And she plans to return to college to train as a personal trainer and nutritionist — something she had never considered before. A photo posted by Sian Ryan sianliftsweights on Jan 16, at 9: What you feel is a rush of tense energy surging through your system, a shortness of breath, foggy thoughts, and a pounding heart. With your therapist's help, you can develop a narrative and understand meaning around what happened so that how much weight do you lose after a break up can properly grieve the loss and move on with your life. I know I have. A photo posted by Sian Ryan sianliftsweights on Sep 29, at Caddell told me, "Stress hormones like cortisol are released, which over time can lead to decreased immune functioning and a lot of other health problems.
Soon, you'll be back to your happy, energetic self. Many people feel lost after a breakup; not because they miss their ex, but because so many of their daily habits once revolved around someone else. Give yourself two rules: Just like you can experience withdrawal if you quit smoking, you can experience similar symptoms after a break up.
Hair grows back, but be warned: I was not eating. With your therapist's help, you can develop a narrative and understand meaning around what happened so that you can properly grieve the loss and move on with your life.
They are either seeking help because they are happy with their partner but are piling on the pounds, or they are unattached and are keen to get in shape to re-enter the singles market.
If you feel like going for a massage, go ahead and splurge. Others, you have to physically force yourself to put down the phone so you best herbs to lose weight fast call your ex.
After a break up, your body naturally feels more lethargic because it's processing the emotional experience you just had. If you find yourself gaining or losing weight, you're definitely not alone. Ms Ryan has also gained 13, Instagram followers, who ask her for dieting and weight loss tips.
Caddell explained, "Another part of your brain, related to your reward system, that also gets activated after a break up is responsible for calculating all kinds of gains and losses, rewards, and making meaning out of the situation, according to Dr.
A bad acai berry fat burner how much to take cut can hurt your already-bruised confidence. You have brain activity that leads to endless pro and con lists Shutterstock Another completely normal yet very frustrating thought pattern is making constant mental pro and con lists about your ex.
Even if you feel like holing yourself up in your room and obsessing about your ex, try to motivate yourself to try something new. They are either seeking help because they are happy with their partner but are piling on the pounds, or they are unattached and are keen to get in shape to re-enter the singles market.
I have no energy. This social support from friends and family do not replace the relationship you had, but can definitely help you cope better and experience a decreased stress response as a result.
You may not be with your ex anymore, but you can still give yourself the love and attention you deserve. Your body is essentially weaker after a break up. Now is a great opportunity to take that dancing class you've always thought about but never done or traveled somewhere you've always wanted to go but never been.
A photo posted by Sian Ryan sianliftsweights on Nov 29, at 3: Resist the urge, however, to call or text whenever you would have when you were still dating.
Break ups can therefore be extremely difficult for us to endure, and do have physical effects. A photo posted by Sian Ryan sianliftsweights on Jan 22, at 1: Now focusing on her body and career, her self-esteem has soared since being dumped. Pinckney told me, "Meditation and breathing [have] been scientifically proven to how much weight do you lose after a break up stress hormones, promote a sense of well being, and help you reconnect to the power within yourself as you go through this time of transition.
For strong diet pills that work new tips on dealing with post-break up pain, click here! This is our body's way of moving backwards before it can move forward again.
Here's what the experts say is really going on. Best how much weight do you lose after a break up to lose weight? Fisher's research this is called the nucleus accumbens.
What you feel is a rush of tense energy surging through your system, a shortness of breath, foggy thoughts, and a pounding heart. Caddell told me, "Helen Fisher has done a great deal of brain research on love and break ups. Share or comment on this article: You experience physical pain Shutterstock If you feel like you're in actual pain after a break burning off belly fat, it isn't just you.
If you are gaining weight most likely it is the little stress monster in your brain known as cortisol that when over stressed will convince you that you need to devour an entire pizza or chocolate cake because you have to have it.
Your hormones get out of whack Shutterstock Cortisol isn't the only hormone in your body that's acting up, either. Not only did your relationship end, but you also feel like a crazy person.
Medical research shows that the same pain receptors that are triggered when you break a leg light up just the same after a painful break up. Women who have chosen to initiate the split tend to lose less weight than those who are the receiving line of the dumping.
My diet was coffee. So she started exercising, but lost interest after a few weeks. Create intentional space for a while and let yourself mourn the end of the relationship.
How Much Fat Per Day – How Many Grams Of Fat Should You Eat?


text:
Georgia Tech Student Copied His High School Debate Coach's Speech For His Epic Performance
Peter Jacobs
YouTube/Andy Blanton
A Georgia Tech student's epic convocation speech to incoming freshmen was taken from his high school debate coach, according to Gawker.
The Georgia Tech speech went viral this week, racking up more than a million views and making a celebrity out of sophomore Nick Selby.
As Gawker reports, Selby's speech is a pretty close copy of a 2008 speech from Andy Stone — the debate coach at Selby's high school. Gawker reporter Neetzan Zimmerman writes, "Did Selby straight-up rip off a speech given by his former debate coach, and pass it off as his own? It would seem so."
For what it's worth, Selby posted on Facebook about his former coach's influence, writing, "I had an awesome speech coach in high school by the name of Andy Stone, and was absolutely thrilled when he agreed to let me use the end of his award-winning speech as the foundation for my own." The full post is below:
Screenshot Via Facebook
Selby's admission went up 13 hours before Zimmerman's article.
The full versions of Selby's and Stone's speeches are below. Although only the end of Selby's speech made the news, the whole thing is filled with good advice for new students and is worth a watch.
The overlap between the two speeches starts at 5:00 in Selby's video and 8:40 in Stone's video.
More: Gawker Georgia Tech Students College

redpajama_set_name: RedPajamaCommonCrawl


text:
Is Award-Winning Journalist and Host Kerstin Lindquist Leaving QVC?
By: Caroline John - Published: January 18, 2023 at 5:33 am
Photo: kramynina/envato
Kerstin Lindquist has been a staple on QVC for a decade in a celebrated media career. In January 2023, the fitness and health expert announced she would be MIA from the home shopping platform. Her longtime viewers are now wondering if Kerstin Lindquist is leaving QVC. The host said she is temporarily stepping back from the TV network for a big reason and will return soon. Find out where Kerstin Lindquist is going right here.
Kerstin Lindquist to Take Hiatus from QVC
In 1999, Kerstin Lindquist graduated with a BA in Political Science from Franklin & Marshall College in Lancaster, Pennsylvania. Early in her broadcasting career, she was a news reporter at news stations in California and Nevada.
Lindquist even won Emmy Awards for her excellence in reportage. One of her most notable news reports was a series of interviews with military personnel stationed in Guantanamo Bay.
She joined QVC in 2011, and she's been an extraordinary presence among health watchers tuning into the home shopping network. Through QVC and her multiple books, Lindquist has helped people and spread awareness on topics about infertility, adoption, fitness, and wellness.
On January 17, Kerstin Lindquist told her social media followers that she would be stepping back from QVC, albeit only for a while. She said that she was going on a mission trip for three months.
She will be serving on this trip far away from home and won't be on-air during that time. However, the QVC host has not revealed details about her journey.
Lindquist's last day on the air at QVC is on January 21 before her sabbatical. She will join her co-host, Alberti Popaj, for Kerstin On Q on Saturday from 10:00 a.m. to 1:00 p.m.
Also Read: Stephanie Duprey Leaving WHEC-TV: Where Is the Rochester Reporter Going?
With additional confirmation from Popaj, Lindquist stated that this is by no means a farewell and will return to QVC after her mission trip. Meanwhile, she thanked all her colleagues and loved ones for their support and encouragement to embark on this journey.


We are specialists in providing different products and services to schools for early years play areas in Aberchirder AB54 7 to help improve the overall learning quality of the pupils. It's essential that children have a place to relax and enjoy themselves during the school day, which means having an early years playgrounds is a must for a good school. We offer a huge range of different play products that can brighten up and bring life to your play-area, improving the quality of learning and fun at your facility.
For more details regarding costs and prices please feel free to use the comment section and we will get back to you as soon as possible. We are happy to give you all the information you require to ensure you get the results you are looking for.
With regard to kids' play-areas, colourful designs are generally installed to brighten up the surfacing and add colourful graphic designs. Pupils will enjoy entertaining games together with increasing their physical health and acquiring necessary skills. Graphics can be installed to suit kids of every age group, from Early Years Foundation Stage up to primary school. Alongside typical, fun recreational designs, you can also find subject oriented designs, including maths and English that can excel children mentally. This may be through things like maths squares, alphabets, words, compasses and geographical maps. These can be both floor and wall https://www.playground-markings-direct.co.uk/graphics/wall/aberdeenshire/aberchirder/ markings that can help kids interact with their surrounding areas.
The vibrant patterns are ideal for getting children to be far more active and healthy, as well as helping them to have fun outside. Because obesity statistics are gradually escalating with kids in the United Kingdom, the markings provide an effective strategy to tackle this problem particularly in primary schools. We may install the colourful recreational markings to many varieties of facility to improve the quality of the institution. They're all made out of top quality substances which means they will be weather resistant and dependable. It's key for floor graphics to be secure because kids will be making use of them all the time. If you have and worn out early years play areas the colourful markings could drastically enhance the overall look and produce a more lively look for the surface. The marking can catch the attention of children of all abilities along with a variety of age groups. It helps give children of all ages to have fun with their time out of class.
You can install a selection of shapes, measurements and colours to obtain a suitable design for your nearby creche https://www.playground-markings-direct.co.uk/client/creche/aberdeenshire/aberchirder/ nursery. The versatile heat applied plastic patterns are resilient effective so they should last a long time in the recreational area. For local schools closest to you in Aberchirder AB54 7 which presently have out of date and old play-area graphics we may recover these to make them look completely new and exciting. We are able to use classic play markings including snakes and ladders and hopscotch, and various other classic features.
What Are Sport Pitch Designs?
Sports pitch designs can vary depending upon the sports you wish to play on the court. Sports line markings available such as netball and hockey. As youngsters can take part in lots of exciting activities, they'll be more concentrated in lessons so it's much easier for them to understand information. Youngsters could also build up interpersonal skills through experiencing activities with other people, together with being much healthier plus more active. Lots of necessary skills like teamwork and solving problems may be taught through playing the different games within the playground. Through enjoying the marking games, the kids can have fun together as a group along with experiencing independent creative https://www.playground-markings-direct.co.uk/graphics/creative/aberdeenshire/aberchirder/ games that come in a range of designs.
It is relatively simple to apply colourful games markings to surrounding areas which therefore means the kids can get back to enjoying the play area quickly. The line markings will be laid out on the play surface and then heated up so they melt and stick to the tarmac. It is an environmentally friendly, safe and fully reliable material which can refresh an existing play-area. The recreational patterns that we offer are excellent for making your area more exciting and educational. We take pride in being able to educate and entertain through colourful playground designs. The cost and pricing for products will vary dependant upon the location of the job and the specification you want for the marking.
Each case we deal with has different requirements as well as specification so there is not a set price for the EYFS markings. If you're interested in finding out the exact cost of your playground markings, get in touch with us today.
If you'd like to get in touch with us to find out more information regarding the huge range of different products and services that we have on offer then please feel free to use the contact form to send us a message if you need more information regarding the costs and prices or specifications. We can help talk you through the various different designs and specifications that are available on the market for early years play areas in Aberchirder AB54 7 and how it'll effect the price.


Bachi Ar Kemone [বাঁচি আর কেমনে] is Bengali folk sad song written by Asharaful Haque Turon , tuned by Avi Akash , music composed by Musfiq Litu and Vocal by HBK Happy . Bachi Ar Kemone is produced and distributed by Rain Music.
All right reserved. This visual content is copyrighted material of Rain Music. Any unauthorized re-production, redistribution or reupload is fully prohibited of this content. Legal action will be undertaken against those who violate the copyright of this content.


Toddler birthday party themes - A concise and specific directory for toddler birthday parties.
Want to make your child's birthday extra special? There are lots to choose from - and they need not cost a lot to organize.
Theme parties for toddlers can be as low-key or full-on as you like. You can have themed cake and decorations only, or have related games and the children dressing up.
This is a really easy toddler birthday party theme to have. Choose 2 colours, and everyone must wear at least 1 item of one of the 2 colours. This is less of a headache than limiting it to one colour - let's face it, boys will be a bit stuck for ideas for a pink party!
The great thing about a colour theme is that toddlers who hate dressing up won't even notice they are complying with the dress code.
The advantage of a pirates and princesses party is that it is relatively easy for the children to dress up for. Many toddler girls already have some sort of princess outfit - a fairy costume will do just as well. Alternatively borrow one from a friend's daughter.
Some boys may not want to dress up. This was the case with my son when he was invited to a Pirates and Princesses party. He wore one of his stripey t-shirts and nobody minded in the least - if this worries you speak to the host beforehand.
You could also have the party at one of those farms that welcome visitors, which often have play facilities on site. Some of them organize parties - check in advance.


You've Signed Your Contract as a New-in-Practice-Pathologist: Now What?
I thought the hardest part of my transition from resident to new-in-practice pathologist would be finding a job. So when I signed a contract with a group, I figured the hard work was over. However, I was surprised with the amount of paperwork and tasks that had to be completed before the end of my fellowship. While my transition to practice began as soon as I finished writing my signature, I had only 6 months to get everything together. There were licensing and credentialing hurdles, issues related to moving to a new city, and of course tying up all the loose ends at my current location. I'm writing this article in hopes of expediting this process for you, the incipient new-in-practice pathologist.
For starters, you will need a lot of documents. I got everything together in a hard copy folder and made PDF copies of all my documents and stored them in the cloud for convenience and security. You'll need a recent CV with explanations of any gaps longer than 3 months, copies of all medical diplomas, residency/fellowship certificates, results of board exams, passport, driver license, birth certificate, NPI number, DEA number, and any previous medical licenses. You'll also need a list of 3 to 4 references with contact information and lists of previous educational institutions and prior hospitals, including dates of attendance, addresses, and phone numbers. You'll also need prior vaccination history, TB skin test results, and your doctor's name and contract information.
I found the main kickoff for this process was receiving my new medical license. Unfortunately, the pace of processing a medical license was largely out of my hands. As such, it is really important to get started as quickly as possible. Many states require background checks with fingerprinting, which can take 6 to 8 weeks. Your current and previous training institutions will have to send in documentation as well, and you'll need to get letters from program directors. I generally checked on my license every 4 weeks for any missing documentation and to see if I could get any documents expedited to the medical board. To put it simply, you should start working on getting your new license as soon as you sign a contract.
Once I had my license, I applied for privileges for various hospitals I would be covering and began enrolling in the various insurance plans and government programs. Luckily, most the paperwork you need to gather for the medical license also applies to these agencies so you don't have to track anything new down. My group covers multiple hospitals, so there were numerous applications to fill out. Thankfully, my group had an employee who managed and filled the majority of the form beforehand, leaving me with only the responsibility of adding my signature. Even if you too have the added convenience of such support staff, it's imperative to return everything quickly so hospital credentialing staff can start processing your applications. This can take up to 3 to 4 months and can vary notably according to hospital.
At 3 months before my start date, I began to arrange housing. I had to find an apartment over the telephone and make arrangements remotely. Most of the units required salary documentation, so I had to talk to the group's practice manager to get a verification of income letter. If you have children, as many of my colleagues do, you'll also need to arrange for daycare and schools, which can be especially time and labor intensive when you're not yet living in the area.
I did a tissue-specific fellowship, but I knew that my new job included general signout responsibilities and performance of bone marrows. I talked with members of my new group to get a feel for what areas I should brush up on before starting my first day. Since I was doing bone marrows, I arranged to spend a couple of days shadowing the bone marrow service at the hospital that I was doing my fellowship. I also read up on neuropathology frozen sections since that seemed like a pretty daunting aspect. I had several friends who were going to be doing FNA clinics and therefore brushed up on FNA-specific skills before starting. Some people spent several weeks with other fellowships to prepare. It is important to get a feel for what your group does, not only to come in well prepared to start working, but also to identify the areas in which you may be less comfortable.
During the last several weeks of my fellowship, I exchanged contact information with co-fellows, attendings, and other colleagues I wanted to keep up with once I left. Unfortunately, a lot of the contacts that I imported to my cell phone were linked to the university email system, so when that account was deleted, my contacts were deleted as well. I can't help but think this is a common oversight. Had I known beforehand, I would have downloaded the contact list into a spreadsheet and reloaded them to my phone. I also collected the wording of particular diagnoses and comments that I thought were good from my residency and fellowship so that I could use them in my own practice. I also saved all the presentations that I did during fellowship and residency and was able to use them as a skeleton for lectures I ended up giving at my new job. Finally, I made sure everyone had my personal email address and changed my contact information in all the medical society and organization web pages, so I would be able to keep up with all future notifications.
Although I thought I was operating ahead of the curve, there were still delays. I ultimately started a month late due to a delay in one insurance provider that look longer than anticipated with enrollment paperwork. Since I could not bill until the paperwork was completed, I spent my first month doing consults, QA, and presenting at tumor boards. Although my intention to be full-fledged at day one didn't come to fruition, my extra preparation that started after I signed my contract was well worth it, and my group was understanding and appreciative once I was up and running.
Dr. Richard Owings is a pathologist in Lafayette, Louisiana with the Delta Pathology Group. He works in a community practice and has a personal focus in breast pathology. He also serves as laboratory medical director for a regional medical center and several community hospitals.


The FL Project Boardshop will be hosting the first rail jam of the year at Trollhaugen during their annual Harvest Festival. Get out there early as registration begins at 10am. There will also be several other activities during the festival which includes chair lift rides and wagon rides. Check Trollhaugen's website for more info.
Well it's about that time of the year that the snowboarding buzz starts. You really know it's almost time when the ski resorts start having their annual fall fairs. Afton's fair and gear swap will be in early october this year.


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Challenging Misconceptions of Islam: Basic Advice for Teachers
We can challenge misconceptions of Islam in school by:
Assistant Headteacher at The Reach Free School, Hertfordshire
18/11/2015 05:14am GMT | Updated November 17, 2016
In May a survey of 6,000 schoolchildren was published by Show Racism the Red Card that concluded many students hold widespread misconceptions and negative attitudes towards British Muslims. The research found that 35% of the 10 to 16 year olds questioned 'agreed' or 'partly agreed' that 'Muslims are taking over our country' whereas only 41% 'disagreed'. In addition to this worrying misconception, most students surveyed believed that Muslims make up around 36% of the population - when in reality the figure is closer 5%. And, sadly, 47% 'agreed' with a statement suggesting that there are poor relations between Muslims and non-Muslims in England.
Although this survey does not - in any way - reflect my own school, it does raise obvious concerns about what students know and understand about Islam and British Muslims as well as how these misconceptions come about. Moreover, it also suggests that as teachers we should be aware of what Islam is and what it means to be Muslim, especially if we are to promote tolerance, respect and community cohesion within the school community.
Of course, one bulwark against Islamophobia is educating students about the religion in RS lessons. This is arguably the case at my school where all students are taught the life of the prophet Muhammad (pbuh) in Year 7 as well as the five pillars of Islam, which are the key foundations of the Islamic faith. However, it is also important that teachers in other subjects are constantly aware of misconceptions about Islam - even if they do not come across as malicious or even Islamophobic - as they could create misleading perceptions of Islam that eventually lead to Islamophobic views.
A good way of challenging misconceptions is to fully understand the language used to describe Islam and Muslims and to challenge the use of that language when it is misused. For instance, a key example is the use of 'devout' and 'jihad'. These two words often get invoked to refer to extremists and a minority of Muslims committing terrorist attacks, but in essence they are not negative things. Although the former term might not seem controversial, some British newspapers have been censored for referring to extremists as 'devout Muslims'.
Firstly, a 'devout believer' is someone who has a strong commitment to a set of basic religious beliefs, ideas and/or principles. A 'devout Muslim' could be someone who is committed to their faith: perhaps praying five times a day; fasting during the holy month of Ramadan; regularly going to mosque and having a strong sense of Islamic identity. It is also important to stress that many of these basic values correspond to British values, such as justice and equality (exemplified by the third pillar of Islam - charity). Moreover, in the UK, the Muslim community upholds the importance of British laws. For instance, Muslim scholars have argued that Muslims living in majority non-Muslim countries must adhere to the secular 'laws of the land' and have no excuse for breaking those laws. Therefore, we should not mix the terms 'devout' with 'extremist' as they mean two very different things.
Perhaps the more controversial argument centres on how we use the term 'fundamentalist'; some commentators suggest that a 'fundamentalist' merely has a strict adherence to their faith whereas others equate it to extremism. In many respects the former usage could be seen as completely benign, but due to confusion with this word, especially in the media, it may be better to refer to 'devout Muslims' when discussing those that take their faith very seriously, in order to avoid any association with illegal or violent extremism.
Secondly, another key misconception is the idea of 'jihad' being extreme or bad per se; interestingly, some scholars have argued that all Muslims are jihadis in the same way that all Christians are followers of Christ. For many Muslims, jihad is simply the religious duty that they have to maintain the religion. This is best explained through a translation of the word from Arabic, which literally means "to strive, to apply oneself, to struggle, to persevere". It can be argued, then, that jihad itself is not a controversial issue when thinking about Islam. It does, however, become an issue if interpreted as a defence of extremist views, such as sympathy with terrorist acts or highly illiberal attitudes towards other faiths, homosexuality and so on (this is where schools' PREVENT training is vital).
Furthermore, another key element of jihad is distinguishing between the 'greater jihad' and the 'lesser jihad'. The former relates to the personal spiritual struggle that Muslims have to adhere to their faith whereas the latter is the defence of Muslims and the faith from aggressors. It is the 'lesser jihad' that has been hijacked by extremists despite the actual rules of 'lesser jihad' stipulating that innocent people must not be harmed, 'enemies' should be treated with justice and that jihad is a form of defence and not aggression; for example, the Holy Qur'an states, 'Fight in the way of Allah against those who fight against you, but begin not hostilities. Lo! Allah loveth not aggressors' (2:190).
Lastly, when challenging misconceptions of Islam in school as well as potential Islamophobia, it is worth considering common stereotypes. For example, students in majority non-Muslim schools may associate Muslims with the minority of extreme and radical preachers often featured in tabloid newspapers as opposed to practising Muslims (and all round British heroes) like Mo Farah, Amir Khan and Moeen Ali. Moreover, there are plenty of examples of Muslims in pop culture, which is often not associated with Islam, such as Zayn Malik - formally of One Direction - as well as Muslims presenting popular news programmes, such as Mishal Husain on BBC Radio 4.
In conclusion, we can challenge misconceptions of Islam in school by:
being aware of the key beliefs of Muslims;
using the correct terminology when discussing Islam;
and, importantly, challenging stereotypes and highlighting examples of Muslim role models in British society.
Islamislamophobiaschoolscommunity cohesionReligious Tolerance


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Q: Input properties in angular directives I'm having a problem with input properties in angular directive used in my reactive form (Side question here: Is it a good practice to use directives in reactive forms?). I want to create universal directive for cross field validation that would take as an input two strings each for the name of a field to validate. Here's some code to illustrate what I mean.
// Directive
import { Directive, Input, OnInit } from '@angular/core';
import { Validator, AbstractControl, NG_VALIDATORS } from '@angular/forms';

@Directive({
    selector: '[appConfirmEqualValidator]',
    providers: [
        {
            provide: NG_VALIDATORS,
            useClass: ConfirmEqualValidatorDirective,
            multi: true,
        }
    ],
})
export class ConfirmEqualValidatorDirective implements OnInit, Validator {

    @Input() confEqSecControlName: string // = 'password' ; would work if uncommented
    @Input() confEqFirstControlName: string //  = 'confirmPassword' ;

    constructor() {
    }

    ngOnInit(): void {
    }

    validate(controlGroup: AbstractControl): { [key: string]: any; } {
        console.log(this.confEqFirstControlName + ' ' + this.confEqSecControlName);

        let firstControl = controlGroup.get(this.confEqFirstControlName);
        let secControl = controlGroup.get(this.confEqSecControlName);

        console.log(firstControl.value + ' fc ' + secControl.value + ' sec');
        if (firstControl && secControl && ( firstControl.value !== secControl.value )) {
            return { 'notEqual': true};
        } else {
            return null;
        }
    }

    registerOnValidatorChange?(fn: () => void): void {
        throw new Error("Method not implemented.");
    }
}

// HTML

        Password

            <input class="form-control" formControlName="password" type="text" id="passwordId" placeholder="Password (required)" />

Danger

        Confirm Password

            <input class="form-control" formControlName="confirmPassword" type="text" id="confirmPasswordId" placeholder="Confirm Password (required)"/>

Not Equal

pastebin for clarity
I'm new to angular but from what I've read in the docs this should work just fine. Well It isn't. The values are not being bound to properties at all, and the console logs 'undefined'. Everything works just fine when I specify default values, but well then with hard-coded values I'd have to make one directive/function for each set of fields. I'd be very grateful for some help, thanks.

redpajama_set_name: RedPajamaStackExchange


UNU-IAS is pleased to announce that the UNU-Shimadzu project Monitoring and Management of Persistent Organic Pollutants in Asia is being showcased at the Shimadzu Corporation booth in the Japan Pavilion during the Seventh World Water Forum currently taking place in Daegu, Republic of Korea (12–17 April 2015).
Persistent organic pollutants (POPs) are among the most pernicious artificial substances ever created. Whether synthesized for use in pesticides, solvents and plastics, or produced as the unwanted by-product of industrial processes, POPs have long been released into the environment by human activity. Once released, POPs persist in the environment for years, or even decades, and can be spread widely from their source by water and air.
For the purpose of establishing proper management of environmental contaminants based on scientific monitoring procedures, focusing especially on the hydrosphere, UNU and Shimadzu Corporation have been carrying out a collaborative project to strengthen research activities and support higher education regarding POPs regulated by the Stockholm Convention, particularly in developing countries in the Asian region.
For more information, please visit the Shimadzu Corporation website.


Read more about red dead redemption 2 cheat codes and rdr2 jack not at camp.
RDR 1 Remastered in RDR 2 HUGE INFO! – New Glitch Shows Jack Marston/Hints at Remaster as Story DLC!
In this #RDR2 video I showcase a glitch that occurs which shows the playable character having Jack Marston's voice. This usually does not occur in the game's storyline, but with what we know about the first game, could potentially mean Rockstar are working on either a remaster or continuing Jack's story in an upcoming DLC!


We show the new model of our popular device.
This product was designed to facilitate combining LED lighting in lines. As it is completely modular, it presents you a simple method of creating long lines of lighting.
The latest cryotherpy appliance for regeneration and health.
Many years of experience, modern machine park and great location comprise the main elements of the success of JBG-2. Hundreds of satisfied customers from all over the world particularly appreciate our creative approach to problem-solving and our involvement in successful project accomplishment.
We are committed to ecology during the production stage as well as later on, making sure that the impact of our equipment on the natural environment is as low as possible.
Out of concern for the high quality, we conduct tests in our certified laboratories which meet the ISO23953-2 standards. In addition, the company's management is carried out on the basis of ISO 9001-2009 standard.


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package org.apache.curator.x.discovery.details;

import org.apache.curator.x.discovery.ServiceInstance;
import org.codehaus.jackson.map.ObjectMapper;
import org.codehaus.jackson.type.JavaType;
import java.io.ByteArrayOutputStream;

/**
 * A serializer that uses Jackson to serialize/deserialize as JSON. IMPORTANT: The instance
 * payload must support Jackson
 */
public class JsonInstanceSerializer<T> implements InstanceSerializer<T>
{
    private final ObjectMapper      mapper;
    private final Class<T>          payloadClass;
    private final JavaType          type;

    /**
     * @param payloadClass used to validate payloads when deserializing
     */
    public JsonInstanceSerializer(Class<T> payloadClass)
    {
        this.payloadClass = payloadClass;
        mapper = new ObjectMapper();
        type = mapper.getTypeFactory().constructType(ServiceInstance.class);
    }

    @SuppressWarnings({"unchecked"})
    @Override
    public ServiceInstance<T> deserialize(byte[] bytes) throws Exception
    {
        ServiceInstance rawServiceInstance = mapper.readValue(bytes, type);
        payloadClass.cast(rawServiceInstance.getPayload()); // just to verify that it's the correct type
        return (ServiceInstance<T>)rawServiceInstance;
    }

    @Override
    public byte[] serialize(ServiceInstance<T> instance) throws Exception
    {
        ByteArrayOutputStream           out = new ByteArrayOutputStream();
        mapper.writeValue(out, instance);
        return out.toByteArray();
    }
}

redpajama_set_name: RedPajamaGithub


text:
Poria cocos polysaccharides exert prebiotic function to attenuate the adverse effects and improve the therapeutic outcome of 5-FU in ApcMin/+ mice
Lin Yin1 na1,
Guoxin Huang1,2,3,
Imran Khan1,
Lu Su1,
Wenrui Xia1,
Betty Yuen Kwan Law1,
Vincent Kam Wai Wong1,
Qiang Wu1,
Jingyi Wang1,
Wai Kit Leong1 &
W. L. Wendy Hsiao1,4
Chinese Medicine volume 17, Article number: 116 (2022) Cite this article
As a first-line chemotherapeutic agent, 5-fluorouracil (5-FU) exhibits many side effects, weakening its efficacy in cancer treatment. In this study, we hypothesize that Poria cocos polysaccharides (PCP), a traditional Chinese herbal medicine with various bioactivities and prebiotic effects, might improve the therapeutic effect of 5-FU by restoring the homeostasis of the gut microenvironment and the commensal gut microflora.
ApcMin/+ mice were employed to evaluate the anti-cancer effect of 5-FU in conjunction with PCP treatment. Body weight and food consumption were monitored weekly. Polyp count was used to assess the anti-cancer effect of PCP and 5-FU. Expressions of mucosal cytokines and gut epithelial junction molecules were measured using qRT-PCR. 16S rRNA gene sequencing of fecal DNAs was used to evaluate the compositional changes of gut microbiota (GM). Transplantation of Lactobacillus johnsonii and Bifidobacterium animalis were performed to verify the prebiotic effects of PCP in improving the efficacy of 5-FU.
The results showed that PCP treatment alleviated the weight loss caused by 5-FU treatment and reduced the polyp burden in ApcMin/+ mice. Additionally, PCP treatment eased the cytotoxic effects of 5-FU by reducing the expressions of pro-inflammatory cytokines, increasing the anti-inflammatory cytokines; and significantly improving the gut barriers by enhancing the tight junction proteins and associated adhesion molecules. Furthermore, 16S rRNA gene sequencing data showed that PCP alone or with 5-FU could stimulate the growth of probiotic bacteria (Bacteroides acidifaciens, Bacteroides intestinihominis, Butyricicoccus pullicaecorum, and the genera Lactobacillus, Bifidobacterium, Eubacterium). At the same time, it inhibited the growth of potential pathogens (e.g., Alistipes finegoldii, Alistipes massiliensis, Alistipes putredinis., Citrobacter spp., Desulfovibrio spp., and Desulfovibrio desulfuricans). Moreover, the results showed that transplantation of L.johnsonii and B.animalis effectively reduced the polyp burden in ApcMin/+ mice being treated with 5-FU.
Our study showed that PCP could effectively improve the anti-cancer effect of 5-FU by attenuating its side effects, modulating intestinal inflammation, improving the gut epithelial barrier, and modulating the gut microbiota of ApcMin/+ mice.
Colorectal cancer (CRC) is a high-risk illness that threatens countless people's health and causes a severe financial burden to society. With more than 1.9 million new cases and 935,000 deaths in 2020, CRC will become the second most common cause of cancer-related mortality worldwide [1]. For CRC therapy, surgery is the first-choice therapy. However, because of the high incidence of relapse and metastasis, chemotherapy still plays a vital role in caring for CRC patients in clinics. For the past 50 years, 5-FU, the derivative of uracil, has served as the classic and standard agent for CRC chemotherapy. 5-FU exerts antitumor effects by interfering with thymidylate synthase and inhibiting DNA and RNA synthesis. As a consequence, 5-FU effectively induces cell cycle arrest and apoptosis of the tumor cells [2]. However, the adverse effects of 5-FU, including gastrointestinal toxicities, peripheral blood cytopenia, and neurologic abnormalities, cannot be ignored [3]. Furthermore, among various side effects of 5-FU therapy, about 50–80% of the patients suffered severe intestinal mucosal damage that caused severe diarrhea, nausea, vomiting, and anorexia [4, 5]. Therefore, it is necessary to develop new strategies to minimize or prevent the adverse effects and improve the therapeutic efficiency of 5-FU.
The host-microbes interaction plays a crucial role in health and disease [6, 7]. Evidence pointed out that illness and drug treatment can lead to the compositional shift of GM. On the other hand, alteration of specific GM can significantly affect the host's drug response and disease development [8]. For example, studies showed that disruption of the microbiota reduced the efficacy of tumor-bearing mice to CpG-oligonucleotide immunotherapy and platinum chemotherapy [9, 10]. Gut microbes facilitating cancer treatment also extended to the targeted immunotherapies, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death ligand 1 (anti-PD-L1) therapies [11, 12]. The influence of GM is also well refracting in CRC development and its response to drug treatment [13, 14]. For example, recent reports showed that cancer chemotherapeutic agents, including 5-FU, could increase the relative abundance of specific pathogens, e.g., Escherichia and Bacteroides fragilis [13, 15]. Another study indicated that altered gut microbiota might cause intestinal mucositis associated with 5-FU therapy [16]. Furthermore, recent reports also pointed out that dysbiosis reduces the antitumor efficacy of 5-FU [17, 18]. On the other hand, the oral administration of probiotics ameliorated 5-FU-induced mucositis in mice [19]. The study further illustrated that combined 5-FU and probiotic treatment suppressed the inflammatory cytokines triggered by the 5-FU treatment in the colon of mice [19]. Based on these results, it is a feasible strategy to improve 5-FU therapeutic effect and make safer treatment through the modulation of GM composition.
Chinese herbal medicines have been served clinically as adjuvant therapy to reduce adverse effects and improve the efficacy of chemotherapeutic agents [20, 21]. Our previous studies found certain Chinese herbal medicines, including saponins from Ginseng, Notoginseng, and Gynostemma pentaphyllum; polysaccharides from Lycium barbarum, Ganoderma lucidum and Poria cocos, exhibit prebiotic effects in both normal and diseased mouse models [22,23,24,25]. Poria cocos (PC, newly named Wolfiporia cocos) is a dietary herbal medicine commonly used to treat gastrointestinal diseases. Polysaccharide is the principal constituent and the main active ingredient of PC. Evidence showed that PC polysaccharides (PCP) possess anti-cancer, anti-inflammation, anti-aging, immunomodulation, and lipid regulation properties [26,27,28,29]. Furthermore, our previous report suggests that PCP can effectively modulate GM and act as a prebiotic agent in mice [23]. In line with our study, a recent study also found that main metabolites of PC significantly altered the gut microbiota and the intestinal metabolites in mice [30]. Besides modulating the dysbiosis in the alcoholic hepatic steatosis mouse model, PCP also alleviated liver symptoms by inhibiting the ethanol-induced fungal overgrowth [31]. Here, we hypothesize that PCP might exert its prebiotic effects to minimize the adverse effects and improve the anti-cancer effect of 5-FU.
In this study, the colonic cancer model ApcMin/+ mice were treated with 5-FU with and without PCP. Polyps counting was used to evaluate the anti-cancer effect of 5-FU with or without PCP. In addition, 16S rRNA gene sequencing of fecal DNAs, inflammatory cytokines test, immunohistochemistry, and fecal microbial transplantation (FMT) were conducted to investigate the potential prebiotic effects of PCP in alleviating adverse effects of 5-FU by modulating the GM and gut microenvironment of ApcMin/+ mice.
Animals and treatments
The ApcMin/+ mice (age 6–8 weeks) were purchased from Jackson's Laboratory and bred in-house for heterozygous mice. The genotype of ApcMin/+ mice was identified using KAPA Mouse Genotyping Kit (Roche, USA). Mice were fed with PicoLab® Rodent Diet 20-5035 (LabDiet, USA). Mice were housed in a 12-h/12-h dark–light cycle facility and kept in the IVC equipment with free access to food and water. 28 ApcMin/+ mice were randomly divided into four groups, i.e., the control group, PCP group, 5-FU group, and PCP + 5-FU group. Dry powder of PCP was dissolved in sterile distilled deionized (DD) water. The mice were gavage daily with 750 mg/kg of PCP or solvent control for four consecutive weeks. In addition, mice in the 5-FU and PCP + 5-FU groups were injected intraperitoneally with 40 mg/kg of 5-FU for five successive days in the 2nd and 4th weeks (Fig. 1A). Food consumption and body weight were recorded weekly. At the end of the experiment, the mice were euthanized and sacrificed following the approved guidelines of the Ethics Review Committee for Animal Research of the Macau University of Science and Technology.
PCP enhanced the anti-cancer effects of 5-FU in ApcMin/+ mice. A The treatment scheme; B The experimental mice's body weight and food consumption. C Effect of PCP and 5-FU on the total number of polyps; and the number and size distribution of the intestinal polyps. The data are presented as the mean ± SD. *p < 0.05, ** p < 0.01, n = 7
Preparation of PCP herbal extracts
Water-soluble polysaccharides of Poria cocos (the content of polysaccharide is ≥ 30%) were purchased from Jiangsu Goodex Mushroom Biotech Co. Ltd. (Yancheng, Jiangsu, China). The quantitation of the PCP was performed as in the previous description [23]. PCP powder was dissolved in dd-water for the later experiments. 5-FU was purchased from Shanghai Macklin Biochemical Co., Ltd. (Shanghai, China).
Fecal samples collection and extraction of genomic DNA
Fecal samples were collected in the 2nd and 4th weeks of the experiment and stored at −80 ℃ for the later experiments. The total DNA was extracted using QIAamp DNA Stool Mini Kit (QIAGEN, German) based on the manufacturer's protocol.
Animal dissection and polyp counting
The mice were terminated and dissected at the end of the experiment for polyp counting. Section of intestine from the cecal junction was collected, rinsed with cold PBS, and fixed in 10% formalin for the tissue section. Mucosal samples were collected from the colon and distal small intestine and frozen for later biochemical analyses. The rest portion of the intestine was cut open longitudinally, rinsed with cold PBS, and fixed in 10% formalin for 48 h, then stained with methylene blue. The number and size of the polyps were scored under the Olympus SZX10 microscope.
Total RNA preparation and quantitative reverse transcription polymerase chain reaction (qRT-PCR).
The total RNAs were extracted from mucosal samples using TRNeasy Mini Kit (QIAGEN, Hilden, German), following the procedures from the manufacturer. The concentration of total RNA was determined by Nanodrop 2000C spectrophotometer (Thermo, USA). Following our previous description, the qRT-PCR reaction was carried out using Applied Biosystems ViiATM 7 PCR system (Carlsbad, CA, USA) [32]. β-actin was used as the internal control to normalize the PCR reaction of each specific marker. The 2−ΔΔCt method was applied to calculate the fold change of relative gene expression. ΔΔCt = (Cttreatment_target gene—Cttreatment_reference gene)–(Ctcontrol_target gene—Ctcontrol_reference gene). qRT-PCR was used to measure the expression of mucosal pro-inflammatory cytokines (IL-1β, IL-6, IL-18, INOS, TNF-α, and FOXP3) and anti-inflammatory cytokines (IL-4, IL-10, IL-12, and IL-13); tight junction proteins (ZO-1 and occluding) and adhesion molecules (VCAM-1, ICAM-1, E-cadherin, and N-cadherin). Specific primer sets were applied to quantify B. animalis and L. johnsonii using qPCR as described [32]. The primer sets used for the PCR analysis were listed in the Additional file 1: Table S1.
Histology and immunohistochemistry staining
H&E, Alcian blue staining, and immunohistochemical (IHC) staining were performed with 5 µm thick paraffin sections following the standard protocol. Specific antibodies for IHC staining included the anti-lysozyme antibody (1:200, A0099, DAKO), E-cadherin (1:200, #3195S, CST), N-cadherin (1:100, 13,116, CST), ZO-1 (1:200, 61–7300, Invitrogen), occludin (1:200, 40–4700, Invitrogen). VECTASTAIN® Elite® ABC Universal Kit (PK-6200, Vector) was used to hybridize the mentioned antibodies. Tissue sections were mounted and viewed under the Leica microscope. The images were taken with the Leica camera (DFC310 FX) and the Leica Application Suite software (Version 4.4.0, Switzerland).
Fecal DNA preparation, 16S RNA gene sequencing, and data analysis
For fecal GM analysis, sequencing of total genomic DNA was carried out using Illumina MiSeq (Illumina, San Diego), targeting the V3–V4 region of the 16S rRNA genes with barcoded 515F and 806R universal primers [33]. The detailed sequencing procedures were performed as previously described [34].
In vitro culture and transplantation of Lactobacillus johnsonii and Bifidobacterium animalis
L. johnsonii (1.3348, China General Microbiological Culture Collection Center) and B. animalis (1.1259, Guangdong Microbial Culture Collection Center) were acquired and cultured in the designated growth medium (Additional file 1: Table S2) and kept in an anaerobic chamber (Whitley A35 Workstation, Don Whitley Scientific Limited, UK) in 5% CO2, 10% H2, and 85% N2 according to Liao et al., 2021 [35]. Bacteria were collected by centrifugation at 5000 rpm for 5 min and diluted to 1 × 109 cells/ml for further experiments. In the microbes transplantation experiment, 20 ApcMin/+ mice (6–8 weeks old) were randomly divided into four groups: vehicle control, 5-FU, B. animalis + 5-FU, and L. johnsonii + 5-FU. 2 × 108 live bacteria from each species were gavaged to mice every other day for four consecutive weeks (Fig. 6B). 5-FU at 40 mg/kg was injected intraperitoneally to mice for five successive days in the 2nd and 4th weeks.
The statistical analysis and graphical presentation of data were performed by GraphPad Prism (8.0). The significant changes were determined by One-way ANOVA (for parametric data) and Kruskal–Wallis (non-parametric data) tests. Bonferroni and Dunn-Bonferroni tests were performed for parametric and non-parametric multiple comparison p values correction.
PCP treatment enhanced the anti-cancer effects of 5-FU in ApcMin/+ mice
To investigate the potential synergistic effect of PCP toward the anti-cancer effect of 5-FU, 6–8 weeks old ApcMin/+ mice were treated with 5-FU with or without PCP for four weeks. The treatment scheme is illustrated in Fig. 1A. There were no significant differences in body weight and food consumption among the groups in the 1st and 2nd weeks. However, the body weight and food consumption of the 5-FU and PCP + 5FU groups started to decline from the 3rd week and on. The decline was minimized in the group co-administrated PCP and 5-FU by the end of the experiment (Fig. 1B). Importantly, PCP treatment enhanced the anti-cancer effect of 5-FU based on the total number and the size distribution of the intestinal polyps in the mice (Fig. 1C).
PCP improved the intestinal epithelial barrier of the control and 5-FU-treated ApcMin/+ mice
The cancer-prone ApcMin/+ mice are known to carry dysfunction of the gut barrier and appear to be associated with spontaneous intestinal polyps formation [36]. The H&E staining of the intestinal villi showed various degrees of damage in the Ctrl and 5-FU groups compared to the PCP and PCP + 5-FU groups (Fig. 2A). Moreover, Alcian blue and lysozyme staining revealed that the number of Paneth cells and goblet cells decreased in the Ctrl and 5-FU groups. PCP alone or co-treatment with 5-FU restored the number of Paneth cells and goblet cells (Fig. 2A, Fig. S1). IHC staining and qRT-PCR showed that tight junction molecules occludin and ZO-1 were at low levels in the Ctrl and 5-FU groups and markedly elevated upon PCP treatment in the PCP and PCP + 5-FU mice (Fig. 2B and )C). In addition, the mRNA expressions of ICAM-1 and VCAM-1 were significantly induced upon 5-FU treatment, but treatment with PCP + 5-FU resumed the level close to the untreated control (Fig. 2C). We also evaluated the expression of the adhesion molecules, including E-cadherin and N-cadherin. Their expressions are the makers of cancer progression and prognosis. The results showed that 5-FU treatment decreased E-cadherin but increased N-cadherin. On the other hand, either PCP or PCP-5-FU treatment substantially enhanced the expressions of E-cadherin and downregulated N-cadherin in the treated mice (Fig. 2C).
PCP improved the intestinal epithelial barrier damaged by 5-FU. A H&E, Alcian blue, and lysozyme stains of the intestine. Alcian blue staining was used to detect the goblet cells. Anti-lysozyme staining was used to detect Paneth cells. The dark brown staining at the bottom of the crypts indicates the location of Paneth cells; B IHC staining of occluding and ZO-1. The positive stains were presented in dark brown staining. Scale bar = 100 μm; C The mRNA expressions of E-cadherin, N-cadherin, occluding, ZO-1, ICAM-1, and VCAM-1 by qRT-PCR; Data are presented as the mean ± SD, n = 3. *p < 0.05, ** p < 0.01, *** p < 0.001
PCP reversed the inflammatory gut environment disturbed by 5-FU treatment
Stimulation of intestinal inflammation and causing mucositis are the main side-effects of 5-FU. Higher expression of pro-inflammatory cytokines is usually involved in the progression of mucositis. Therefore, we evaluated the expressions of the mucosal pro-inflammatory and anti-inflammatory cytokines using the qRT-PCR test. Our results showed that treatment with PCP alone markedly (p < 0.01) increased the expression of anti-inflammatory cytokines (IL-4, IL-10, IL-12, and IL-13) compared to the control mice (Fig. 3A). Conversely, 5-FU treatment decreased anti-inflammatory cytokines' expression while drastically increasing pro-inflammatory cytokines' expression (Fig. 3A and B). Results also clearly showed that the intervention of PCP can overturn the upregulated IL-1β, IL-6, IL-18, iNOS, TNF-α, and FOXP3, and the down-regulated IL-4, IL-10, IL-12, and IL-13 that caused by the treatment of 5-FU (Fig. 3A and B).
Expressions of mucosal cytokines in the guts of the mice treated with PCP, 5-FU, or PCP + 5-FU. The expressions of anti-inflammatory cytokines (A) and pro-inflammatory cytokines (B) were measured by qRT-PCR. The data are presented as the mean ± SD, n = 3. *p < 0.05, ** p < 0.01, *** p < 0.001
PCP alone and in combination with 5-FU modulated GM diversity and composition of the mice
To investigate the role of PCP in regulating GM diversity and composition of mice treated with 5-FU, fecal genomic DNA was extracted from the mice and executed 16S rRNA gene sequencing. Alpha-diversity analysis showed that mice treated with 5-FU alone or combined with PCP lowered the diversity and richness of GM compared to the control and PCP groups (Fig. 4A). Moreover, the PCA plot showed the 5-FU and 5-FU + PCP groups deviated from the Ctrl and PCP clusters. However, PCP intervention brought the 5-FU cluster closer to the control group (Fig. 4B). The taxonomic comparison showed that Bacteriodetes, Firmicutes, and Proteobacteria were the dominant phyla among all the experimental groups (Fig. 4C). 5-FU treatment decreased the relative abundance of Bacteroidetes, while clearly increasing the relative abundance of Deferribacteres, Eukaryota, and Verrucomicrobia (Fig. 4C). LEfSe analysis showed that the increase of the Verrucomicrobia contributed to the enrichment of the family of Akkermansiaceae (Fig. 4D). Besides, the families of Enterobacteriaceae and Gammaproteobacteria were significantly increased in the 5-FU group (Fig. 4D). As a note, expansion of the Enterobacteriaceae is associated with inflammation and CRC [37]. Additionally, the family of Lactobacillales was significantly enriched in the PCP + 5-FU group, which could result from the enrichment of Lactobacillus (Fig. 4D). We also observed enhancement of the families Barnesiellaceae and Anaeroplasmataceae in the PCP + 5-FU group (Fig. 4D).
PCP treatment modulated the gut microbial diversity and composition in mice treated with 5-FU. A Alpha diversity analysis of the gut microbiota from each group. B PCA plots are applied to display the clustering of gut microbiota. C Average relative abundance of the dominant phyla. The y-axis represents the average percentages of OTUs reads. Different colors display significant changes in abundant phylum taxa of different groups. D The overall exhibition of LEfSe analysis by using taxonomic cladograms
PCP alone or co-administration with 5-FU increased the relative abundance of beneficial bacteria while decreased the potential pathogens
According to the previous reports, 5-FU tends to increase the relative abundance of potential pathogens while inhibiting beneficial bacteria growth. Our result showed that PCP treatment alone or with 5-FU boosted the total beneficial bacteria while suppressing the potentially pathogenic bacteria in the treated mice (Fig. 5A, Additional file 1: Tables S3, and S4). Heatmap analysis showed that 5-FU stimulated the growth of certain potential pathogenic bacteria, including Alistipes finegoldii, Alistipes massiliensis, Alistipes spp., Citrobacter spp., Desulfovibrio spp., and Desulfovibrio desulfuricans. PCP intervention, by and large, reversed the effect of 5-FU on these potential pathogens (Fig. 5A and B). Additionally, some beneficial bacteria, such as Bacteroides acidifaciens, Bacteroides intestinihominis, Bifidobactrium choerinum, Butyricicoccus pullicaecorum, Lactobacillus johnsoni, Eubacterium spp. were reduced in the 5-FU treated mice; while increased in the PCP and PCP + 5-FU groups (Fig. 5B). Moreover, Pearson's correlation analysis revealed a clear positive correlation between the potential pathogens and the pro-inflammatory cytokines (IL-1β, TNF-α, iNOS, and FOXP3). And a negative correlation between the potential pathogens and the anti-inflammatory cytokines (IL-4, IL-10, and IL-12). Interestingly, the results also showed a positive relationship between the beneficial bacteria and the anti-inflammatory cytokines and a negative relationship between the beneficial bacteria and the pro-inflammatory cytokines (Fig. 5C).
The effects of PCP treatment on beneficial and potential pathogens and the correlation between bacteria and the expression of inflammatory cytokines. A The proportion of potential pathogens and beneficial bacteria from detected bacteria. B Heatmap showing the relative abundance in the respective groups. C Pearson's correlation among the bacterial species and inflammation-associated cytokines
Colonization of Bifidobacterium animalis and Lactobacillus johnsonii reduced the polyp counts in ApcMin/+ mice
To further explore whether PCP-induced genera are responsible for the improvement of the anti-cancer efficacy of 5-FU, we selected the candidate bacteria for bacteria transplantation. From the 16S sequencing data, we identified two bacteria genera, Bifidobacterium and Lactobacillus, that displayed significant responses to PCP treatment, alone or in the presence of 5-FU. At the 4-week treatment time point, we observed diminishing OTUs of Bifidobacterium and Lactobacillus in most experimental groups (Fig. 6A). This phenomenon might be associated with the increased number of polyps in the mice. Based on these data, we selected two bacteria from each genus, the Bifidobacterium animalis and Lactobacillus johnsonii, to engage in the implantation experiment. The colonization of the implanted bacteria was monitored by PCR with each specific primer sequence. The data showed that both implanted bacteria successfully colonized the recipient ApcMin/+ (Fig. 6C). The data also showed that 5-FU suppressed the growth of B. animalis and L. johnsonii (Fig. 6C). Moreover, transplantation of B. animalis and L. johnsonii significantly reduced the numbers and size of the polyps compared to the untreated control and 5-FU groups (Fig. 6D).
Colonization of B. animalis and L. johnsonii improved the anti-cancer effect of 5-FU in ApcMin/+ mice. A Presentations of the OTUs taxa of Bifidobacterium and Latobacillus in 2 and 4 weeks. B The treatment schemes. Detailed procedures are listed under M&M; C Measurement of colonized B. animalis (left panel) and L. johnsonii (right panel) in the guts of four groups of experimental mice. Quantitation of bacteria was performed by qPCR on fecal DNA collected 2 and 4 weeks from each treatment group; D The total number and the distribution of polyps in the experimental mice. Data are presented as the mean ± SD, n = 5. *p < 0.05, ** p < 0.01, *** p < 0.001
5-FU is a common chemotherapeutic agent for treating various cancers, especially colon cancer. While treating cancer, 5-FU therapy also evokes multiple adverse effects in patients and hampers the efficacy of the treatment. In this study, we present evidence that the adverse effects of 5-FU can be circumvented by co-treatment with polysaccharides derived from the dietary herbal medicine Poria cocos, in ApcMin/+ mice. First, we found that PCP could effectively alleviate the weight loss and food consumption reduction associated with 5-FU treatment. In addition, PCP also significantly improves the efficacy of 5-FU against polyp formation in mice treated with PCP + 5-FU (Fig. 1). To understand the enhancing effect of PCP on the effectiveness of 5-FU, we examined intestinal integrity, immune response, and gut microbial composition in mice given various treatments.
The gut aligns with an epithelial layer overlaid with a mucosal layer for housing symbiotic microorganisms and suppressing the access pathobionts. The integrity of the intestinal epithelial barrier is guided by the tight junctions of the epithelial cells. The destruction of intestinal barrier integrity increases intestinal permeability, leading to microbes invasion, exacerbating inflammation, and promoting CRC risk. Our study showed that 5-FU treatment could decrease the expression of the intercellular cell adhesion protein complex and reduce the number of goblet and Paneth cells. On the other hand, PCP treatment restored the function of goblet cells and Paneth cells, enhanced the expression of intercellular cell adhesion protein complex, and further stabilized and rebuilt the intestinal epithelial barrier. Moreover, PCP effectively reversed the shift of N- to E-cadherin for the control and 5-FU treated ApcMin/+ mice. High N-cadherin and low E-cadherin indicate poor prognosis and a hallmark of epithelial-mesenchymal transition of tumors [38].
Macrophages are the most prominent innate immune cells in the gut and carry two phenotypical types. M1 macrophages produce proinflammatory cytokines such as TNF-α, IL-1β, IL-6. In contrast, M2 macrophages produce anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. However, the phenotypic features of macrophages are extremely plastic and can be shifted upon microenvironmental signals. The imbalance of M1/M2 macrophages is associated with various pathological conditions [39]. ApcMin/+ mice are known to inherit inflamed intestinal tract [36]. In this study, we found that 5-FU treatment worsened the state of the intestinal tract of ApcMin/+ mice by lowering the anti-inflammatory cytokines while markedly boosting the pro-inflammatory cytokines compared to the untreated control. This finding is aligned with the frequent recurrence of intestinal mucositis in patients undergoing 5-FU [5]. Interestingly, PCP treatment reversed the shift by reducing the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, and iNOS) and increasing the expression of anti-inflammatory cytokines (e.g., IL-4 IL-10, and IL-13) compared to the control group (Fig. 3). Our results echo the previous reports that PCP possesses anti-inflammatory, anti-cancer, and immunomodulation effects [26,27,28].
CRC is a multifactorial disease influenced by both genetic and environmental factors. However, a large body of literature has demonstrated the role of gut microbiota in cancer initiation and progression [40]. This study detected a few signature gut bacteria associated with inflammation. At the phylum level, 5-FU treatment significantly increases the relative abundance of Verrucomicrobia, and the increment contributed to the marked increase of Akkermansia muciniphila (Fig. 4C and 5B). A. muciniphila was enriched in CRC patients and designated as a CRC biomarker [41]. The Deferribacteres was also elevated in the 5-FU-treated mice in our study. We found that the increment is mainly contributed to the increase of the Desulfovibrio desulfuricans (Fig. 4B and 5B). Deferribacteres, a sulfate-reducing bacteria (SRB), has been linked to intestinal inflammation in different mouse models [32, 42, 43]. SRB produces hydrogen sulfide, a potential genotoxic, cytotoxic agent, and can cause inflammation and cancer in the gut [44, 45]. Moreover, 5-FU increased the growth of a few other potential pathogens, e.g., Shigella sonnnei, Alistipes spp., and Citrobacter spp., that were closely associated with gastrointestinal diseases [46,47,48,49]. Meanwhile, 5-FU treatment decreased a few SCFA-producing bacteria, such as Bacteroides intestinihominis, Butyricicoccus pullicaecorum, Lactobacillus johnsoni, Bifidobactrium choerinum, Eubacterium sp. SCFAs-producing bacteria plays essential roles in maintaining gut epithelial barrier integrity and intestinal immunity [50]. Our findings are in line with other reports in which 5-FU is found upregulating potential pathogens while inhibiting the beneficial bacteria in the gut [15, 51, 52]. Notably, our data showed that the intervention of PCP could reverse the disturbed GM composition. Furthermore, the combined treatment of PCP and 5-FU significantly increased the beneficial bacteria while decreasing potential pathogens compared with 5-FU alone. These results imply that one of the mechanisms of PCP to improve the anti-cancer effect of 5-FU might be through its modulation of the dysbiosis in the 5-FU treated ApcMin/+ mice. In the microbial transplant experiment, we demonstrated that colonization of L. johnsonii or B. animalis enhance the anticancer effect of 5-FU (Fig. 6D). We also observed that 5-FU treatment significantly reduced the colonization of both implanted bacteria, reiterating the overall toxic effects of 5-FU on beneficial bacteria, especially on SCFA-producing bacteria. SCFAs are the important metabolites from GM fermentation. Many studies showed that SCFAs possess prominent bioactivities in anti-inflammatory reactions, gut barrier maintenance, and renew the colonic epithelia cells [53,54,55]. Our previous study showed that activation of genes encoded biogenesis and metabolic functions in B. animalis might have contributed to the reduction of polyps burdening in ApcMin/+ mice [35]. Among many probiotic functions [56], an early report revealed that L. johnsonii was deficient in the cancer-prone mouse colony, while higher in abundance in a more cancer resistant mouse colony. The study further showed that administration of L. johnsonii reduced inflammation and genotoxicity to mice from the cancer-prone colony [57].
PCP alleviates the adverse effects and improves the efficacy of 5-FU in ApcMin/+ mice by improving gut barrier integrity, reversing the inflammatory immune response, and balancing the gut microflora's dysbiosis. In addition, PCP alone exerts a strong prebiotic effect on the polyp baring ApcMin/+ mice. Our findings imply that PCP has great potential to serve as an adjuvant drug in enhancing the efficacy of 5-FU as a chemotherapy agent for CRC and other cancer types.
16S amplicon data and analysis are deposited in the CNCB (BioProject: PRJCA009723).
5-FU:
5-Fluorouracil
Apc:
Adenomatous polyposis coli
PCP:
Poria cocos Polysaccharides
CRC:
FMT:
Fecal microbial transplantation
IL:
iNOS:
Inducible nitric oxide synthases
TNF-α:
Tumor necrosis factor-α
FOXP3:
Forkhead box P3 protein
ZO-1:
Zonula occludens-1
VCAM-1:
Vascular cell adhesion molecule-1
ICAM-1:
Intercellular adhesion molecule-1
IHC:
Immunohistochemical
Sulfate-reducing bacteria
SCFA:
Short chain fatty acid
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The authors thank the Department of Pathology, University Hospital, for the technical advice on H&E staining and IHC.
This project was supported by the Science and Technology Development Fund, Macau (File no. 0054/2018/A2), the National Natural Science Foundation of China (File no. 31900103), the Foundation of Traditional Chinese Medicine Bureau of Gaungdong Province (File no. 20221369), and the Specialized Research Fund for the Technology Innovation of FoShan City, FoShan, China.
Lin Yin and Guoxin Huang equally contributed to this work
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China
Lin Yin, Guoxin Huang, Imran Khan, Lu Su, Wenrui Xia, Betty Yuen Kwan Law, Vincent Kam Wai Wong, Qiang Wu, Jingyi Wang, Wai Kit Leong & W. L. Wendy Hsiao
Clinical Research Center, Shantou Central Hospital, Shantou, China
Guoxin Huang
Zhuhai MUST Science and Technology Research Institute, Zhuhai, China
Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong, China
W. L. Wendy Hsiao
Lin Yin
Lu Su
Wenrui Xia
Betty Yuen Kwan Law
Vincent Kam Wai Wong
Qiang Wu
Jingyi Wang
Wai Kit Leong
LY performed animal experiment, DNA extraction, qPCR, staining, data assembly and wrote the manuscript; GH performed animal experiment, data analysis and revised the manuscript; IK performed data analysis; L.S performed animal experiment; WX provided technical assistance; BYKL, VKWW, and QW helped with the experiment design; JW and WKL conducted the animal works; WLWH designed the research project, interpreted and discussed the results, revised and finalized the manuscript. All authors read and approved the final manuscript.
Correspondence to W. L. Wendy Hsiao.
The animal study was approved by the Ethics Review Committee for Animal Research of the Macau University of Science and Technology.
The authors have no conflicts of interest to declare.
Additional data are provided in the supplementary file named Additional file 1. Table S1. The primer sequences of qPCR assays. Table S2. The formulation of the basic bacterial growth medium. Table S3. The relative abundance of potential pathogens. Table S4. The relative abundance of beneficial bacteria. Figure S1. The quantitation of goblet cells and Paneth cells.
Yin, L., Huang, G., Khan, I. et al. Poria cocos polysaccharides exert prebiotic function to attenuate the adverse effects and improve the therapeutic outcome of 5-FU in ApcMin/+ mice. Chin Med 17, 116 (2022). https://doi.org/10.1186/s13020-022-00667-8
Colonic cancer


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text:
Jan. 6 'heroes' honored for defending Capitol from Trump mob
VIDEO COURTESY AP
Speaker of the House Nancy Pelosi of Calif., applauds U.S. Capitol Police Chief J. Thomas Manger, during a Congressional Gold Medal ceremony honoring law enforcement officers who defended the U.S. Capitol on Jan. 6, 2021, in the U.S. Capitol Rotunda in Washington, today.
Charles and Gladys Sicknick, father and mother of slain U.S. Capitol Police Officer Brian Sicknick, are greeted by Senate Majority Leader Chuck Schumer of N.Y., center, with Senate Minority Leader Mitch McConnell of Ky., and House Minority Leader Kevin McCarthy of Calif., at right, during a Congressional Gold Medal ceremony honoring law enforcement officers who defended the U.S. Capitol on Jan. 6, 2021, in the U.S. Capitol Rotunda in Washington, today. The members of the Sicknick family declined to shake hands with McConnell and McCarthy. At left is U.S. Capitol Police Chief Thomas Manger and House Speaker Nancy Pelosi of Calif.
Washington Metropolitan Police Department officer Daniel Hodges arrives at the Cannon Building, June 9, in Washington. Top House and Senate leaders will present law enforcement officers who defended the U.S. Capitol on Jan. 6, 2021, with Congressional Gold Medals today, awarding them Congress's highest honor nearly two years after they fought with former President Donald Trump's supporters in a brutal and bloody attack.
Former Washington Metropolitan Police Department officer Michael Fanone listens as the House select committee investigating the Jan. 6 attack on the U.S. Capitol holds a hearing at the Capitol in Washington, July 21. Top House and Senate leaders will present law enforcement officers who defended the U.S. Capitol on Jan. 6, 2021, with Congressional Gold Medals today, awarding them Congress's highest honor nearly two years after they fought with former President Donald Trump's supporters in a brutal and bloody attack.
Related Photo Gallery: Jan. 6 'heroes' honored for defending U.S. Capitol from Trump mob
WASHINGTON >> Law enforcement officers who defended the U.S. Capitol on Jan. 6, 2021, were honored today with Congressional Gold Medals, praised as "heroes" for securing democracy when they fought off a brutal and bloody attack by supporters of then-President Donald Trump.
House Speaker Nancy Pelosi opened an emotional ceremony, tensions still raw in the stately Capitol Rotunda, which was overrun that day when Trump supporters roamed the halls trying to stop Congress from certifying Joe Biden's election.
"January 6 was a day of horror and heartbreak; it is also a moment of extraordinary heroism —staring down deadly violence and despicable bigotry," Pelosi said.
In bestowing Congress' highest honor, Pelosi praised the heroes for "courageously answering the call to defend our democracy in one of the nation's darkest hours."
Senate Republican leader Mitch McConnell said: "Thank you for having our backs. Thank you for saving our country. Thank you for not only being our friends, but our heroes."
But showing the raw political and emotional fallout from the insurrection and its aftermath, representatives of one of the medal recipients — the family of fallen officer Brian Sicknick — declined to shake hands with the Republican leaders, snubbing McConnell's outstretched palm.
To recognize the hundreds of officers who were at the Capitol on Jan. 6, the medals will be placed in four locations — at U.S. Capitol Police headquarters, the Metropolitan Police Department, the Capitol and the Smithsonian Institution. In signing the legislation last year, Biden said that one will be placed at the Smithsonian museum "so all visitors can understand what happened that day."
Metropolitan Police Chief Robert Contee said for some officers today was their first time visiting the Capitol since that horrific day, a scene filled with the clanking sound of metal steel flag poles being wielded as weapons, "the air still thick" with chemical sprays as officers were assaulted by the mob of Trump supporters.
"Many of us still carry the mental, physical and emotional scars," Contee said.
"It was your blood, your sweat and your tears that marked these grounds," he said.
Contee said the medal for the city's police officers who rushed to help their Capitol Police allies defend the dome that day was symbolic of their "contributions not just to Washington, D.C., but to the entire country on Jan. 6."
U.S. Capitol Police Chief Thomas Manger called it "a day unlike any other in our nation's history. And for us. It was a day defined by chaos, courage and tragic loss."
The ceremony at the Capitol comes as Democrats, just weeks away from losing their House majority, race to finish a nearly 18-month investigation of the insurrection.
Without support from GOP leadership, Democrats and just two Republicans have led the probe and vowed to uncover the details of the attack, which came as Trump tried to overturn his election defeat and encouraged his supporters to "fight like hell" in a rally just before the congressional certification.
Awarding the medals is among Pelosi's last ceremonial acts as she prepares to step down from leadership. When the bill passed the House more than a year ago, she said the law enforcement officers from across the city defended the Capitol because they were "the type of Americans who heard the call to serve and answered it, putting country above self."
Dozens of the officers who fought off the rioters sustained serious injuries. As the mob of Trump's supporters pushed past them and into the Capitol, police were beaten with American flags and their own guns, dragged down stairs, sprayed with chemicals and trampled and crushed by the crowd. Officers suffered physical wounds, including brain injuries and others with lifelong effects, and many struggled to work afterward because they were so traumatized.
Four officers who testified at a House hearing last year spoke openly about the lasting mental and physical scars, and some detailed near-death experiences.
Metropolitan Police Officer Daniel Hodges described foaming at the mouth, bleeding and screaming as the rioters tried to gouge out his eye and crush him between two heavy doors. Metropolitan Police Officer Michael Fanone, who rushed to the scene, said he was "grabbed, beaten, tased, all while being called a traitor to my country." Capitol Police Officer Harry Dunn said a large group of people shouted the N-word at him as he was trying to keep them from breaching the House chamber.
At least nine people who were at the Capitol that day died during and after the rioting, including a woman who was shot and killed by police as she tried to break into the House chamber and three other Trump supporters who suffered medical emergencies. Two police officers died by suicide in the days that immediately followed, and a third officer, Sicknick, collapsed and later died after one of the rioters sprayed him with a chemical. A medical examiner determined he died of natural causes.
Several months after the attack, in August 2021, the Metropolitan Police announced that two more of their officers who had responded to the insurrection had died by suicide. The circumstances that led to their deaths were unknown.
The June 2021 House vote to award the medals won widespread support from both parties. But 21 House Republicans voted against it — lawmakers who had downplayed the violence and stayed loyal to Trump. The Senate passed the legislation by voice vote, with no Republican objections.
Pelosi, McConnell, House Republican leader Kevin McCarthy and Senate Majority Leader Chuck Schumer attended the ceremony and awarded medals.
The Congressional Gold Medal, the highest honor Congress can bestow, has been handed out since 1776. Previous recipients include George Washington, Sir Winston Churchill, Bob Hope and Robert Frost. In recent years, Congress has awarded the medals to former New Orleans Saints player Steve Gleason, who became a leading advocate for people struggling with Lou Gehrig's disease, and biker Greg LeMond.
Signing the bill at the White House last year, Biden said the officers' heroism cannot be forgotten.
The insurrection was a "violent attempt to overturn the will of the American people," and Americans have to understand what happened, he said. "The honest and unvarnished truth. We have to face it."
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