every 3 months. If you have a lot of pets in your home and find clumps of animal hair in every nook and cranny despite regular cleanings you might want to get in the habit of checking air filters every month because it is very likely your filters are clogged.
The Honeywell 50150 HEPA Air Purifier Cleaner is great for small rooms.
If you don't have central air or don't often run your air conditioner or you want the best quality air possible you can always go the route of buying an air purifier.
When shopping air purifiers look around for a model that is uses a HEPA filter. HEPA stands for High Efficiency Particulate Air and refers to the fact that the filter is manufactured, tested, and certified in accordance with current standards. HEPA filters then must capture 99.97% of 0.3 micron particles in the air. See the similarity to MERV 13? For pet dander alone a HEPA filter might be overdoing it, but because you don't use your air conditioning system regularly or your have allergy problems, the higher filtration capacity makes the purchase worthwhile.
The BlueAir 650E HEPASilent Air Purifier is perfect for those who need extra protection in multiple rooms.
Keep in mind that air purifiers come in a wide range of capacities. Some are designed to work in a small bedroom or office, others for more open spaces like living rooms that connect to hallways and kitchens. You should decide how much you are willing to spend and how allergies affect you throughout the day. If allergies are really only a problem at night, think about buying a smaller purifier to keep in your bedroom. It is a safe bet to say that the bigger the purifier the more you will pay but that also means it is designed to move and scrub more air of allergy causing contaminants.
Thank you for reaching out to us. The CADR is shown for most air purifiers on our site. If you will confirm the air purifier model you are referring to we would be happy to research that for you.
What is the device's clean air delivery rate (CADR)? The Association of Home Appliance Manufacturers rates air cleaners according to their clean air delivery rates (CADR), which indicate how much filtered air the cleaner delivers. There are different CADRs for tobacco smoke, pollen, and dust. The higher the numbers, the faster the unit filters air.
Hello Cheryl, we suggest that you use a MERV 11 filter to help remove the dander and allergies! I use that rating in my home and I have two dogs.
Have 2 cats that I am allergic to, but just found out…….so, need filter that will help me clean the dander and allergies out of the air.
Thank you for sharing this with us! How big is your home that needs to be filtered? I would also suggested getting an allergy friendly air filter for your HVAC/Furnace system.
Help! Just found out I'm severely asthmatic to my 2 dogs and Persian cat. They are like my kids my pulmonolgist has suggested strongly that I need to find them new homes. I am getting a monthly injection of xoliar at the hospital. I'm hoping for a resolution (a happy one…❤) need to know what the best air purifier is???!!


As we heard that Cagla&Patrick wanted to book us for their Pre-Wedding Party, we was really curious about it. Cagla is a turkish girl and Patrick is half german half french. He studied in Cambridge and as fate willed he met Cagla and fall in love with her. In turkish tradition the engagement have to celebrate as a big party like a wedding. So, Cagla&Patrick decided to do an Engagement- or so called Pre-Wedding Party.
even so the photos were sooo beautiful.


I randomly write articles where I attempt to share my knowledge and some times I go on rants about the most trivial of things. Occasionally, I tell stories and am funny.
For roughly 9 months, I had been working on the new website for the BZFlag project with the help of some awesome contributors; the planning and early work started in July 2018 but full speed development didn't really start until November 2018. On April 1st, 2019, the site was made live! I love a good and elaborate April Fools' joke, so what better way of participating this year than by launching a completely redesigned website for a project close to my heart? I mean, I also finally released my AOLer plug-in this year to troll but that's beside the point.
A month ago, I went on a rant about showing your contributors some love and while I stand by that sentiment, I've learned something new in the past month: the importance of a community manager/advocate. Or just community engagement, in general.
I've been lurking around the open source community for about a decade now. I say lurking because I feel like I lurk more than I actually contribute. Though, judging by the little squares on my GitHub profile, I am by definition: fairly active. My favorite time of the year is Hacktoberfest because I do my best to find a community I don't typically hang around and see if I can contribute. Sure, I could always go to those "we'll accept any PR during Hacktoberfest" repositories, but where's the fun in that?
I've been wanting to write something on my blog because I haven't written anything since May and for me, that's a long time. So I decided I'd write about why I decided to create stakx.
Happy new year! ...in March. It's a new year and I come bearing gifts as your resident BZFlag Santa Claus from beautiful Los Angeles, California: the place with a Starbucks in every corner and mispelled names on coffee cups in every trashcan. I'm here to bring you a surprise new chapter for BZFlag Plug-ins for Dummies covering world weapons, custom flags, and the latest improvements to the world weapon API.
It's been a busy semester, I just completed my second to last semester of my college career. The end of 2017 is approaching and what I have accomplished in the past year? Looking back, I don't really feel like I accomplished anything significant but here are some highlights.
It only took until I reached my final year in college to finally find a class I found challenging and actually learned from (excluding GIS classes). I've always been fascinated by cryptography and have always wanted to learn but never found the time to do so on my own. Until I took this class, I had no knowledge of how crytography actually worked. I found this assignment to be incredibly fun because it was challenging for me.
I never expected the BZFlag Plug-ins for Dummies series to get much traffic due to its nature; a very small community, few to no developers, etc. With regards to the current status of the project, I feel that I have covered enough of the API and plug-in writing to be helpful to new developers. For this reason, I'll be putting this series on hold for a while; by doing so, it'll allow me to focus on other projects that require my attention.
A common task to achieve in plug-ins is to have a countdown or time delayed functionality. As an example, a plug-in introducing a custom game mode such as Last Tank Standing will need a countdown for the last 5 seconds of each round and will need to kick a new player at a set interval. This is C++ so there's no magic setTimeout() function that we can use and there's no API function; instead we'll have to make use of the bz_eTickEvent and time_t objects.
The next topic I'd like to cover regarding plug-in writing is how to create custom map objects. Have you ever played the King of the Hill (KOTH), All Hands on Deck (AHOD), or Jumping Skills? In this chapter we'll be building a plug-in that knows when players enter a specified zone to control the hill, capture the flag, or save at a check point. Prior to May 2015, you would have to write all of the logic and math yourself if you wanted to support custom zones. Thanks to the bz_CustomZoneObject class, courtesy of yours truly, all of the math and logic has been moved to the API and requires no effort on your part.
In honor of my latest commit, of adding a new parameter to bz_addURLJob(), this chapter will be covering making URL requests and handling the return data. Why would a plug-in need to make URL calls? Well, a plug-in may need to communicate with an API but don't expect instant results, there'll be a small delay. A common plug-in that makes use of API calls would be my own League Overseer, which communicates with the league's API to report matches automatically. There are two different ways of doing URL jobs in a plug-in.
If you've been following my BZFlag Plug-ins for Dummies series, you may have noticed the radio silence for the past two weeks. Don't worry, the project is still alive and scheduled to continue. The past two weeks have just been incredibly busy for me with work, summer school, and projects so I haven't had time to write any new chapters; heck even my GitHub contributions graph has been quiet. I've got a new chapter for that series planned for July 29, so don't worry you'll be able to continue writing plug-ins.
After last week's pretty long chapter, this'll be shorter in comparison. So far we've written simple plug-ins where the behavior we define is all the behavior the plug-in gets. But what if we want to allow the server owners or map makers to control the behavior of the plug-ins. This can be done in several ways but in this chapter, we'll be covering using configuration files.
It's the 4th of July and you know what that means for me, right? It means I do my best to avoid spending time with friends and extended family. Today, I spent time improving my docs.allejo.io domain, which is used for hosting the documentation for my projects/libraries.
For those of you who think I write these chapters ahead of time, you're wrong.
We've both made it to chapter 3; we should be proud. You, because you've made it this far. Me, because I've been able to write this on a weekly basis without missing a day thus far. Today, we'll be talking about slash commands. Don't worry, like always, we'll be going step by step.
I told you it wouldn't take another 2 years until the next post. We're back and in this chapter we'll be discussing player records and modification API events.
Back in 2015, I said I'd write this series. Well, here it is. Better late than never. Right? In this first chapter, I'll be going over the structure of a plug-in while building our first sample plug-in.
So Fridays are typically my days off from work and school; they're awesome and I'm always looking forward to them. However, this morning I woke up to a not so awesome Friday. Everything on my computer had crapped out.
I'm often curious to see other people's personal websites and am disappointed when I notice that their websites are dated or unmaintained. The pot calling the kettle black, huh? My personal website has become the most neglected project I maintain but I plan on changing that. I intend on writing more often, hence this post.
A while back, I mentioned that I was working on my own static website generator and that I was going to post about it later. For the past 6 months, I've been working on Stakx on and off and I've finally reached a point where I can easily and efficiently build a website with Stakx.
I've been wanting to write about the Santa Monica Youth Tech Program (YTP) for quite some time and what my experience was like as a participant in 2012 and now as a staff member. After searching for posts regarding YTP, all I could find were articles written by program partners and guest presenters.
I have spring break coming up in about 2 weeks; while that would typically have me excited, I'm too distracted and drained for any unnecessary emotions. I've been in a rather odd slump the past few months with where I'm at.
Clickbait — You won't believe what I've seen!
"How did you learn all of this?"
Since I've started taking more computer related classes and have met some pretty cool people, the most common question I keep getting is: "how did you learn all of this?" As a friend pointed out a few days ago, I've been fooling around with code and technology for almost a decade now; I'm not entirely satisfied with the progress I've made, since I wish I had time to learn so much more.
I've recently been working with joining Wufoo and DaPulse together happily in marriage and have made solid progress. However, one problem I encountered was the lack of consistency between Wufoo's POST data and API responses for their date fields. For example, I would get dates formatted as YYYYMMDD from the POST data received from their webhooks but I'd get YYYY-MM-DD whenever I sent an API request.
At one of my jobs, we have recently moved from Asana to DaPulse for task management and collaboration. I'm not part of either's marketing team nor am I sponsored by either of them so I won't advocate for either or say one's better than the other. We also use Wufoo for forms and we used to use Zapier to automatically create entries in Asana and assign them to my coworkers and myself based on the entries. At the time of writing this, Zapier falls unbelievably short with their support of DaPulse to the point where it's actually quite embarrassing and they shouldn't even be offering it in the first place.
It's been an eternity since I launched my Jekyll based website (this one) but up until now, I hadn't done much with it nor had I done much with Jekyll. It wasn't until recently where at both of my jobs, I started using Jekyll a lot more and was able to experiment and discover some better practices. I'm no Jekyll expert but I finally feel comfortable enough with Jekyll and Liquid to work with it efficiently to get a product out. Better yet, I am comfortable enough to be able to assist on #jekyll; that's an IRC channel for you youngins who only know Slack.
Throughout my time with BZFlag, I have written a large amount of plug-ins. Nowadays, I have adopted the API as my child. By this, I mean that I have started to contribute a lot to the API and documenting it for others to use. I have also shaped certain parts of it to my liking mainly so it benefits my plug-ins.
I'm very proud to announce the birth of a new project and its first release! It's called PhpSoda and it's not for the type of soda that you drink (even though I love soda), it's actually an acronym for the Socrata Open Data API. What's Socrata? Well they're a pretty neat company that hosts a lot of open data for governments. They host open data for the US Federal Government and for local governments like the City of Santa Monica, where I work at the time of writing this.
A really long time ago I posted that I was an underachiever and sorry to disappoint but I still am. Well... Sorta. Maybe. Mostly.


text:
Q: Ubuntu 16.04: How to get libx86emu x86emu-demo to work? Does anyone know how to get libx86emu x86emu-demo to work?
https://github.com/wfeldt/libx86emu
Test.bin
00000000 55 8B EC 51 C7 45 FC 00 00 00 00 8B 45 FC 50 E8
00000010 09 00 00 00 83 C4 04 33 C0 8B E5 5D C3 55 8B EC
00000020 B8 01 00 00 00 5D C3

00: 55                      push   ebp
01: 8b ec                   mov    ebp,esp
03: 51                      push   ecx
04: c7 45 fc 00 00 00 00    mov    DWORD PTR [ebp-0x4],0x0
0b: 8b 45 fc                mov    eax,DWORD PTR [ebp-0x4]
0e: 50                      push   eax
0f: e8 09 00 00 00          call   0x1d
14: 83 c4 04                add    esp,0x4
17: 33 c0                   xor    eax,eax
19: 8b e5                   mov    esp,ebp
1b: 5d                      pop    ebp
1c: c3                      ret
1d: 55                      push   ebp
1e: 8b ec                   mov    ebp,esp
20: b8 01 00 00 00          mov    eax,0x1
25: 5d                      pop    ebp
26: c3                      ret

./x86emu-demo -l 0 -s 0 Test.obj
I need to be able to execute x86 machine code similar to the above sample. libx86emu decodes and executes the first three instructions then decodes the fourth instruction incorrectly. I only need to be able to emulate 32-bit x86, I don't need any OS support.
Only about half of the libx86emu x86test regression tests pass.


I have gone back to last body of work before life got in the way. These are a set of watercolour/gouaches I completed in summer of 1994 shortly before moving to Edinburgh. I then completed a small run of etchings based on these drawings. That was pretty much, excepting a few drawings and a couple of paintings completed when an artist in residence at City Arts which leaned towards that area,all I done since! Seems incredible but as I said life got in the way….


text:
The immunological and genetic aspects in psoriasis
Liangdan Sun1,2 &
Xuejun Zhang1,2
Psoriasis is a chronic and immune-mediated inflammatory skin disorder associated with complex genetic susceptibility. Studies focused on the immunological mechanism have revealed innate and adaptive immune activation in psoriatic lesions, including large numbers of immune cells activated to produce many cytokines, chemokines, and other inflammatory molecules. Knowledge on the genetic basis of psoriasis highlights genetic susceptibility factors that play a crucial role in regulation of immunity, epidermal proliferation, and skin barrier formation. Genetic susceptibility factors affecting both the immune system and epidermis could predispose to disease. Herein, we review the current knowledge on the role of genetic and immunological factors in the development of psoriasis.
Psoriasis (MIM *177900) is a common, chronic, and immunologically mediated inflammatory skin disease that affects individuals at rates varying from 0.5% to 4.6% across diverse ethnic populations (Lebwohl [2003]). Symptoms typically develop in early adulthood, between the age of 15 and 25 years old (Henseler and Christophers [1985]), but individuals of all ages can be affected. The disease has certain distinct but overlapping clinical phenotypes, including psoriasis vulgaris, which appears in approximately 90% of all patients (Griffiths and Barker [2007]), and at least 10% to 30% of patients develop arthritis (Nickoloff and Nestle [2004]; Ibrahim et al. [2009]). Although psoriasis is rarely life threatening, its morbidity and associated comorbidities have a severe negative impact on the quality of life of the patients and also confer a certain socioeconomic burden. Over the past few decades, substantial researches on the pathogenesis of psoriasis have been a focus in the field of cutaneous disease. However, the mechanism of psoriasis pathogenesis likely involving the complex interplay among genetic, immunological, and environmental risk factors (Nestle et al. [2009]) has not been fully elucidated.
The concordance of monozygotic twins both suffering from psoriasis has been reported to approximately 70%, and the sibling recurrence risk is estimated to range between 4 and 11 (Bhalerao and Bowcock [1998]). Through a conventional family-associated on genetic linkage approach, psoriasis-associated chromosomal regions have been identified. A major genetic determinant of psoriasis, designated psoriasis susceptibility 1 (PSORS1), resides in the major histocompatibility complex (MHC) on chromosome 6p21, tightly linked to HLA-Cw6, which is as the most frequently detected allele in psoriasis (Veal et al. [2002]; Nair et al. [2006]). More recently, with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, genome-wide association studies (GWAS) have evolved into a powerful tool for investigating the genetic architecture of human complex diseases (Manolio et al. [2008]). Taking advantage of GWAS, researchers have revealed many novel and/or confirmed previous genetic loci associated with disease, and ongoing studies are exploring additional genetic factors for associated with psoriasis.
The cellular features of psoriasis are epidermal hyperplasia and altered keratinocyte differentiation, but substantial evidence implicates both innate and acquired immunity in the disease pathogenesis (Gaspari [2006]). The disease state is triggered by an activated cellular immune system, marked infiltration of T cells, dendritic cells (DCs), and inflammatory cytokines in psoriatic skin lesions (Bowcock and Krueger [2005]). As in other immune-mediated diseases, such as rheumatoid arthritis (RA), Crohn's disease (CD), multiple sclerosis (MS), and juvenile-onset diabetes, psoriasis is regarded as a T cell-mediated autoimmune disease (Lowes et al. [2007]). Therefore, it fits the definition of an autoimmune disease (Davidson and Diamond [2001]). Recent progress in the understanding of both the immunological and genetic basis of the disease has provided a deep insight into the pathogenesis. In this review, we detail the recent advances in the understanding of psoriasis pathogenesis, including the information regarding immunological factors, genetic aspects, and susceptibility genes shared with other autoimmune or inflammatory diseases.
Immunological factors
Cells and molecules of immunity
Psoriasis is characterized by hyper-proliferation and aberrant differentiation of keratinocytes (KCs), vascular abnormalities, and inflammatory infiltration. The cell types in psoriatic plaques are involved in wound repair and/or are composed of the antigen-presenting cells (APCs), including T lymphocytes cells, KCs, DCs, Langerhans cells (LCs), and macrophages. The cellular innate and adaptive immune responses, especially the activation of T cells, play a dominant pathogenic role in psoriasis (Krueger [2002]; Cai et al. [2012]). Evidence for the central role of T lymphocytes has been found in animal models of psoriasis (Boehncke and Schon [2007]), successful treatment of psoriasis patients with cyclosporine A to inhibit T cell proliferation and cytokine production (Mueller and Herrmann [1979]) and specifically recruited T cell clones that permanently involve the psoriatic inflammation (Vollmer et al. [2001]). A dense infiltration is composed of clusters of CD4+T cells and antigen-presenting DCs in the dermis, while CD8+T cells and neutrophils are predominant in the epidermis of psoriatic lesions (Lowes et al. [2007]). The expression of activation markers by both CD8+T and CD4+T cells has been observed in psoriatic lesions, and most of the T cells can also express the memory cell antigens (Liu et al. [2007]). Once the psoriatic plaques appear after T cell infiltration as the activated memory-effector T cells, cytokines, such as interleukin (IL)-2, tumor necrosis factor-α (TNF-α), and interferon γ (IFN-γ) could be generated, which stimulate an inflammatory response and change the characteristic of psoriasis (Austin et al. [1999]; Friedrich et al. [2000]). An interrelation exists in that, CD4+T cells may provide critical inductive and helper signals, while CD8+T cells are likely to be the principal effector agents in the pathogenesis of psoriasis (Gudjonsson et al. [2004]). Thus, in the epidermal compartment of psoriatic lesions, CD8+T cells could be activated and proliferated after CD4+T cells interact with antigen-presenting cells.
The changes in keratinocyte activation and proliferation that cause them to mature too rapidly result in psoriasis. Keratinocytes in psoriatic lesions produce an array of immune response-related proteins, such as the S100 proteins and intercellular adhesion molecule 1 (ICAM-1), CD40, and HLA-DR, which attract leukocytes. The link is that a positive feedback leads leukocytes to upregulate the S100 proteins (Bowcock and Krueger [2005]).Upon activation, KCs express a plethora of cytokines, chemokines, and accessory molecules, transmitting both positive and negative signals to immune cells (Albanesi et al. [2005]). KCs also produce endothelial cell mitogens such as VEGF and PDGF, leading to angiogenesis (Costa et al. [2007]).
DCs are professional APCs involved in the regulation of the balance between immunity and immunological tolerance. Cytokine profile studies have shown that dermal DCs obtained from psoriatic lesions mediated a T cell response with high levels of IL-2 and IFN-γ (Nestle et al. [1994]). Plasmacytoid DCs (PDCs) have been identified in the psoriatic skin and in uninvolved, healthy-looking psoriatic skin and were shown to be the principal IFN-α-producing cells in early and developing psoriasis (Nestle et al. [2005]). Myeloid DCs, which are activated by PDCs and keratinocyte-derived cytokines, are also accumulated in the psoriatic tissues (Zaba et al. [2009]) and are believed to be required for sustaining and amplifying the T cell inflammatory reaction (Chu et al. [2011]). Studies have shown that DCs may be the primary cell type that drives T-helper 17 (Th17) differentiation in psoriasis through the production of IL-6 and IL-23 (Chu et al. [2011]). The crucial link between DCs and the IL-23/Th17 axis has been further strengthening the suggestion that DCs obtained from psoriatic lesions could activate T cells to produce both IL-17 and IFN-γ (Zaba et al. [2009]).
LCs reside in the basal and suprabasal layers of the skin and are closely associated and interact with KCs through E-cadherin (Tang et al. [1993]). A role for LCs has been indicated in the pathogenesis of psoriasis (Cumberbatch et al. [2006]), inducing the generation of distinct IL-22-producing Th22 cells infiltrating into the skin (Fujita et al. [2009]). Macrophages can contribute to both epithelial-based and T cell-mediated pathways of inflammation in psoriasis (Clark and Kupper [2006]). Macrophages interact with KCs and secrete a variety of pro-inflammatory cytokines, such as TNF-α, IFN-α/β, IL-1β, IL-6, IL-12, IL-10, and IL-18 cytokines, under various conditions (Wang et al. [2009a]). Previous researches have suggested that the maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with a sufficient release of TNF-α (Wang et al. [2006]). As mentioned above, the cellular features of psoriasis are epidermal hyperplasia and altered keratinocyte differentiation, but mounting evidences have implicated both innate and acquired immunity in the disease progression of the disease (Nestle et al. [2009]).
Several cytokines and chemokines, which induced keratinocyte proliferation, are strongly expressed in the psoriatic skin. It has been well established by many experimental studies that psoriatic inflammation mediated by T-helper 1 (Th1) cells (Uyemura et al. [1993]; Schlaak et al. [1994]). Characterization of cells and cytokines involved in the initiation and maintenance of psoriasis showed elevated levels of IFN-γ, TNF-α, and IL-12, but not of IL-4, IL-5, or IL-10, at both the mRNA and protein levels (Nestle et al. [1994]; Schlaak et al. [1994]; Austin et al. [1999]). Th17 cells, a newly appreciated T cell subset that produce IL-17 (Miossec et al. [2009]) and IL-22 (Liang et al. [2006]), have been implicated in psoriasis. As a potent pro-inflammatory cytokine, IL-17 may stimulate keratinocytes to produce neutrophil-attracting CXC chemokines (Nograles et al. [2008]), as well as CCL20, which draws CCR6+ cells into sites of inflammation (Harper et al. [2009]). A mixed Th1 and Th17 inflammatory environment is found in the affected skin during the disease process (Lowes et al. [2008]). IL-23, which is composed of two subunits, a unique p19 subunit and a p40 subunit shared with IL-12 (Lee et al. [2004]), represents a cytokine pathway that is differentially increased in psoriatic lesions and is important in Th17 cells. IL-23 is overproduced by DCs (Lee et al. [2004]) and stimulates Th17 cells within the dermis to make cytokines in psoriatic lesions. Recent studies have demonstrated that the IL-23/Th17 cell axis plays an important role in the pathogenesis of psoriasis and presents a potential therapeutic target (Di Cesare et al. [2009]; Nakajima [2012]). In addition to IL-23 and IL-17, IL-22 has also been reported to induce cutaneous inflammation in an experimental murine model of psoriasis and has also been shown to induce in vitro an inflammatory-like phenotype in vitro (Van Belle et al. [2012]). IL-22 is a member of the IL-10 cytokine family, which is primarily secreted by Th17 cells (Trifari et al. [2009]). IL-22 is remarkably over-expressed in psoriasis, most likely as a result of upregulated the levels of IL-23 and IL-6 (Boniface et al. [2007]; Zheng et al. [2007]). TNF-α has been identified as a promising target molecule, with the expression of TNF-α and its receptors enhanced in psoriasis (Ettehadi et al. [1994]). The efficacy of TNF-α antagonists in the treatment of psoriasis suggests a central role of this factor in psoriatic plaque formation (Tobin and Kirby [2005]).
In addition to T cell-derived cytokines, numerous antigen-presenting cells infiltrate the psoriatic skin and produce inflammatory cytokines. A variety of chemokines and chemokine receptors are present in psoriatic plaques. The percentages of peripheral blood CD8+T cells expressing CXCR6 are higher in psoriasis patients than in healthy individuals, and CXCL16-CXCR6 interactions mediate the homing of CD8+T cells to psoriatic lesion (Gunther et al. [2012]). In immune-pathogenesis of psoriasis, including TARC (CCL17), MIG (CXCL9), IP10 (CXCL10), MDC (CCL22), and RANTES (CCL5), as well as CXCR2, CXCR3, CCR4, CCL27-CCR10, MIP3α (CCL20), MIP3β (CCL19), and CCR6, all involved in the inflammatory response of psoriasis (Nickoloff and Nestle [2004]). Once chemokines bind to their respective receptors, they activate the cells to release of cytokines and growth factors to form a thick, erythematous scaly plaque.
Inflammation pathways
Psoriasis is a representative inflammatory skin disease, which is mediated through a cytokine network. The activated DCs and T cells are central in its pathogenesis, creating a 'Type 1' inflammatory pathway, which links the activation of multiple inflammatory responses, such as the release of IFN-γ, IL-23, and IL-12 into the lesions (Lew et al. [2004]). This model is conceptually useful, but it accounts for only a small fraction of the pathogenesis and cannot explain the total inflammatory character of psoriatic lesions.
Previous studies have shown that the activity of the p38 mitogen-activated protein kinases (MAPKs) is increased in the psoriatic skin, supporting the potential role of these kinases in the pathogenesis of psoriasis (Funding et al. [2007]). The mitogen- and stress- activated protein kinases 1(MSK1) are found to be involved in the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein in keratinocytes and regulate the expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α (Funding et al. [2006]). Evidence shows that MAPK inhibitors are effective anti-inflammatory drugs that reduce the synthesis of inflammation mediators at multiple levels and block pro-inflammatory cytokine signaling (Kaminska and Swiatek-Machado [2008]). It has therefore been confirmed that the pathway of the p38 MAPK/MSK1 signaling pathway may play a potential role in psoriasis by producing pro-inflammatory cytokines (Arthur and Darragh [2006]).
Clearly, transcription factors, such as signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3) and nuclear factor-κB (NF-κB), are activated in psoriasis. Research on the transcriptional regulatory network for psoriasis shows that E2F transcription factor 1 (E2F1), jun proto-oncogene (JUN), NF-κB 1, STAT1, STAT3, and SP3 are pivotal in the transcriptome network involved in the mechanism of psoriasis (Lu et al. [2013]). NF-κB is a key regulatory element in inflammatory pathways, in cellular proliferation and differentiation, and in apoptosis as well as a crucial mediator in psoriasis (Goldminz et al. [2013]). In a mouse model of psoriasis, NF-κB signaling is essential for the pathogenesis and is strongly activated in psoriatic lesions (Wang et al. [2009b]). Compared to the non-psoriatic skin, the samples of the psoriatic skin demonstrate elevated levels of activated, phosphorylated NF-κB (Lizzul et al. [2005]). It is targeted by numerous effector cells, including keratinocytes, Th17, and DCs, which respond to extracellular stimuli consisting of TNF-α, plasmin, and TLRs (Goldminz et al. [2013]). A blockade of NF-κB signaling within various target cells leads to decrease production of pro-inflammatory cytokines.
The Janus kinase (JAK)/STAT signaling pathway is well known to be involved in many cellular processes including inflammation. The JAK/STAT pathway converts cytokine signals into genomic responses that regulate proliferation and differentiation of the immune cells (Kaminska and Swiatek-Machado [2008]). JAK inhibitors may be a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, and antiallergic properties. When keratinocytes from the psoriatic skin were cultured, a significant induction of the STAT1-induced transcriptional activity was stimulated with either IFN-γ or IFN-α (Hald et al. [2013]).STAT3 are involved in the upregulation of keratin 17 (K17) expression induced by IL-22. Both STAT1 and STAT3 pathways are involved in the upregulation of K17 expression induced by IL-17A, and this regulation could be partially suppressed by STAT1 or STAT3 small interfering RNAs and inhibitors (Shi et al. [2011]). Taken together, these cellular signaling pathways, which have been shown to be involved in the progression of psoriasis, present potential targets for new prosiasis therapies.
Linkage and candidate gene association study
Although psoriasis has a multifactorial etiology, it is strongly influenced by genetic factors (Lowes et al. [2007]). Compared with the general population, a higher incidence of the disease has been identified among first-degree and second-degree relatives of psoriasis. The risk of psoriasis is greater in monozygotic twins than in dizygotic twins, confirming the genetic basis of the disease (Nestle et al. [2009]). Prior traditional approaches, such as family-based linkage studies and population-based candidate gene association studies, have had some success in identifying genetic risk factors. The major locus strongly associated with psoriasis is PSORS1 on chromosome 6p21, spanning approximately 300 kb of the MHC class I region (Veal et al. [2002]). Large-scale resequencing has established HLA-C and its HLA-Cw*06 allele as the most likely PSORS1 candidate genes (Nair et al. [2006]). Variants associated with the HLA-Cw*06 allele contribute to one-third and one-half of the genetic susceptibility to psoriasis (Elder [2006]) and are determinant for the development of early-onset psoriasis (Zhang et al. [2003]).
In addition to PSORS1, linkage analyses and association studies have highlighted psoriasis loci on several other chromosomes outside of the MHC region, designated PSORS2-PSORS10 (Bowcock and Krueger [2005]; Perera et al. [2012]). PSORS2 was localized to the chromosomal region 17q25.3 in a family of European ancestry and has also been observed in a Taiwanese family with multiple psoriasis-affected members (Jordan et al. [2012]). Two disease-causing CARD14 mutations in psoriasis identified by using genomic capture and DNA sequencing suggest that the involvement of PSORS2 is due to the mutation of this gene (Jordan et al. [2012]). In the PSORS3 locus, on chromosome 4q (Matthews et al. [1996]), evidence from an association study suggests a putative association between the interferon regulatory factor 2 (IRF2) and psoriasis, which indicates that the IRF2 gene as a candidate for PSORS3 (Foerster et al. [2004]). PSORS4 is in the 1q21 region (Matthews et al. [1996]), where a common deletion (LCE3C_LCE3B-del) in the late cornified envelope (LCE) cluster is associated with psoriasis (Coto et al. [2011]). The locus, PSORS5, on chromosome 3q21 has been found in family-based analysis studies (Enlund et al. [1999]). The cystatin A, zinc finger protein 148, and solute carrier family 12 member A8 (SLC12A8) genes are proposed as candidate genes at the psoriasis susceptibility locus PSORS5 (Samuelsson et al. [2004]; Huffmeier et al. [2005]). PSORS6, located at 19p13 (Lee et al. [2000]), has been suggested to interact with PSORS1 (Huffmeier et al. [2009]). PSORS7 at 1p (Veal et al. [2001]), PSORS8 at 16q (Nair et al. [1997]), and PSORS9 at 4q31-34 (Yan et al. [2007]; Zhang et al. [2007]) are all linked to psoriasis. Although other susceptibility loci and genes have also been postulated, it is difficult to replicate the results of these studies, a result of interethnic differences and environmental variations.
Genome-wide association studies
GWAS have become an effective approach for identifying genetic variants associated with disease risk (Price et al. [2010]). To date, several large GWAS for psoriasis in both the European and Asian populations have been performed (Nair et al. [2009]; Zhang et al. [2009]; Ellinghaus et al. [2010]; Huffmeier et al. [2010]; Strange et al. [2010]; Stuart et al. [2010]; Sun et al. [2010]; Tsoi et al. [2012]) to identify novel susceptibility genes and mechanisms associated with psoriasis with kinds of algorithms (Tables 1 and 2). It is worth mentioning that the most highly significant associated single nucleotide polymorphisms (SNPs) in different populations are localized in the MHC class I region, which encodes the HLA molecules HLA-A, HLA-B, and HLA-C. The findings of GWAS pertaining to psoriasis and psoriatic arthritis GWAS (Liu et al. [2008]) demonstrate that the strongest associated SNP alleles are highly correlated with the HLA-Cw*06, which is consistent with the previously described involvement of the PSORS1 region. Through in-depth analyses of the GWAS data, two additional susceptibility loci within the HLA region have been shown to confer risk of psoriasis in both Chinese and European lineages (Feng et al. [2009]).
Table 1 The genetic loci associated with psoriasis identified by GWAS
Table 2 The algorithms of psoriasis GWAS
The GWAS of psoriasis patients have implicated several other susceptibility genes that are involved in various biological processes, including the IL-23/Th17 pathway (Ellinghaus et al. [2010]; Huffmeier et al. [2010]; Nair et al. [2009]; Strange et al. [2010]), NF-κB signaling (Nair et al. [2009]; Strange et al. [2010]; Stuart et al. [2010]), epidermal cell differentiation (de Cid et al. [2009]; Sun et al. [2010]; Zhang et al. [2009]), MHC class I processing (Strange et al. [2010]; Sun et al. [2010]), the ubiquitin pathway (Capon et al. [2008]; Sun et al. [2010]), and Th2-type response (Nair et al. [2009]) as well as genes with yet unknown functions. As mentioned above, the functional role of IL-23-induced and Th17 cell-mediated chronic inflammation is highlighted in the immune-pathogenesis of psoriasis. In GWAS findings of both European and Chinese populations, different SNP alleles associated with psoriasis in and upstream of the IL12B gene and the IL23R gene have been identified, confirming the role of the IL-23/Th17 axis in psoriasis pathogenesis (Cargill et al. [2007]; Nair et al. [2009]; Zhang et al. [2009]). IL12B (encoding the p40 subunit of IL-23 and IL-12) and IL23A (encoding the p19 subunit of IL-23) are heterodimerize to form IL-23. The IL-23/Th17 pathway signaling could promote cellular immune responses by strengthening of a subset of IL-17-expressing T cells (Bettelli et al. [2007]) or dysregulation of expression ultimately resulting in psoriasis.
Several mediators of the NF-κB signaling pathways are linked to psoriasis (Goldminz et al. [2013]). As revealed by GWAS, TNFAIP3 (TNF-α-induced protein 3) and TNIP1 (TNFAIP3-interacting protein 1), the gene products of which modulate this pathway show a strong association with the disease (Elder [2009]; Nair et al. [2009]). Genetic variants in the TRAF3IP2 (TRAF3-interacting protein 2),which encodes a protein involved in IL-17 signaling, are implicated in psoriasis susceptibility (Ellinghaus et al. [2010]; Huffmeier et al. [2010]). TRAF3IP2 interacts with tumor necrosis factor receptor-associated factor (TRAF) proteins and either I-êB kinase or mitogen-activated protein kinase to activate either NF-κB or Jun kinase (Ellinghaus et al. [2010]). Encoding endoplasmic reticulum aminopeptidase 1 (ERAP1), located in 5q15 associated region, which encodes an amino peptidase regulatory factor for the quality of peptides bound to MHC class I molecules, is implicated in psoriasis in both European and Chinese populations (Strange et al. [2010]; Sun et al. [2010]). Compelling evidence shows that it exits the interaction between the HLA-C and ERAP1 loci in the psoriasis pathogenesis process. ERAP1 variants could influence psoriasis susceptibility in individuals who carry the HLA-C risk allele (Strange et al. [2010]).Variants of the gene encoding zinc-finger protein 313 (ZNF313) are also associated with psoriasis as well (Capon et al. [2008]). ZNF313 has a similar role of as the ubiquitin ligase of TRAC-1 to regulate T cell activation. The present data also provide evidences that skin barrier function plays a role in psoriasis susceptibility. A deletion polymorphism of two genes (LCE3C and LCE3B) is associated with psoriasis in different populations (de Cid et al. [2009]; Zhang et al. [2009]). The LCE genes encode the stratum corneum proteins of the cornified envelope, which is important in epidermal terminal differentiation (Mischke et al. [1996]). Genetic susceptibility variant(s) within the LCE genes may influence the development of psoriasis by interrupting the terminal differentiation of keratinocytes. Collectively, the genetic determinants could lead to dysregulation of innate and adaptive immunity and to epidermal barrier dysfunction in disease process.
Common genetic factors in autoimmune or inflammatory diseases
To evaluate the relationship between psoriasis and autoimmune disease, the findings of one retrospective study suggest that psoriasis patients are more likely to be diagnosed with an autoimmune disease than individuals without psoriasis (Wu et al. [2012]). Common autoimmune or inflammatory (immune-mediated) diseases, such as RA, CD, MS, celiac disease (CeD), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE), are highly prevalent in psoriasis patients. Psoriasis and psoriatic arthritis (PsA) are interrelated disorders that share pathophysiological mechanisms. The occurrence of psoriasis in conjunction with chronic inflammatory arthritis is range from 10% to 30% of individuals with the disease.
Many confirmed and nominally associated psoriasis susceptibility loci show a high level of overlap with the associated loci of other autoimmune diseases. This marked overlap of autoimmune disease susceptibility loci may occur when the same variants contribute to multiple diseases or when different variants in the same gene confer susceptibility to various autoimmune diseases. Typically, psoriasis is concomitant with autoimmune and inflammatory diseases (Makredes et al. [2009]), sharing many susceptibility genes between them (Table 3). Several associated genes are also implicated in other immune-mediated disorders, notably CD (Ellinghaus et al. [2012]), offering insights into the postulated shared pathogenesis of CD and PS. In addition to psoriasis, IL23R is associated with IBD, PsA, and MS (Duerr et al. [2006]; Begovich et al. [2007]; Liu et al. [2008]), highlighting the functional role of the IL-23/Th17 axis in immune-mediated inflammatory and autoimmune processes. Furthermore, many genes involved in the NF-κB pathway, such as TNFAIP3 and NFKB1A, are also linked to risk for other autoimmune diseases (Fung et al. [2009]; Han et al. [2009]; Bowes et al. [2010]; Li et al. [2013]). Although HLA-C remains the strongest susceptibility candidate gene in psoriasis, evidences for an interaction between HLA-C and other autoimmune diseases have been confirmed by GWAS (Raychaudhuri et al. [2012]). These and other regions of genetic association shared with autoimmune diseases indicate that psoriasis may have similar immune mechanism and pathogenic pathways. However, common susceptibility genes among different phenotypes suggest that genetic variation may influence the entire pathways to increase the risk for multiple diseases.
Table 3 Susceptibility genes in risk loci shared by autoimmune or inflammatory diseases
Our understanding of the genetic basis of psoriasis has been rapidly advanced by GWAS approach. More than 40 robust susceptibility loci have been identified and confirmed to be associated with psoriasis using this technique. However, most of the identified risk variants are expected to be tagged as SNPs, and the functional coding variants of these susceptibility genes, particularly those that are of low frequency and rare, are largely refractory to the interrogation by GWAS. Therefore, such variants have not been systematically investigated. With the development of technologies for next-generation sequencing (NGS) technologies, such as exome sequencing analysis, the systematic investigation of coding variants is possibly. Recently, a large-scale sequencing analysis of functional coding variants was performed to investigate the contribution of functional coding variants to the genetic susceptibility of psoriasis in a Han Chinese population, identifying seven common and low-frequency nonsynonymous variants within known psoriasis susceptibility genes, including IL23R, GJB2, LCE3D, ERAP1, CARD14, and ZNF816A, that are associated with psoriasis risk (Tang et al. [2013]).
The pathogenesis of psoriasis involves a complicated interaction between genetic and immunological and environmental components. During recent years, there have been great advances and tremendous achievements in immunity and genetic research on psoriasis that have contributed to the understanding of the mechanism of psoriasis. It is clear that Th1, Th17, and Th22 cells, which interact with each other, mediate the immunity response in disease development. Recent GWAS have identified a variety of genetic components involving both the immune system and the epidermis that affect psoriasis pathogenesis. Several genetic factors and pathways shared with autoimmune and inflammatory (immune-mediated) diseases highlight a common mechanism in different diseases. However, a substantial proportion of the involved genetic factors have yet to be identified, and it is difficult to clarify how these genetic factors and pathways intersect and contribute to inflammation, proliferation, and altered differentiation in psoriasis. Fine mapping and resequencing efforts, together with extensive functional studies, are required to detect all potential causal variants for the susceptibility to psoriasis. Recent advances in next-generation sequencing technologies will enable the increased understanding of the pathogenetic mechanisms and will position a number of confirmed genes or pathways as potential targets for future therapeutic intervention.
LDS M.D. Ph.D is a Professor of Dermatology, Assistant Director, Key Lab of Dermatology, Ministry of Education, Committee Member of Youth Commission of Genetics of China, Committee Member of Human and Medical Genetics of Genetics Society of China, and Director of Research Department at the First Affiliated Hospital of Anhui Medical University.
XJZ M.D. Ph.D is a Professor of Dermatology, Director of Institute of Dermatology, Anhui Medical University, Director of Key Lab of Dermatology, Ministry of Education, President of Chinese Society of Dermatology, Board of Director, International League of Dermatological Societies, President of Asian Dermatological Association, Associate editor, Journal of Investigative Dermatology, Editorial Advisory Board Member, British Journal of Dermatology, Editorial Board Member, Journal of Dermatological Science, Editorial Board Member, and International Journal of Dermatology.
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This work was supported by the National Science Fund for Excellent Young Scholars (81222022) and the Outstanding Talents of Organization Department of the CPC (Communist Party of China) Central Committee program.
Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, No. 81, Meishan Road, Hefei, 230032, Anhui, China
Liangdan Sun & Xuejun Zhang
Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, No. 81, Meishan Road, Hefei, 230032, Anhui, China
Liangdan Sun
Xuejun Zhang
Correspondence to Liangdan Sun.
XJZ conceived of the review and participated in its design and coordination. LDS designed the review, drafted the manuscript, and gave the final approval of the version to be published. Both authors read and approved the final manuscript.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sun, L., Zhang, X. The immunological and genetic aspects in psoriasis. Appl Inform 1, 3 (2014). https://doi.org/10.1186/s40535-014-0003-1

redpajama_set_name: RedPajamaCommonCrawl


So there you are my friends. I hope you enjoyed this list of MLK quotes and got value from them. May this American icon and visionary's words live on! Share with me what you favorite ones were as well as if you have any to add! Much love.


Burgtheater GmbH, Wiener Staatsoper GmbH and Volksoper Wien GmbH are the stage companies of the Austrian Bundestheater Group.
An interested party is anyone who comes to the box office of the Austrian Bundestheater Group to purchase tickets for themselves or others.
A visitor is anyone who, on the day of their theatre visit, is in possession of a valid ticket for the respective performance or for any other respective event (e.g. matinee) of one of the stage companies.
An ordering party is anyone who sends a written order to one of the stage companies.
Tickets for performances of the stage companies are sold by Theaterservice GmbH (hereinafter referred to as "ThSG").
Tickets must be paid for in cash, by debit card or credit card (American Express, Diners Club, Visa, MasterCard, Eurocard and JCB Card). It is also possible to purchase tickets by telephone when paying by credit card. ThSG shall retain the right to determine, in consultation with the stage companies, a minimum amount under which payment by credit card shall not be accepted. Tickets are sold online via the following websites: www.bundestheater.at, www.burgtheater.at, www.wiener-staatsoper.at, www.volksoper.at, www.theaterservice.at.


We have added a new member to the staff team: Sonny Rise. (That final "e" is pronounced like the good old Canadian "eh".) Sonny will be serving as the Children's Ministry Assistant while Christie Thomas is on maternity leave. We believe Sonny is the perfect person for the role she will be taking on. Let me tell you a little bit about her.
Sonny moved to Edmonton from British Columbia, and has been attending Bethel for almost a year now. She is an experienced teacher who served in the public school system for over 20 years in BC, teaching at a variety of elementary age levels. She has many skills ranging from music (piano and guitar) to drama, dance, and athletics (coaching and personal fitness) as well as sewing and knitting. She is passionate about her faith in Jesus Christ, cares deeply about children, and is active in a number of community volunteer activities. Sonny is the mother of two adult children—Dawn in Calgary and Curtis in Edmonton. (Curtis and fiancé Anya Kisseleva both attend Bethel).
Sonny already started work this past week, "learning the ropes" from Christie. We are grateful to have her on board!
This is Christie's last Sunday on staff. While Christie is laying down her role as Director of Early Childhood Ministries for a while, we are really not saying "goodbye." She, Jonathon, and family will remain very much a part of the Bethel Community. Her due date is March 27—the secret's out, it's a boy! She hopes to return by March of next year.
Be sure to warmly greet Sonny and to keep Christie, new baby, and family, in your prayers.


Highlights: Tour at your own pace over 2 days with this 48-hour Trolley Pass! Old Town Trolley Tours allows you to get off at any of the convenient stops situated close to all popular attractions, shops and restaurants. When you're ready, just re-board the Old Town Trolley and it's on with the tour.
Kids go FREE for the month of October. One Child FREE per paid Adult ticket.Veteran's Ride FREE on Nov 10-11.
Guests may hop on and off the trolleys and spend as much time at each attraction as they please over a 48-hour period. Alternatively, passengers can ride the trolley from one end of its line to the other and enjoy a two-hour completely guided and narrated tour of the city of San Diego! With 10 stops at more than 100 points of interest, this highly customizable tour is great for exploring the city.
This active military base in San Diego, California is the largest naval base on the west coast of the United States. Those who wish may participate in tours as long as they are with a group of 10+.
Operating Times: Daily. Times vary depending on season.
Winter-(Oct 29- Feb 28, 2018): 9am- 5pm (last tour departs Old Town at 3pm); Spring- (Mar 1-Jun 15): 9am to 6pm (last tour departs Old Town at 4pm); Summer-(Jun 16-Aug 19): 9am -7pm (last tour departs Old Town at 5pm); Fall -(Aug 20-Oct 29): 9am to 6pm (last tour departs Old Town at 4pm); Closed Thanksgiving and Christmas Day.
Booth Location: Main Stop (Stop A) Old Town located at 4010 Twiggs Street; (Stop B) 1004 N Harbor Dr.- San Diego Embarcadero at Harbor Drive and Broadway; (Stop C) Seaport Village at 470 Kettner Blvd; (Stop E) Horton Plaza Shopping Center; (Stop H) Coronado McP's-1107 Orange Ave.
2nd day does not need to be consecutive. Patrons with eTickets (voucher) or mobile ticket can board at any Old Town Trolley boarding location.
Without an e-Ticket voucher or mobile ticket you must go to the ticket booth location with invoice order number.