text:
My name is Eysan,25 years..and sexy..so sweet..carefull...
Here you can find different chat programs and the chat2 or Mibbit in the chat page is suitable for mobile devices like smartphone or tablet.
This move is partly due to the innovation displayed by the creators of Gayconnect, utilizing technology such as Web RTC HTML5 to establish new features and create a multi-platform experience accessible over a huge range of devices.
The website exploded towards the end of 2017 and the beginning of 2018 as users flocked to the website thanks to its accessibility and ease of use.
Also, for our m IRC users we will post all of the necessary commands and their functions.
You will get the opportunity to watch and listen to radions and Tv stations live, read the Albanian, Kosova, & Macedonia newpapers and much more...


text:
I Was Caught In A Flood, And My Boyfriend Saved Me
If you find yourself stuck in your car during a flood, do not panic. Stay calm and follow these 6 tips.
Don't have an account? Register Now.
Enter your account data and we will send you a link to reset your password.

subset: commoncrawl


text:
We help families and not-for-profits steward their wealth with confidence.
Independent since 1997.
We have a dedicated section providing the latest insights from our investment teams and how we are managing our clients' wealth through this period. All of our investment professionals are available by phone or email, and will be happy to speak with you at your convenience.
View more
We are a discretionary investment counsellor helping our clients steward their wealth with confidence.
Helping INDIVIDUALS
Stewarding your family wealth
Workingwith NOT FOR PROFITS
Bringing broad experience to your decision making
Partneringwith advisors
Defend, consolidate and grow your practice
Client stories
Understanding my entrepreneurial mindset
We helped Paul by being as progressive with investments as he'd been with his career.
Read Paul's story
Working with someone for the whole journey
We helped Elaine by earning her trust and establishing a long term relationship.
Read Elaine's story
Getting a handle on my financial future
We helped Jasmine by giving her the confidence that she was making the right choices for her financial future.
Read Jasmine's story
It was hard to earn so we don't want to lose it
We helped Karen and Andrew by preserving and protecting their hard-earned wealth.
Read Karen and Andrew's story
Making investment decisions on behalf of the foundation
We supported Douglas by bringing our broad experience to his foundation's decision making.
Read Douglas' story
Advisor story
Helping to grow my practice
We partnered with Carl to assist the growth in his high net worth business with our broad investment platform and service offering.
Read Carl's story


text:
SAA celebrated its 50th Anniversary with a week-long event
In his Welcome Address prior to the Lecture, Director-General and Chief Executive Officer, Civil Aviation Authority of Singapore, Mr Lim Kim Choon said, "SAA has come a long way from its basic beginnings. Today, SAA stands as a globally recognised centre for learning in aviation. The challenge ahead for SAA is to build on its legacy of achievement and continue to strengthen its engagement with the global aviation community and strive to meet their training needs."
To mark the 50th anniversary, a Memorandum of Understanding (MOU) was signed between Singapore and ICAO to provide fifty training fellowships to ICAO member States for training at SAA in 2009. The MOU was signed by Mrs Lim Hwee Hua, Senior Minister of State for Finance and Transport and President Kobeh. Through the MOU, specialised aviation training programmes at SAA will be made available to developing countries to help them build up their human resources critical to the development of civil aviation.
A gala dinner graced by 300 guests was held that evening at the Conrad Centennial Singapore. The dinner paid special tribute to SAA's eminent instructors, alliance partners and present and past CAAS staff who have contributed significantly to the Academy's success. The programmes of the dinner include a multimedia show to commemorate the 50 years of achievements, a special performance by SAA instructors, a national costume parade by SAA participants and staff, and a cake-cutting ceremony.


text:
Loans LatestMar-Key 6, rated A+, is 29 per cent filled at the time of writing. The yield on offer is 7 percent. Platform lending of the kind we facilitate here at Money&Co. can be a lucrative activity. The average yield achieved by our registered lenders over more than five years of loan facilitation on this platform is more than 8 per cent, before we deduct our one per cent charge. That return has handsomely outperformed retail price inflation, which has averaged around two per cent over this time.
Historical Performance And IFISA Process Guide
Risk: Security, Access, YieldDo consider not just the return, but the security and the ease of access to your investment. We write regularly about these three key factors. Here's one of several earlier articles on security, access and yield.


text:
Heating Instructions
Our Yes Chef! home dining range has been created to help you put a fabulous meal on the table with no more than one, two or three simple instructions.
AApple & Blackberry Crumble
BBeef Bourguignon with Potato Dumplings Blue-eye Trevalla Braised Eggplant with Grilled Tortillas Bread & Butter Pudding Butter Chicken
CCape Grim Scotch Fillet Chat Potato, Confit Garlic & Thyme Chicken & Leek Pie Couscous
DDuck Cassoulet Dutch Cream Potato Mash
FFish Pie of Salmon, Ling & Prawns
KKing Prawn Risotto
LLamb Moussaka Linguini Bolognese
MMamma Spinola's Chicken Marinated Spatchcock Middle Eastern Roast Cauliflower
PPavlova & Mixed Berries Pecan Pie Potato Gratin
SSaffron Pilaf Salmon En Papillote Seasonal Green Vegetables Spinach & Ricotta Gnocchi Sweet Potato, Beetroot & Tahini
TTraditional Lasagne
VVegetarian Quiche


text:
Steve's extensive knowledge as a builder and framer for the last 25 years has played well into his current position with LG Building. With experience in new home construction including everything from rough carpentry to finish work, he enjoys contributing to the variety of work available on the job site as well as completing daily challenges.
In his spare time, Steve enjoys playing sports with his kids.


text:
Pastoral Care
The pastoral care system in St. Joseph's aims to create an environment where everyone in the school community feels valued, and where everyone is treated with respect. We believe that pastoral care is effective when there is sound teaching, active learning, and good order in class and around the School.
We try to achieve this by encouraging understanding, respect, and openness between staff and pupils. This is supported by agreed, achievable and explicit school rules, routines, and pastoral care procedures with a strong emphasis on positive behaviour management. We believe it is very important to work with the family, and see our partnership with parents as being crucial for the successful implementation of our Pastoral Care Policy.
St Joseph's has a strong Year Head team and a very effective Form Teacher system which operates with the support of the Heads of Junior and Senior school, and two Vice Principals. The roles and responsibilities of all are clearly defined and understood by pupils, staff, and parents.
"At St Joseph's, hard work, relationship building, and acknowledging success no matter what scale, are the keys to ensuring our pupils achieve their true potential. Achievement is acknowledged and celebrated at all times." Mrs Mc Carron (Vice Principal, Pastoral)
Just some of the ways that the achievements and successes of our pupils are celebrated are:
Prize-giving ceremony
Incentive trips
Class rewards
Comments in daybook / verbal acknowledgements
Postcards/letters home
Pupil of the month awards
Display work
School representation at relevant events
Roles and Responsibilities such as Head Boy, prefects, captains and vice- captains.


text:
Week 2 8-14 October
Day 8 (Monday) Another day I decided to use the prompt, which is "Star". We watched the new series premier of Doctor Who last night. The new Doctor is definitely a STAR.
Day 9 (Tuesday) The prompt is "Precious". I was initially thinking of something else, but then I saw this ballot drop box. Our precious democracy is sustained, in part, by our participation. DO IT. VOTE! I saw a piece on this morning's news. Reporter went to Orange County, CA (where I used to live). He sought out the UC Irvine students lined up at a bus stop on campus. He asked them, "who's planning to vote in the midterms?". Crickets. Not a SINGLE one responded. That's disheartening. The 26,000 students on campus could change the election results in OC. If they voted.
Day 10 (Wednesday) Cosplay Drink and Draw stared up again after a 3 year hiatus. I finally decided I missed it enough to do it myself. The former organizers helped with advice and contacts.
Day 11 (Thursday). The early morning news caught my attention. Two astronauts, one American and one Russian, were launched from Kazakhstan, bound for the International Space Station. The rocket failed after launch. The Soyuz capsule had a "ballistic landing", meaning it was explosively separated from the rocket and it's path to earth was extreme. The astronauts pulled nearly 7 g's during the descent. But they landed safely and were soon reunited with waiting family. On Thursday mornings I volunteer at the Museum of Flight in Seattle and today I was assigned to the Space Gallery where there is a space-flown Soyuz capsule. I mentioned the event to many of the visitors I greeted. I didn't have time during the shift to sketch it, so I sketched it from my photo.
Day 12 (Friday) This is the inked portion of an on-location sketch I did while on an outing to Swanson's Nursery with Urban Sketchers Seattle.
Day 13 (Saturday) While at the local library looking at the salmon run, I picked up an oak leaf and some acorns.
Day 14 (Sunday) Sketched from a photo. Used brown ink and a tiny bit of watercolor for accent. It's a wall in Queen Ann neighborhood we sketched at last month.


text:
NEW YORK (AP) - Members of the Congressional Black Caucus have joined New York Gov. Andrew Cuomo in calling on the U.S. Senate to reject Supreme Court nominee Brett Kavanaugh because of his expansive interpretation of gun rights and the Second Amendment.
Cuomo, a Democrat, said Saturday that Kavanaugh's past opinions show that he believes it's a constitutional right to carry "even the most dangerous assault weapons."
Rep. Gregory Meeks, a New York Democrat, called Kavanaugh's nomination "a grave threat to reasonable gun control measures enacted by states."
Meeks and other lawmakers joined Cuomo at a Manhattan news conference to urge the Senate to block Kavanaugh's nomination.
Kavanagh has taken stands favoring broad gun rights in his current job as a judge on the D.C. Circuit Court of Appeals.


text:
Download 13 Reasons Why S03 Complete [All Episodes ] Netflix Series HD 720p 480p Web-DL [5GB & 2GB Pack]. This is The One Of The Best Series Of NetFlix. This Series Not Available In Hindi Yet.
13 reasons why season 3
Download dual audio movies in 1080p 720p & 480p Best qualities 300Mb Movies 700Mb Movies Hollywood movies download in Hindi dubbed new movies 2019
MoviesRex.In is The Best Website/Platform For Bollywood And Hollywood HD Movies. We Provide Direct Google Drive Download Links For Fast And Secure Downloading. Just Click On DownloadButton And Follow Steps To Download And Watch Movies Online For Free.
Download 13 Reasons Why S03 Complete [All Episodes ] Netflix Series HD 720p 480p Web-DL ~ MoviesRex.in
IMDb Ratings: 7.9/10 Show Title: 13 Reasons Why 3 Creator: Brian Yorkey Stars: Dylan Minnette, Katherine Langford, Christian Navarro Release Date: TV Series (2019 ) Genres: Crime, Drama, Mystery Language: English Subtitles: English
13 Reasons Why S3 (TV Series) Storyline:
Watch 13 Reasons Why S03 Now on MoviesRex Katherine Langford received a Golden Globe nod for her role in this series based on Jay Asher's best-selling novel.
how can i watch 13 reasons why without Netflix The official Netflix synopsis for 13 Reasons Why reads: "Eight months after preventing Tyler (played by Devin Druid) from committing an unthinkable act at Spring Fling, Clay (Dylan Minnette), Tony (Christian Navarro), Jessica (Alisha Boe), Alex (Miles Heizer), Justin (Brandon Flynn) and Zach (Ross Butler) find ways to shoulder the burden of the cover-up together while helping Tyler move toward recovery.
"But when the aftermath of a tumultuous Homecoming game culminates in the disappearance of a football player, and Clay finds himself under police scrutiny, it's up to a shrewd outsider to steer the group through an investigation that threatens to lay bare everyone's deepest secrets.
"The stakes are raised as the consequences of even the most well-intended actions can alter a life forever."
The tagline for the series, however, reveals the central mystery of the new series will be around the death of a major character.
Download 13 Reasons Why S03 Complete Netflix Series HD 720p Web-DL 5.5GB


text:
This browser doesn't support Spotify Web Player. Switch browsers or download Spotify for your desktop.
On this week's episode, I talk about some of my highlights from the healthcare IT and tech innovation conference HIMM19, I get into several stories of security breaches and hacks, talk MSIX updates and much more!
Listen to HIMMS19 Highlights, Skype Privacy Concerns, Major Security News & More in full in the Spotify app


text:
Some of the goods in your pantry (like baking soda and vinegar) perform as powerful all-objective cleaners and, even much better, cost next to nothing at all. So the next time you happen to be staring down a huge mess but you happen to be out of your favored cleansing product or service, do not run to the retail outlet — attempt a person mixing up a person of these Do it yourself home made cleaners instead. These pure items will kick grime to the suppress and retain your wallet joyful.
Significant Basic safety Idea: Under no circumstances blend ammonia-centered cleaners with chlorine bleach or items containing bleach, such as powdered dishwasher detergent. The fumes they are going to make are exceptionally perilous. Ahead of executing any mixing, examine the product or service labels 1st. Always label any bottles of Do it yourself cleaners with all the ingredients inside. In scenario a boy or girl or animal will get into it, it's critical to know what the combination contains.
one. Scented All-Intent Cleaner
What you may want:
- One part white vinegar
- One part drinking water
- Lemon rind
- Rosemary sprigs
Combine the previously mentioned ingredients collectively, pour into a spray bottle, shake, and then let infuse for a 7 days before using. After finished, you can use the pure remedy to get rid of really hard drinking water stains, clear trash cans, wipe away wall smudges, and a lot additional. In addition to a fresh scent, the lemon rind may possibly enable strengthen cleansing electric power. Warning: Do not use acidic cleaners on granite, as they will etch the stone.
2. Kitchen area Cleaner and Deodorizer
What you may want:
- four tablespoons baking soda
- one quart heat drinking water
To clear kitchen counters, appliances, and the inside of your refrigerator, all you want is baking soda. "It would make a terrific deodorizer and can be used to glow stainless steel sinks and appliances," claims Carolyn Forte, director of the Fantastic Housekeeping Institute Cleansing Lab. To deodorize surfaces, use the remedy previously mentioned or pour baking soda straight from the box and into your drain or rubbish disposal to get rid of odors. To glow and get rid of places from stainless steel, make a paste of baking soda and drinking water. Use it with a damp fabric and rub gently in the direction of the metal's grain. Rinse and buff dry.
three. Do it yourself Glass Cleaner
What you may want:
The next time you want to clean your windows and mirrors, blend these ingredients and pour them in a spray bottle. Hint: Will not clear windows on a scorching, sunny day, simply because the remedy will dry far too promptly and depart tons of streaks. For mirrors, spray the remedy on a paper towel or soft fabric 1st before wiping.
four. Selfmade Brass Cleaner
What you may want:
- White vinegar or lemon juice
- Table salt
To clear non-lacquered cabinet pulls, toilet appointments, and additional, dampen a sponge with vinegar or lemon juice, then sprinkle on salt. Lightly rub more than surface area. Rinse comprehensively with drinking water, then quickly dry with a clear soft fabric.
five. Organic Heavy-Duty Scrub
What you may want:
- one/2 lemon
- one/2 cup borax powder
Rust stains on porcelain or enamel sinks and tubs are no match for this cleaner. Dip the lemon into the borax and scrub the surface area, then rinse. (This is not harmless for marble or granite.) Idea: You can locate borax, a laundry booster, in the detergent aisle or buy it on Amazon.
six. Do it yourself Grease Cleaner
What you may want:
Sudsy ammonia contains detergent that will help get rid of tricky grime. Combine one/2 cup with plenty of drinking water to fill a a person-gallon container. Then clear your oven racks, stove hood, and grill by dipping a sponge into the remedy and wiping more than the surface area before rinsing with obvious drinking water. You can also soak oven racks and grill grates in the combination right, with a very little extra ammonia if they are specifically soiled.
seven. Previous-Vacation resort Clothing Stain Remover
What you may want:
- one gallon scorching drinking water
- one cup powdered dishwasher detergent
- one cup common liquid chlorine bleach, not ultra or concentrate
Handle badly stained but washable white outfits by mixing the previously mentioned ingredients into a stainless steel, plastic, or enamel bowl (not aluminum). Soak garment for 15-20 minutes. If stain is however there, let it soak a bit lengthier, then clean the product as usual.
8. Organic Marble Cleaner
What you may want:
- 2 drops gentle dishwashing liquid
- 2 cups heat drinking water
Combine dishwashing detergent and drinking water the next time you want to clear pure stone countertops. Sponge more than marble and rinse wholly to get rid of any cleaning soap residue. Buff with a soft fabric do not let the marble air-dry. Warning: Under no circumstances use vinegar, lemon, or any other acidic cleaner on marble or granite surfaces it will eat into the stone.


text:
Mini Review ARTICLE
Transcription Factors in Eosinophil Development and As Therapeutic Targets
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Dynamic gene expression is a major regulatory mechanism that directs hematopoietic cell fate and differentiation, including eosinophil lineage commitment and eosinophil differentiation. Though GATA-1 is well established as a critical transcription factor (TF) for eosinophil development, delineating the transcriptional networks that regulate eosinophil development at homeostasis and in inflammatory states is not complete. Yet, recent advances in molecular experimental tools using purified eosinophil developmental stages have led to identifying new regulators of gene expression during eosinophil development. Herein, recent studies that have provided new insight into the mechanisms of gene regulation during eosinophil lineage commitment and eosinophil differentiation are reviewed. A model is described wherein distinct classes of TFs work together via collaborative and hierarchical interactions to direct eosinophil development. In addition, the therapeutic potential for targeting TFs to regulate eosinophil production is discussed. Understanding how specific signals direct distinct patterns of gene expression required for the specialized functions of eosinophils will likely lead to new targets for therapeutic intervention.
Eosinophils differentiate in the bone marrow from an eosinophil lineage-committed progenitor (EoP) that is derived from the granulocyte/macrophage progenitor (GMP) in mice and the common myeloid progenitor or an upstream multipotent progenitor in humans (1, 2). Cell fate choices, including lineage commitment, are specified by the action of primary, or lineage-determining, transcription factors (TFs) and then reinforced by induction of secondary TFs that orchestrate gene expression and lineage commitment and differentiation. TF concentrations can be important, as lineage-determining TFs can antagonize each other's activity (3, 4). We have recently shown that markedly more transcriptome changes (1,199 genes) are associated with eosinophil maturation from the EoP than with eosinophil lineage commitment (EoP from GMP, 490 genes), highlighting the greater transcriptional investment necessary for terminal differentiation (5). These dynamic changes in gene expression during eosinophil development included a repertoire of TFs, many of which had never previously been associated with eosinophil development (5). New information from genome-wide and single-cell RNA sequencing (scRNA-seq) studies have built upon well-established models of transcriptional regulation of eosinophilopoiesis. The molecular regulatory network that yields functional, mature eosinophils from EoPs is slowly being delineated. Defining how eosinophil production is regulated is critical to understanding how dysfunction of the immune response results in eosinophil overproduction and will likely lead to new eosinophil-targeting therapeutics.
Eosinophil Lineage Commitment
The first stage in eosinophil development is commitment to the eosinophil lineage by a myeloid multipotent progenitor to generate an EoP (Figure 1). The EoP is identified via surface expression of CD34, interleukin 5 (IL-5) receptor alpha (IL-5Rα, a.k.a. CD125), and low levels of c-KIT (CD117) in murine bone marrow (1). In humans, EoPs are identified by surface expression of CD34, CD38, and CD125 (2). EoPs reside in small numbers primarily in the bone marrow (~0.05% of lineage-negative CD34+ cells), with even lower levels found in peripheral blood and in human umbilical cord blood (2). Targeting the EoP and the steps determining eosinophil lineage fate for treatment purposes is an attractive strategy, as it would prevent the production of mature eosinophils and all of their immune-activating contents; thus, delineating the factors that are essential for eosinophil lineage commitment will likely be clinically relevant.
Figure 1. Transcription Factor (TF) expression during eosinophil development. Eosinophils differentiate in the bone marrow from an eosinophil lineage-committed progenitor (EoP) that is derived from the granulocyte/macrophage progenitor (GMP) in mice and the common myeloid progenitor (CMP) in humans. For eosinophil lineage commitment to occur, the myeloid progenitor (GMP or CMP) must express C/EBPα, C/EBPε, interferon regulatory factor 8 (IRF8), and PU.1. Expression of friend of GATA-1 (FOG-1) declines, allowing for increasing expression and activity of GATA TFs, which is necessary for EoP production. Following lineage commitment, eosinophil granule protein gene expression is markedly increased with the collaborative interaction between C/EBPε, PU.1, and GATA-1. To assist with the elevated granule protein synthesis in the EoP and eosinophil precursors, XBP1 expression is increased and promotes survival during the demanding maturation process. Expression of activator isoforms of C/EBPε peaks during eosinophil maturation and then declines during the final stages. Expression of ID2 increases during eosinophil maturation and enhances the rate of maturation.
Eosinophil Lineage Instruction by GATA-1 and GATA-2
It is well established that myeloid progenitor expression of the TF GATA-1 is essential for eosinophil lineage commitment (6–9). The findings of these earlier studies were supported recently by global gene expression profiling of single murine multipotent progenitor cells revealing that the commitment to the eosinophil lineage segregated with Gata1 expression (10). In addition, scRNA-seq of murine GMPs (Lin−CD34+c-KIT+CD16/32hi) revealed a rare GMP subset with eosinophil lineage potential and that maintained expression of Gata1 (11).
Two nuclear factors, friend of GATA-1 (FOG-1; Zfpm1) and interferon regulatory factor 8 (IRF8; Irf8 or Icsbp), have been shown to be important for regulating Gata1 expression and/or function in myeloid progenitors and, consequently, to affect eosinophil production. FOG-1 is a transcriptional cofactor that facilitates binding of GATA factors to DNA and recruits chromatin remodeling complexes (12–14). FOG-1 is highly expressed by multipotent progenitors, antagonizes GATA-1 transcriptional activity, and must be downregulated to allow for eosinophil lineage commitment (15, 16). Loss of FOG-1 expression in mice is early embryonic lethal from severe anemia due to the requirement for FOG-1 for the formation of erythroid-lineage progenitors (17). FOG-1 deficiency in hematopoietic stem cells results in increased commitment along the myeloid lineages and aberrant expression of myeloid-related genes in megakaryocytic and erythroid cells (18), highlighting the role for FOG-1 in suppressing myeloid cell development. In contrast, loss of Irf8 expression in mice resulted in reduced EoP (and eosinophil) frequency in the bone marrow and lower Gata1 expression in the EoPs that were produced (19), suggesting that the TF IRF8 is critical for upregulating and/or maintaining GATA-1 expression in myeloid progenitors for eosinophil lineage commitment. Notably, murine GMPs with eosinophil lineage potential and that maintained Gata1 expression also expressed intermediate levels of Irf8 (11).
Murine EoPs express both GATA-1 and GATA-2, whereas GMPs express no GATA-1 and low to no level of GATA-2 (5, 20). Ectopic expression of GATA-2 in murine GMPs and human CD34+ hematopoietic progenitors was sufficient to instruct commitment to the eosinophil lineage (7, 20) and induce expression of GATA-1 (20). GATA-1 and GATA-2 have identical DNA sequence binding preferences, but their target genes and transcriptional responsibilities can be cell specific and/or overlapping, likely via a multitude of coregulators (e.g., FOG-1) (21). Targeted deletion of GATA-1 or GATA-2 has revealed that they control distinct biological processes that affect multiple hematopoietic lineages (21). Taken together, these studies emphasize the essential and instructive role for GATA TFs in eosinophil development; yet, targeting GATA-1 or GATA-2 therapeutically is likely to have significant and unacceptable effects on other hematopoietic lineages.
C/EBPα Co-Expression with GATA-1 or GATA-2
In addition to expressing GATA-1 and GATA-2, EoPs express relatively high levels of the TF CCAAT/enhancer-binding protein alpha (C/EBPα) (20). C/EBPα is necessary for eosinophil development, as C/EBPα-deficient mice lack eosinophils (and neutrophils) (22). The level of C/EBPα expression is important for eosinophil- vs neutrophil-lineage commitment, as elevated expression of C/EBPα in GMPs due to an impaired protein degradation pathway results in increased neutrophil differentiation at the expense of eosinophils (23). In addition, the order of expression of GATA factors and C/EBPα is critical for eosinophil lineage commitment (8, 20, 24). Enforced expression of GATA-1 or GATA-2 in a C/EBPα-expressing progenitor results in eosinophil lineage commitment (20). In contrast, ectopic expression of GATA-2 prior to C/EBPα expression leads to basophil-lineage commitment (20). It is believed that C/EBPα is at least partially responsible for the downregulation of FOG-1 expression in myeloid progenitors promoting eosinophil development (15).
C/EBPε Promotes Eosinophil Cell Fate
Multiple isoforms of the TF C/EBPε with distinct transcriptional functions (e.g., activators and repressors) are expressed during eosinophil maturation, and expression levels of the varying isoforms change with developmental stage (25, 26), reinforcing that ratios of TFs with combinatorial and even antagonistic activities are highlights of the eosinophil developmental program. Low levels of the activator C/EBPε isoforms are expressed in CD34+ hematopoietic progenitors, and all isoforms increase in expression during IL-5-mediated differentiation, with the repressor isoforms predominating during later stages of maturation (25). Mice deficient in C/EBPε fail to generate mature eosinophils or normal neutrophils (27), supporting a critical role for C/EBPε in a common upstream myeloid progenitor. Notably, ectopic expression of the activator isoforms of C/EBPε in umbilical cord blood CD34+ progenitors resulted in markedly increased commitment to the eosinophil lineage (25). In contrast, expression of the repressor isoforms decreased eosinophil cell fate, but not other myeloid lineages (25), suggesting that inducing expression of repressor isoforms in early myeloid progenitors may specifically inhibit eosinophil production. Expression of the four isoforms of C/EBPε results from differential splicing and alternative use of promoters (26, 28), but the critical transcriptional regulators that orchestrate the expression of the different isoforms is not known.
Unclear Roles for PU.1
The TF PU.1 is a member of the ETS family of DNA-binding proteins with an essential function in both myeloid and lymphoid development (29, 30). Though the PU.1 expression level in myeloid progenitors has been shown to be important in regulating macrophage and neutrophil cell fates (3, 31), a definitive early role for PU.1 in eosinophil lineage commitment has not been defined. Gene expression analysis of PU.1-deficient fetal liver cells revealed expression of eosinophil peroxidase and major basic protein (Prg2), but little to no Il5ra (32), suggesting that PU.1 is not essential for eosinophil lineage commitment, but studies with a specific focus on the eosinophil lineage potential of hematopoietic cells deficient in PU.1 are needed.
Summary of Eosinophil Lineage Commitment
In summary, eosinophil lineage commitment occurs in a myeloid multipotent progenitor that expresses C/EBPα, C/EBPε, and IRF8 followed by concomitant declining FOG-1 expression and increasing GATA-1 and GATA-2 expression (Figure 1). This hierarchical combination of TFs has been shown to be necessary for eosinophil lineage commitment.
Eosinophil Maturation
Human eosinophils have characteristic morphologic features, including a bilobed nucleus and cytoplasmic granules filled with cationic proteins that are packaged in a specific manner (Figure 1). Eosinophils are terminally differentiated and do not proliferate once they leave the bone marrow. We noted that mature eosinophils share expression of 60 TFs with EoPs and express an additional 35 TFs that EoPs do not (5), suggesting that it requires a greater number of TFs to produce a more complex and differentiated cell. Identifying the critical TFs for specific eosinophil functional responses will provide potential new therapeutic targets.
PU.1 Priming for Transcription
Recent studies in macrophages have revealed a collaborative interaction between PU.1 and other lineage-determining TFs, such as C/EBPα, to open chromatin and "prime" genes for transcription (33, 34). Consistent with this role as a "pioneer" TF, PU.1 has been shown to cooperatively regulate the expression of eosinophil granule protein genes (35–37), including PRG2 (major basic protein) and RNS2 (eosinophil-derived neurotoxin), highlighting an important role for PU.1 in eosinophil maturation. Future studies are needed to determine how the distribution of PU.1 across the genome differs between granulocytes (eosinophils, neutrophils, basophils, and mast cells) and what partnerships are critical for terminal differentiation of the distinct cell types.
C/EBPε Interaction with PU.1
One of the PU.1 collaborators in regulating gene expression during eosinophil maturation is the TF C/EBPε. The peripheral blood and bone marrow of adult mice deficient in C/EBPε have a pronounced increase in immature myeloid precursors, indicating a blockade in terminal granulocyte differentiation in the absence of C/EBPε (27). In addition, ectopic expression of C/EBPε in CD34+ hematopoietic progenitors increased the rate of eosinophil maturation (25). C/EBPε is important for the expression of secondary granules in both neutrophils and eosinophils (36, 37), and C/EBPε deficiency results in impaired functional responses for neutrophils (27). Individuals with mutations that abolish C/EBPε expression produce abnormal neutrophils and eosinophils that lack specific granules; thus, these individuals suffer from early and frequent bacterial infections (26, 38, 39), providing clinically relevant support for a critical role for C/EBPε in terminal differentiation of granulocytes. Interestingly, peripheral blood eosinophils predominantly express one of the repressor isoforms of C/EBPε (36), suggesting that C/EBPε's repressive activity is more important during late-stage eosinophil maturation.
XBP1 Is Required for EoP Survival
Murine EoPs have been shown to contain nascent granules (1, 5) and express granule protein mRNAs at a higher level than mature eosinophils (5); thus, early EoP differentiation likely represents a developmentally restricted period during eosinophilopoiesis when protein production and endoplasmic reticulum (ER) demand peaks. XBP1 (Xbp1) is a TF that is involved in the unfolded protein response triggered by ER stress (40). In response to ER stress, Xbp1 mRNA is spliced by the endoribonuclease IRE1α followed by translation of the active TF XBP1. Accumulation of the spliced Xbp1 mRNA was higher in GMPs and EoPs than eosinophil precursors, and no spliced Xbp1 mRNA was noted in mature eosinophils, which is consistent with activation of the ER stress pathway during high protein synthetic demands through eosinophil maturation (41). Notably, loss of Xbp1 expression in hematopoietic cells resulted in a compete loss of mature eosinophils (41). EoPs were present in the bone marrow but at a lower frequency in Xbp1-deficient than Xbp1-sufficient mice, likely due to poor survival (41); thus, Xbp1 is essential for eosinophil maturation but not lineage commitment.
ID2 Enhances Terminal Differentiation
Inhibitor of DNA-binding (ID) proteins is a family of negative transcriptional regulators that heterodimerizes with basic helix-loop-helix TFs and prevents binding to the DNA (42). Expression of ID2 was upregulated during eosinophil maturation, and ectopic expression of ID2 in human CD34+ hematopoietic progenitors resulted in increased mature eosinophils, with no change in frequency of the earlier precursors (43), suggesting that ID2 enhances terminal differentiation. In contrast, expression of ID1 declines during eosinophil maturation and inhibits terminal differentiation (43).
Eosinophil Function
In addition to orchestrating eosinophil production, TFs also participate in eosinophil functional responses and survival. Glucocorticoids are the first-line therapy for eosinophil-associated disorders, such as allergy, asthma, eosinophilic gastrointestinal disorders and hypereosinophilic syndrome (44, 45); yet, there are a subset of individuals with severe asthma with eosinophilia despite high doses of glucocorticoids (46–48) and patients with hypereosinophilic syndrome often become glucocorticoid refractory (49, 50). The TF NFIL3 has recently been shown to be induced by IL-5 stimulation in eosinophils and to protect against glucocorticoid-induced apoptosis (51), suggesting that targeting NFIL3 in patients may restore glucocorticoid sensitivity. STAT6 is another TF that has been shown to regulate eosinophil functional responses, specifically in experimental asthma. Sensitized mice with STAT6-deficient eosinophils were protected against mucus overproduction and airway hyperresponsiveness following allergen challenge (52), highlighting an important role for STAT6 signaling in eosinophils in allergic asthma. Yet, eosinophil-intrinsic STAT6 was not required for eosinophil recruitment into tissues in response to parasitic infection (53), highlighting the need for further investigations to delineate the impact of environmental signals on gene regulatory programs. Together, these studies suggest that targeting TFs in specific clinical settings may impact eosinophil function and survival.
Conclusion and Future Directions
As there have been no described TFs that are specific to the eosinophil lineage, targeting eosinophil production currently has been achieved primarily via indirect means. A wealth of evidence support a critical role for the cytokine IL-5 in mediating disease-associated eosinophilia, and neutralizing IL-5 indirectly suppresses eosinophil maturation (54). IL-5 is produced by type 2 helper T (Th2) cells and the TF GATA-3 has been shown to control expression of IL-5 in Th2 cells (55). In addition, group 2 innate lymphoid cells (ILC2s) produce large amounts of IL-5 upon activation by epithelial-derived cytokines (56, 57) and GATA-3 is essential for ILC2 development (58); thus, GATA-3 is an attractive therapeutic target to prevent IL-5 expression. Notably, treatment with a DNA enzyme that cleaved GATA3 mRNA resulted in reduced airway eosinophilia and plasma levels of IL-5 in individuals with asthma (59, 60), highlighting the feasibility of targeting TFs in patients with eosinophil disorders. With emerging technology and public databases of information available to investigators around the world, the future for research in eosinophil development is bright. Many new questions have arisen as our knowledge expands. Recently, a new regulatory eosinophil subset has been described in the murine lung and with a transcriptome that differed from that of inflammatory eosinophils (61). In addition, thymus-resident eosinophils have a distinct phenotype from other tissue-resident eosinophils (62). Together, these studies indicate that extrinsic signals from the local environment likely affect gene expression via changes in the regulatory program or that these eosinophil subsets are produced via a differential developmental program. Understanding how specific signals direct distinct patterns of gene expression required for the specialized functions of tissue-resident eosinophils will likely lead to new targets for therapeutic intervention.
Author Contributions
The author confirms being the sole contributor of this work and approved it for publication.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the NIH grant R01AI130033.
1. Iwasaki H, Mizuno S, Mayfield R, Shigematsu H, Arinobu Y, Seed B, et al. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. J Exp Med (2005) 201(12):1891–7. doi:10.1084/jem.20050548
2. Mori Y, Iwasaki H, Kohno K, Yoshimoto G, Kikushige Y, Okeda A, et al. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. J Exp Med (2009) 206(1):183–93. doi:10.1084/jem.20081756
3. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H, et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol (2003) 4(10):1029–36. doi:10.1038/ni973
4. Walsh JC, DeKoter RP, Lee HJ, Smith ED, Lancki DW, Gurish MF, et al. Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. Immunity (2002) 17(5):665–76. doi:10.1016/S1074-7613(02)00452-1
5. Bouffi C, Kartashov AV, Schollaert KL, Chen X, Bacon WC, Weirauch MT, et al. Transcription factor repertoire of homeostatic eosinophilopoiesis. J Immunol (2015) 195(6):2683–95. doi:10.4049/jimmunol.1500510
6. Kulessa H, Frampton J, Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev (1995) 9(10):1250–62. doi:10.1101/gad.9.10.1250
7. Hirasawa R, Shimizu R, Takahashi S, Osawa M, Takayanagi S, Kato Y, et al. Essential and instructive roles of GATA factors in eosinophil development. J Exp Med (2002) 195(11):1379–86. doi:10.1084/jem.20020170
8. McNagny K, Graf T. Making eosinophils through subtle shifts in transcription factor expression. J Exp Med (2002) 195(11):f43–7. doi:10.1084/jem.20020636
9. Yu C, Cantor AB, Yang H, Browne C, Wells RA, Fujiwara Y, et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J Exp Med (2002) 195(11):1387–95. doi:10.1084/jem.20020656
10. Drissen R, Buza-Vidas N, Woll P, Thongjuea S, Gambardella A, Giustacchini A, et al. Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing. Nat Immunol (2016) 17(6):666–76. doi:10.1038/ni.3412
11. Olsson A, Venkatasubramanian M, Chaudhri VK, Aronow BJ, Salomonis N, Singh H, et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature (2016) 537(7622):698–702. doi:10.1038/nature19348
12. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, et al. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell (1997) 90(1):109–19. doi:10.1016/S0092-8674(00)80318-9
13. Fox AH, Liew C, Holmes M, Kowalski K, Mackay J, Crossley M. Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. EMBO J (1999) 18(10):2812–22. doi:10.1093/emboj/18.10.2812
14. Pal S, Cantor AB, Johnson KD, Moran TB, Boyer ME, Orkin SH, et al. Coregulator-dependent facilitation of chromatin occupancy by GATA-1. Proc Natl Acad Sci U S A (2004) 101(4):980–5. doi:10.1073/pnas.0307612100
15. Querfurth E, Schuster M, Kulessa H, Crispino JD, Doderlein G, Orkin SH, et al. Antagonism between C/EBPbeta and FOG in eosinophil lineage commitment of multipotent hematopoietic progenitors. Genes Dev (2000) 14(19):2515–25. doi:10.1101/gad.177200
16. Du Roure C, Versavel A, Doll T, Cao C, Pillonel V, Matthias G, et al. Hematopoietic overexpression of FOG1 does not affect B-cells but reduces the number of circulating eosinophils. PLoS One (2014) 9(4):e92836. doi:10.1371/journal.pone.0092836
17. Tsang AP, Fujiwara Y, Hom DB, Orkin SH. Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev (1998) 12(8):1176–88. doi:10.1101/gad.12.8.1176
18. Mancini E, Sanjuan-Pla A, Luciani L, Moore S, Grover A, Zay A, et al. FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors. EMBO J (2012) 31(2):351–65. doi:10.1038/emboj.2011.390
19. Milanovic M, Terszowski G, Struck D, Liesenfeld O, Carstanjen D. IFN consensus sequence binding protein (Icsbp) is critical for eosinophil development. J Immunol (2008) 181(7):5045–53. doi:10.4049/jimmunol.181.7.5045
20. Iwasaki H, Mizuno S, Arinobu Y, Ozawa H, Mori Y, Shigematsu H, et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev (2006) 20(21):3010–21. doi:10.1101/gad.1493506
21. Katsumura KR, Bresnick EH, Group GFM. The GATA factor revolution in hematology. Blood (2017) 129(15):2092–102. doi:10.1182/blood-2016-09-687871
22. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A (1997) 94(2):569–74. doi:10.1073/pnas.94.2.569
23. Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature (2013) 495(7442):524–8. doi:10.1038/nature11930
24. Nerlov C, McNagny KM, Doderlein G, Kowenz-Leutz E, Graf T. Distinct C/EBP functions are required for eosinophil lineage commitment and maturation. Genes Dev (1998) 12(15):2413–23. doi:10.1101/gad.12.15.2413
25. Bedi R, Du J, Sharma AK, Gomes I, Ackerman SJ. Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood (2009) 113(2):317–27. doi:10.1182/blood-2008-02-139741
26. Lekstrom-Himes JA. The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation. Stem Cells (2001) 19(2):125–33. doi:10.1634/stemcells.19-2-125
27. Yamanaka R, Barlow C, Lekstrom-Himes J, Castilla LH, Liu PP, Eckhaus M, et al. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc Natl Acad Sci U S A (1997) 94(24):13187–92. doi:10.1073/pnas.94.24.13187
28. Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, et al. CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. Proc Natl Acad Sci U S A (1997) 94(12):6462–7. doi:10.1073/pnas.94.12.6462
29. McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J (1996) 15(20):5647–58.
30. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science (1994) 265(5178):1573–7. doi:10.1126/science.8079170
31. Dahl R, Simon MC. The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol Dis (2003) 31(2):229–33. doi:10.1016/S1079-9796(03)00152-9
32. Lee J, Rosenberg HF. Eosinophils in Health and Disease. 1st ed. London, Waltham, MA: Elsevier/Academic Press (2013). xxiii, 654 p.
33. Heinz S, Glass CK. Roles of lineage-determining transcription factors in establishing open chromatin: lessons from high-throughput studies. Curr Top Microbiol Immunol (2012) 356:1–15. doi:10.1007/82_2011_142
34. Heinz S, Romanoski CE, Benner C, Glass CK. The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol (2015) 16(3):144–54. doi:10.1038/nrm3949
35. van Dijk TB, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP. The role of transcription factor PU.1 in the activity of the intronic enhancer of the eosinophil-derived neurotoxin (RNS2) gene. Blood (1998) 91(6):2126–32.
36. Du J, Stankiewicz MJ, Liu Y, Xi Q, Schmitz JE, Lekstrom-Himes JA, et al. Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. J Biol Chem (2002) 277(45):43481–94. doi:10.1074/jbc.M204777200
37. Gombart AF, Kwok SH, Anderson KL, Yamaguchi Y, Torbett BE, Koeffler HP. Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1. Blood (2003) 101(8):3265–73. doi:10.1182/blood-2002-04-1039
38. Gombart AF, Shiohara M, Kwok SH, Agematsu K, Komiyama A, Koeffler HP. Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein–epsilon. Blood (2001) 97(9):2561–7. doi:10.1182/blood.V97.9.2561
39. Rosenberg HF, Gallin JI. Neutrophil-specific granule deficiency includes eosinophils. Blood (1993) 82(1):268–73.
40. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature (2002) 415(6867):92–6. doi:10.1038/415092a
41. Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, et al. The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol (2015) 16(8):829–37. doi:10.1038/ni.3225
42. Kee BL. E and ID proteins branch out. Nat Rev Immunol (2009) 9(3):175–84. doi:10.1038/nri2507
43. Buitenhuis M, van Deutekom HW, Verhagen LP, Castor A, Jacobsen SE, Lammers JW, et al. Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2. Blood (2005) 105(11):4272–81. doi:10.1182/blood-2004-12-4883
44. Klion AD. Eosinophilia: a pragmatic approach to diagnosis and treatment. Hematology Am Soc Hematol Educ Program (2015) 2015:92–7. doi:10.1182/asheducation-2015.1.92
45. Uppal V, Kreiger P, Kutsch E. Eosinophilic gastroenteritis and colitis: a comprehensive review. Clin Rev Allergy Immunol (2016) 50(2):175–88. doi:10.1007/s12016-015-8489-4
46. Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med (2009) 360(10):985–93. doi:10.1056/NEJMoa0805435
47. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet (2012) 380(9842):651–9. doi:10.1016/S0140-6736(12)60988-X
48. Pavord ID, Haldar P, Bradding P, Wardlaw AJ. Mepolizumab in refractory eosinophilic asthma. Thorax (2010) 65(4):370. doi:10.1136/thx.2009.122697
49. Debierre-Grockiego F, Leduc I, Prin L, Gouilleux-Gruart V. Dexamethasone inhibits apoptosis of eosinophils isolated from hypereosinophilic patients. Immunobiology (2001) 204(4):517–23. doi:10.1078/0171-2985-00060
50. Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol (2009) 124(6):1319–25.e3. doi:10.1016/j.jaci.2009.09.022
51. Pazdrak K, Moon Y, Straub C, Stafford S, Kurosky A. Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3. Apoptosis (2016) 21(4):421–31. doi:10.1007/s10495-016-1226-5
52. Stokes K, LaMarche NM, Islam N, Wood A, Huang W, August A. Cutting edge: STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation. J Immunol (2015) 194(6):2477–81. doi:10.4049/jimmunol.1402096
53. Voehringer D, van Rooijen N, Locksley RM. Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages. J Leukoc Biol (2007) 81(6):1434–44. doi:10.1189/jlb.1106686
54. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy (2012) 42(5):712–37. doi:10.1111/j.1365-2222.2011.03854.x
55. Ray A, Cohn L. Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest (1999) 104(8):985–93. doi:10.1172/JCI8204
56. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature (2010) 464(7293):1367–70. doi:10.1038/nature08900
57. Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker JE, et al. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature (2010) 464(7293):1362–6. doi:10.1038/nature08901
58. Tindemans I, Serafini N, Di Santo JP, Hendriks RW. GATA-3 function in innate and adaptive immunity. Immunity (2014) 41(2):191–206. doi:10.1016/j.immuni.2014.06.006
59. Homburg U, Renz H, Timmer W, Hohlfeld JM, Seitz F, Luer K, et al. Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma. J Allergy Clin Immunol (2015) 136(3):797–800. doi:10.1016/j.jaci.2015.02.018
60. Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM, Kappeler D, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med (2015) 372(21):1987–95. doi:10.1056/NEJMoa1411776
61. Mesnil C, Raulier S, Paulissen G, Xiao X, Birrell MA, Pirottin D, et al. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest (2016) 126(9):3279–95. doi:10.1172/JCI85664
62. Becher B, Schlitzer A, Chen J, Mair F, Sumatoh HR, Teng KW, et al. High-dimensional analysis of the murine myeloid cell system. Nat Immunol (2014) 15(12):1181–9. doi:10.1038/ni.3006
Keywords: hematopoiesis, eosinophilopoiesis, transcriptional regulation, eosinophil development, eosinophil lineage commitment
Citation: Fulkerson PC (2017) Transcription Factors in Eosinophil Development and As Therapeutic Targets. Front. Med. 4:115. doi: 10.3389/fmed.2017.00115
Received: 16 May 2017; Accepted: 06 July 2017;
Published: 24 July 2017
Edited by:Mats W. Johansson, University of Wisconsin-Madison, United States
Reviewed by:Steven J. Ackerman, University of Illinois at Chicago, United States
David Voehringer, University of Erlangen-Nuremberg, Germany
Copyright: © 2017 Fulkerson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Patricia C. Fulkerson, email@example.com


text:
Alan Sidorov writes: I began my racing career living in a pup tent near Snetterton race track in England, and have since competed and won in a variety of categories around the world. As for advanced driving, I began teaching for the Jim Russell Racing School in the UK, specializing in the advanced driving and skid circuit areas. I worked with numerous corporations, police, automotive writers and so on.
In the USA, I was a consultant for ten years with the Skip Barber Racing and Advanced Driving Schools, during which time I rewrote all the school curricula, developed an intensive instructor training program, (just because someone drives a racing car doesn't automatically make them a skilled teacher) and designed special programs for high schools and corporations as well as developing an instrumented vehicle testing program. I also got involved in development work for various manufacturers, some precision driving for films, and crash investigation.
I currently live in Whistler, British Columbia. In addition to writing on the subject of driving, I do private training clinics and some movie work, as well as public speaking on development of safe motoring skills.
Click below to go to Alan's article:


text:
I am seeking for a good teacher to learn English for Grade 5. Please contact me.
[email protected]
Request Contact Number
Get Contact Details Instantly
We use cookies to help provide you the best experience on our website. By continuing to use our site, you constent to our use of these cookies. More Information I accept


text:
10U and 12U Bat Rule - The Smithville Board of Directors has approved the following rule update for 2020 (excludes 8U):
All bats must be stamped with 1.20 bpf. These are the only approved bats per the Little League Softball rulebook.
10U and 12U Draft - To ensure league parity and competitiveness, both the 10U and 12U softball divisions will be re-drafted. All 10U and 12U girls will be required to attend the Evaluation period on Sunday, March 1st.
Evaluation Dates/Times
March 1 - 12:00-1:00 pm - Softball 8U
March 1 - 1:00-3:00 pm - Softball 10U
March 1 - 3:00-5:00 pm – Softball 12U
Softball Rules Posted - The 2020 softball rules have been updated and are now posted on the website.


text:
You may save multiple profiles and activate the correct one at your preference. The site survey page displays a list of all Infrastructure and Ad-hoc wireless networks available for connection. Smart Home by Brian Bennett Dec 3, Figure Add Profile: If your network is slow or acting weird, it's possible someone is stealing your signal and maybe more. Setup Status vista The driver will be installed to your computer. Figure Utility – Link Status
|Date Added:
|13 February 2014
|File Size:
|7.22 Mb
|Operating Systems:
|Windows NT/2000/XP/2003/2003/7/8/10 MacOS 10/X
|Free* [*Free Regsitration Required]
Figure 17 Ad-hoc Mode The system will restart automatically.
Figure Wireless Zero Configuration: This one tip will help you sleep better tonight A few seconds are all you need to get a better night's rest. Planning Your Wireless Network Appendix 2. Smart Home by Brian Bennett Dec 3, Networking by Aloysius Low Oct 4, Table Profile Advertisements or commercial links.
If you're asking for technical help, please be sure to include all your system info, including operating system, model number, and any other specifics related to the problem.
Create A New Profile Getting To Know Cwp If no connection, it will show Status Disconnected.
CNet CWP Free Driver Download (Official) () –
Click Finish To Complete vista Figure Autoplay Menu vista System Requirements OS Required. Choose Configuration Txburst Or Wifi cwp-845 Figure Utility – Link About Planning Your Wireless Network Phones by Shara Tibken Oct 25, Profile The Profile can keep your favorite wireless settings among your home, office and other public hotspots.
You can reset counters if you need, otherwise click OK. Table Statistics Leap Figure Add Profile: Double Click on Wireless Zero Configuration to go into its properties.
CNET CWP-854 User Manual
CNET's Forum on networking and wireless is the best source for finding help, troubleshooting, and getting buying advice from a community of experts. You are reporting the following post: Page 26 – Wcp-854 Authentication: Please try again now or at a later time.
Asus has built a fast router with something for everyone Asus has built a fast router with something for everyone by Dan Dziedzic. Make sure you have installed the correct utility and driver for your WLAN card.
Page 24 – Figure Add Profile: Getting To Know The Utility 3. Open or Shared Key Life in the slow lane: Open Or Shared Key Figure Utility – Advanced


text:
Driver's Education
Summer driver education classes are cancelled due to COVID-19. If you need a refund, please send an e-mail to email@example.com or call (541) 667-6100 ext. 20005.
Las clases de manejo durante el verano se han cancelado debido al COVID-19. Si necesita un reembolso, por favor envíe un mensaje a email@example.com o llame al (541) 667-6100 ext. 20005.
Dear Student and Parent,
Welcome to the Hermiston School District's Driver and Traffic Safety Education Program. To be effective, this will not be the "Easy School of Driving." Your success will require discipline, a willingness to learn new things and perhaps change old habits, and your time. Our program would be incomplete without your active participation, and your collective desire to learn. We highly value the time that you'll devote to this task and believe that without that commitment, our efforts will be greatly diminished. We want to thank you for your willingness to learn and maintain safe habits that are designed to produce exceptional drivers who are able to freely choose to drive crash and ticket free for an entire lifetime.


text:
IBS (Irritable Bowel Syndrome)
IBS is the most common condition diagnosed by gastroenterologists and is one of the most frequently seen conditions by primary care physicians.
Wrong diet, stress, insomnia, food intolerances and changes in gut bacteria may all trigger symptoms of IBS.
Triggers can vary from person to person, making it almost impossible to name specific foods or stressors that everyone with the disorder should avoid.
IBS affects people of all genders and all ages but only a fraction of individuals with symptoms of IBS tends to seek medical attention. Most individuals will eventually consult their GP for those symptoms, and the factors that drive this consultation are symptom severity, especially pain, and concerns that symptoms might indicate an underlying severe disease, such as cancer.
IBS often remains undiagnosed, but it is thought that about 20% of the world population is affected. People often feel depressed and helpless not being able to do things they want or living their life to the fullest as IBS symptoms affect and influence their daily lives greatly.
You may be affected by IBS if you regularly experience the following symptoms:
- Abdominal pain and severe cramping
- Diarrhoea or constipation
- Bloating
- Flatulence
- Frequent and/or loose stools
- Sudden urge in bowel movement
- Food intolerance
- Insomnia and exhaustion
- Anxiety and depression
- Back pain and frequent urination
- Reflux
- Difficult defecation or pain during it
All the above are a good reason to visit your GP and get diagnosed also making sure there are no underlying conditions which may attribute to the symptoms. Symptoms may vary from person to person and are influenced by the food consumed, seasonal changes, travel etc. It helps keeping a food diary recording everything you consume and checking your gut reaction to it.
What to avoid
It is best to avoid foods which stimulate intestine and can trigger diarrhoea such as:
- Artificial sweeteners like Xylitol and sorbitol (soft drinks often include those)
- Caffeine and alcohol
- Processed and sugary foods
- Dairy and fatty foods
- Avoid foods high in FODMAPS which stands for Fermentable Oligo Di-and-Monosaccharides and Polyols. Explained simply, foods rich in FODMAPs are sugar-based carbohydrates that ferment quickly but absorb poorly thus irritate the stomach lining and produce a lot of gas.
FODMAPs classify as the following:
- Oligosaccharides: Consisting of carbs like fructans (fructo-oligosaccarides and inulin) and galacto-oligosaccharides, dietary sources of oligosaccharides include wheat, rye, certain fruits and vegetables, and legumes.
- Disaccharides: Disaccharides mainly include lactose, and familiar foods that contain them like milk, soft cheeses, and other dairy products.
- Monosaccharides: consist of fruits, agave, and honey.
- Polyols: sorbitol, mannitol, and xylitol, which are found in sweeteners.
FODMAP Foods
Honey, Golden Syrup, Maple Syrup, Fructose, Dried Fruit, Fruit juice, Apple, Mango, Pear, etc.
All types of Animal Milk, Custard, Ice Cream, Yogurt, Cheeses.
Vegetables: Beetroot, Asparagus, Cabbage, Broccoli, Brussel Sprouts, Eggplant; Wheat and Rye cereals.
Baked Beans, Chickpeas, Kidney Beans, Lentils.
Apple, Apricot, Avocado, Blackberry, Cherry, Lychee, Nectarine, Peach, Plum, Watermelon, Mushrooms, Sweet Corn, Sweeteners (Xylitol, Mannitol, Sorbitol, etc).
As there are a few types of IBS, there is one in particular – IBS-D associated with diarrhoea, which Enterosgel® can assist with. Enterosgel® helps in alleviating the symptoms naturally and effectively, giving you peace of mind and detoxifying your body.
Learn more on IBS and Gut Health in our blog.


text:
Nine the mouse comforter
$ 26.00
by Moulin Roty
Sorry, this item is currently sold out.
Exclusive Item: Special order from France
Please allow 8 extra days for shipping
Please allow 8 extra days for shipping
Exclusive Item: Special order from France
Please allow 8 extra days for shipping
Please allow 8 extra days for shipping
Delightfully graphic mouse, all in jersey in soft gentle colours. Corners knotted like the corners of a pillow. Easy for little hands to grab. It can be embroidered with the child's first name.
Cuddle Alert: This is baby's new best friend, you'd better get 2!
More details about this product:
- Brand: Moulin Roty (Les Petits Dodos)
- Product Type: Baby Lovey
- Sku: M663017
- Age: 0+
- Washing instructions: Machine washable at 30°C on wool cycle.No tumble dry.
- Material: cotton, acrylic, elastane
Tag associated with this item:Age: 0-12mCollection: LoveysCurrently AvailableFor Newborns & InfantsMousePrice: $31 - $40Ships from the U.S.
Presented by Bonjour Petit, Moulin Roty is a French toy company that has been crafting quality toys and their accompanying stories for 40 years. With a focus on preserving the childhood soul, Moulin Roty is devoted to promoting "softness, fantasy and tenderness." Each character is designed in France using the finest French fabrics and materials. Moulin Roty is also very proud to be a worker-owned cooperative, putting quality, creativity and excellence first!


text:
Really good quality
Easy to set up with some practise. Comes with great quality aluminium poles. The ventilation is excellent and the inner had very little condensation after a frosty night. However, the pegs have started to bend and the flysheet door can be a bit tricky to open from the inside without getting wet in the morning. For the money though, this is fantastic value.


text:
According to Liberum Capital Markets, the crisis with the diamond industry will not end soon.
During the year we received very little positive news about the business. The glut of the diamond and polished stones market, as well as the steady fall in prices, continues to put pressure on companies in both directions, both in the miners and in the miners, until the very end of the year. and sell.
Ben Davis, an analyst at Liberum, says "the diamond market is going through one of its worst years." He said: "Although there is some optimism about reducing mine output and stopping glut that will revive diamond prices, I think the 2020 H2 will remain difficult for businesses."
Excessive saturation of the diamond market and lack of funding from banks hurt traders' profits. They also currently have excess inventory that loses value and the liquidity of this commodity decreases.
The effects of over-supplying and cheaper stones are being felt throughout the industry. Smaller mining companies such as Gem Diamonds, Lucara Diamond and Petra Diamonds are reporting permanent losses, and major manufacturer De Beers has taken counter-measures to these impacts.
De Beers offers more flexibility to its customers, allowing them to opt out of some of their diamonds, and last month they cut prices by 5%. The company also spends more on advertising to drive consumption.
According to Davis, however, more measures will be needed to revive consumption. Especially if the jewelry business comes to life and lab-produced diamonds also reduce their competitive output.
Source: Bloomberg Finance L.P.
Graphs: Used with permission of Bloomberg Finance L.P.
Trader Martin Nikolov
Read more:


text:
|Author Name
|KIMOTO Hiroshi (Toyo Kanetsu Solutions K.K.) / SAWATANI Yuriko (Nagoya University of Commerce and Business) / SAITO Naho (International Foundation for Information Technology) / IWAMOTO Koichi (Senior Fellow, RIETI) / TANOUE Yuta (The Institute of Statistical Mathematics) / INOUE Yusuka (University of Tokyo)
|Creation Date/NO.
|December 2018 18-P-019
|Research Project
|Productivity Revolution through IoT
|Download / Links
This paper describes the first scientific and basic survey data which can explain the present situation of the development of digital technology for information technology (IT), Internet of Things (IoT), big data, and artificial intelligence (AI) in Japan's fourth industrial revolution. And this paper describes the result of the analysis of the survey study. Big companies are trying to develop new business using digital technology but SME's is still fall behind. The difference of each industrial sector is more clear.
If this survey study shall be done every two years, the dynamic survey will be possible, which is the first purpose.


text:
Syria: teaching in a warzone
Academics at the University of Manchester awarded Syrian President Bashar al-Assad with the Notorious Belligerent Prize last week. He won for his "spectacular obtuseness and refusal to put anyone or anything before his personalised rule." The accolade is intended as a "gentle way of mocking" the Nobel Peace Prize.
But, with reports of atrocities coming out of the country every day, for many the situation in Syria is deadly serious, including for one University of Manchester student who spent his summer on the frontlines of the civil war ravaging the country.
While most students were likely on holiday, or at home, Ibrahim Olabi was in his home country of Syria teaching law to militant fighters.
"I studied last year something called public international law," said Olabi, a third year law student. "So I came across something called international humanitarian law, or known as the law of armed conflict, which regulates or tries to reduce the consequences of any war.
"Being from Syria I constantly think how I can apply this knowledge to my home country and how I can use this knowledge to its benefit."
And apply he did. At the end of the last academic year, Ibrahim departed for Turkey, where he would cross the border into Syria and head for the northern city of Aleppo. During his nearly three month stay in the country he lived in an area under constant threat of attack, with next-to-no electricity, and suffering from severe food shortages, in order to establish what is the first organisation inside Syria training non-government fighters in the laws of war.
"It started with the idea of doing face-to-face seminars, so I would go speak to some leader in the Free Syrian army, explain the idea, and then ask him to get other brigades and battalions that may be interested," Ibrahim told The Mancunion during an interview last week. "So a couple of days later we arrange a time and here I am giving a seminar to a group of fighters who are the ones taking decisions on the ground. Some were directly frontline people who had been called back for this training – I was impressed that the leader did that. He said 'it is important for you guys to know these laws.'"
After his exams in June, Ibrahim visited a friend at Amnesty International in London and they identified the key topics he would need to cover in the IHL training in Syria; the treatment of detainees, summary executions (executions without a trial), child soldiers, and targeting civilians.
A research team of friends based in Manchester gathered material on the relevant laws and then worked to simplify them.
"There is no point for example in going into Navy warfare or warplanes, because the rebels, or non-state actors, do not have this kind of weaponry. So we identified the kind of laws that are relevant to the Syrian fighters, we've translated them and made them a lot more simplified," he said. "Because there is no point in me going to a fighter and saying the 'third Geneva convention clause number one states…' and reading it like this, because it is a bit complicated.
"So we've simplified them into simple flowcharts of dos and don'ts and put them into a PowerPoint presentation. We sat with a couple of Muslim scholars so that we can focus on the overlap between international humanitarian law and sharia law, because that's the way that you will be able to convince a lot of fighters."
As well as straightforward classes, Ibrahim and associates in Syria developed short videos to help visually demonstrate the laws, which are currently being edited with the goal of broadcasting them on local television networks.
"For us to reach more people we created videos," he said. "One-minute sketches that reflect these humanitarian principles. These videos are acted out, so we've got people in military costumes, real guns, real locations, real ambulances, real tanks, areas that were 'missiled' – real destruction – things that Hollywood would pay millions to get. The scenarios are either drama or action – at the peak of the drama or action the video stops and the relevant laws are read out on screen by someone."
Ibrahim and his group, called the Syria Legal Development Programme, have also received help from academics in England, including University of Manchester law professor Mark Reiff, who praised Ibrahim's work.
"He is really pretty amazing in what he is doing and the amount of effort he has been putting in," said Reiff. "He is trying to help provide the rebels guidance on how to comply with the laws of way in a way that they trust more than with other more traditional international organisations.
"Most regular armies give their soldiers training in these laws, but as rebel groups are not regular armies they have to look elsewhere. The Red Cross and other international organisations have traditionally been the people who have done this.
"Ibrahim is providing to rebels the training soldiers in regular armies might get. And this is a good thing because the more people understand these laws the more likely they are to comply with them. It is in everybody's interest."
Ibrahim has been working in Syria since the uprising started working initially as a "media activist, so I would usually take CNN, BBC journalists, German newspaper journalists around to the frontline so they could get what they want, which they can't do on their own due to the language barrier and they don't know where to go."
Having been travelling back and forth to Syria since the outbreak of war in 2011, Ibrahim has seen harrowing things he will never forget. One of the hardest experiences for him was when enemy snipers opened fire on a group of rebel fighters and he was powerless to help.
"I was on the frontline with a journalist and about fifteen fighters were running to storm a building," said Ibrahim. "Sadly they didn't know there were snipers on the other side and they crossed thinking it was clear and when they crossed they shot them all down. They didn't all die, but they had to stay down.
"It is one of the most horrific things I have seen, because we can't go out and get them because we will be shot at. There was fifteen or twenty of them, initially about only six died. By the end of the day they had all died, they bled out to death, because we couldn't reach them.
"We tried everything, we tried burning tires to create smoke so the sniper wouldn't see, but they would just fire randomly. So that was one of the most difficult scenes, because I could see them they were like one hundred metres away and one, he was looking directly at me and I was unable to do anything. It is a bit emotional. That was one of the most difficult things I've seen."
The Assad regime continues to run a relentless bombing campaign against rebels, using fighter jets to attack at will. The constant threat has led Ibrahim to always be on alert when he hears the sound of a plane flying overhead, which is a habit that has been hard to shake, even back in Manchester.
"When I hear a plane I automatically go into cover, or at least check out what is going on. At Manchester Airport, I know I am at an airport so logically I will hear planes, but even though, I step out, I hear a plane and I go to cover. Its what happens if I hear fireworks or anything like that, there is an initial shock," he said.
But, things in Syria have changed since the outbreak of fighting, when governmetn jets would fly day and night. Rebels began shooting planes down – now they only fly at night. This presents its own problems to deal with.
"[They] shoot at anything that has its lights on," Ibrahim said. "You can't see them and they have night vision. You can travel by care but you have to focus a lot; turn on the light, turn off the light, turn on the light, turn off the light so that if you get bombed there is a little bit of a margin of error – you might a escape.
"Also, there are lots of checkpoints in the city and they tell you to turn off your lights long before you reach the checkpoint because if they see a car stopping with lights on they will know there is a checkpoint down there and it will get bombed. Even at night, in the houses we try to dim the lights, if you had electricity of course."
The next step for Ibrahim and the Syria Legal Development Programme is to try and register as a charity with the UK government and then start working on funding. The organisation has already has already received numerous emails from lawyers, law students, and other organisations looking to collaborate with them. Among the former is UNICEF, "they wanted to know more about what we were doing for child protection and how I was focusing on this issue," said Ibrahim. "I told them about the program and they said they were happy to send me any materials they had, materials on laws. And they've got a lot of presentations they could send and were happy to offer legal consultation when it comes to questions that relate to children."
"We also got approached by an organisation called Geneva Call, which is one of the largest organisations that deals with the legal training of non-state actors, it is made for this purpose. They have trained people in Palestine, Lebanon, and now they are trying to train people in Syria but it is difficult because they can't get into the country easily because of bureaucracy or safety of staff and so on. So they got in touch with us and said how can we help, how can we cooperate."
Ibrahim added that his teaching in Syria put pressure on him because the fighters take his what he says to be accurate, and that he was warned not to judge his students.
He said, "everything I say they take for granted, which puts huge pressure on me.
"Before I did this I consulted a group called Libyan lawyers for justice – I asked them about the psychology of tackling such seminars, because you need to be very careful and the most important thing that they told me was don't judge them. Don't ask them to tell you something that they've done, don't give examples of breaches their comrades have made. Don't make them feel judged…If they remember something they have done – a breach they have made – they will keep quiet about, but they will not do it again.
"I'm not taking their names, I don't know who they are. It's just me knowing one person who knows the rest and I'm speaking to them, and I'm with them at the frontline, we can get bombed together at the same moment and they appreciate that. So they were like 'yeah sure, give us whatever knowledge you've got.'"
Trackback from your site.


text:
VoiceMail Pro OTO 1st, 2nd & 3rd: There are two front end options and three other OTOs aka One Time Offers. The 1st VoiceMail Pro OTO is Pro Unlimited License, the 2nd VoiceMail Pro OTO is Agency License, the 3rd VoiceMail Pro OTO is Reseller License. There is no other VoiceMailPro OTO Down Sell. The product is Ankur Shukla. All the links >>>
All 3 VoiceMail Pro OTO Links Below
It Is Mandatory to Get Front End Before Any OTO From Below, Can Get Any 1 Or More OTOs From Below If Already Got Front End!
Front End:
=>> VoiceMail Pro
OTO 1 (Pro Unlimited Version):
=>> VoiceMail Pro OTO 1
OTO 2 (Agency License):
=>> VoiceMail Pro OTO 2
OTO 3 (Reseller License):
=>> VoiceMail Pro OTO 3
Front End Walk Through
What is VoiceMail Pro:
There are 100s of visitors coming to your site every day. They want to ask you more questions about your business. Buy from you, close a deal. They want to get more info about your product or service & do business with you. BUT – they are lazy to fill out the ugly contact form on your site and just wait to hear back from you. MAYBE you will get back to them and maybe you won't. That's what they think. BUT – on the other hand, when people try to reach you on your home phone or mobile and they can't… they can leave a VOICEMAIL and that almost always gets a response from you. How about if you could add the same MAGICAL voicemail feature to your WEBSITE?. Allow anyone coming to your site to leave a voicemail instantly and then get back to them?. Well, that's exactly why we created VOICEMAIL PRO. Now you can get unlimited voicemails from your website, add this to your site in just 60 seconds.
Get Testimonials / Feedback & Messages: This is an amazing way to collect testimonials, feedback and voice messages from your visitors,
Grow Your Website Leads & Traffic Easily: This builds you get thousands of leads from your website and helps you grow your website traffic fast,
Build A List in a NEW Way From Your Site: This is an amazing way to builds your list and you can export these leads into CSV anytime you want.
Here's What Early Users Say About VoiceMail Pro:
Great way of connecting with leads and turning into sales, thank you ankur,
Thanks for the opportunity to see this here. Excellent product it will be a winner,
Aloha… super excited as my real estate business is built on relationships & having voice capabilities will really set me a part from the crowd & get more leads… I'm In,
Ankur has done it done. He has delivered a product that has become necessary for adapting my marketing strategy to the latest trends in internet usage. And as typical it is easy to use and efficient. This is the kind of software that makes me happy.
Wow! this looks amazing. My first preference on either end of the spectrum, as a website owner, or as a curious customer, is to connect to others through voice. This is a great development. Thanks You,
This software make it even easier for visitors to communicate with the site owner. Talking is more easier than writing. This is clever Ankur,
Amazing game changer! Awesome thumbs up, greetings from Germany,
WOW! I love this! I am not a big texted but – voice mail is where it's at! Thanks!!!,
What can I say? Ankur comes out with another stellar game changing program!! Bravo!!,
I have tried other systems to get VoiceMail Pro and would love one that works! This service would allow me to send customers to my website for communications, and Upsell them to other products,
Certainly would be more direct and less frustrating than posting a toll-free number pretending that all agents are currently busy and to leave a message at the tone,
What??? Website Voice mail???? Really????? Forget free, where can I buy this right now??? Sign me up…..,
A great add-on to boost up customer service. Always looking for a differentiator when it comes to giving great service,
Very cool idea! I think this has tremendous potential for someone wanting to get you a message instantly. Sometimes people don't want to send and email or support ticket because it seems like it will be lost in the multitude of others and maybe never gotten back to. Will VoiceMail Pro, it might definitely appeal to a certain segment of visitor. I will use this with my local agency and also with my web hosting company. Can't wait to try it out. Thanks!,
A message to my website would be good for local client lead capture. It is certainly better than get spammed to death from txt on my cell phone, which I hate,
I operate a designated driver service – we drive impaired people home in their own vehicle. People visit out website for 2 reasons: 1.To get information and 2.To book rides. Website Voicemail is a perfect solution for both kinds of website visitors – they can leave their questions and we can call them back with answers – they can leave their reservations details and we can complete the reservation.
VoiceMail Pro Works on any website – WordPress, InstaPage, ClickFunnel, Convertri, HTML, PHP, Magento & Everything Else:
Increase interaction with your audience: Add VoiceMail Pro to your website and visitors will be able to send you voice messages from anywhere on your website by simply clicking on a button. You can use a custom button or the VoiceMailPro side button. It also provides a hosted voicemail page, so you can receive voice messages without installing anything on your website,
Easy for visitors to send a message: Visitors don't need an account to send you voicemail. A message can be sent with just a few clicks without typing anything. Visitors can listen to their recording before sending it. The widget allows to record messages as many times as they want, so they can practice before sending it to you,
Get Visitors' Contact Details: Visitors have the option of entering their contact information before sending a message. By default these fields are optional but you can make them mandatory to make sure visitors leave their info, so you can email or call them back,
Increase Audience Interaction: Some of your audiences may be more comfortable with speaking rather than constructing a written version of their thoughts,
No App Installation Needed: VoiceMail Pro supports desktop and laptop native audio recording so there's no need to install an app for it to work,
Compatible with Mobile: As with desktop, your audience can record messages on their Android, iPhones and iPads without an app,
Better Prospecting: Many sales agents can gauge how the client will be by listening to their voice. This tool allows you to do exactly that.
Frequently Asked Questions
How many messages can I receive & how many sites can I use this for?
You can receive 5,000 voice messages with the VoiceMailPRO for up to 25 Websites. If you want to use this for unlimited messages and unlimited websites then upgrade to the UNLIMITED package on the next page after you order this.
Can I sell this to my clients?
You can use this only for your own website but if you want to use for clients, we have the AGENCY and RESELLER plans available that allow you to create 100 or 250 client accounts – that upgrade offer is shown after you purchase an account today from us, this upgrade is only for customers so it is shown only after you purchase.
Tags: VoiceMail Pro OTO | Voice Mail Pro OTO | VoiceMailPro OTO | OTO | OTOs | https://oto.mrbookmarks.com/voicemail-pro-oto/


text:
Egg shells
Collection by Karen Osmond
Winter Birches III
This is another version of Winter Birches. 9"x11" eggshell mosaic
Lutikalai Gallery
Mosaic Eggshell Vase
DIY Faux Mini Mosaic Tiles: Eggshell !!
Overstock.com: Online Shopping - Bedding, Furniture, Electronics, Jewelry, Clothing & more
Shop for Handmade Eggshell Mosaic 'Crackled Gold' Decorative Box (Thailand). Get free shipping On EVERYTHING* at Overstock - Your Online Home Decor Outlet Store! Get 5% in rewards with Club O! - 5572069
Look of Mosaic Technique with Eggshells
Want to try something new and expand your creativity. Jewelry craft ideas don't get more unique than the look of mosaic technique with eggshells. Use actual shells to create pendants and pieces that will surely stand out.
Virginia Escobar - Pendant - Egg shells, oxidized 925 silver, cotton thread, 2014
Items similar to Eggshell & Polymer Clay Pendant on Etsy
This piece is a triangular pendant with rounded edges that I made by combining the traditional Eggshell Mosaic technique with polymer clay. I tinted it by hand and sealed with a matte finish. It's reversible: its backside was textured by means of a texture sheet by Mathilde Colas ("Crepidules") and finished with pearled Teal acrylic paint to give it a nice shine. It hangs on a 17" black wire with a screw clasp. Triangle dimensions: 2 5/8" x 2 5/8" x 1/4" Similar items…
Картинки по запросу Egg shell Mosaics
This item is unavailable
Egg Shell Pendants Mosaic Jewelry Costume by LallyBrochFarm, $15.00
Elisabet Moreno is a jewelry designer that establishes a dialogue between tradition and innovation, investigating the matter and the form through the study of ancestral arts, such as metalwork and Japanese lacquer, and their experimental application in the creation of jewels.
This item is unavailable | Etsy
Find the perfect handmade gift, vintage & on-trend clothes, unique jewelry, and more… lots more.
This item is unavailable
Unique One of a Kind Egg Shell Jewelry Necklace Earrings


text:
Craigslist mariestad free stuff west valley I Am Looking Sexy Meeting
I'm just looking for new friends myb date. I'm a stay at home mom of.
|Relationship Status:
|Never Married
|I Looking Real Dating
|San Bernardino, CA
|Dyed brown
|Relation Type:
|Adult Women Ready Adult Fun
Views: 7660
I would treat you to anything you wanted to. Sex personal ready maruestad for fun Blk woman in search of handsome white male Adult wants real sex Cardiff Naughty lady wants sex tonight Shakopee Curious bbw looking for someone to experiment with :)im a cute bbw size 1618 latina please respond with pics.
Looks are not really important; however, I want a man who cares about his appearance and practices good hygiene.
I'm also available via webcam, but you should be willing to prove you are both girl and real, via live webcam. I am just a and have fun.


text:
Firebrand Training Qualifies 3,000th Microsoft MCSE student
Accelerated Learning company Firebrand Training has produced another 3,000 qualified MCSE students, in just over 3 years.
[UKPRwire, Wed Jan 21 2009] Accelerated Learning company Firebrand Training has produced another 3,000 qualified MCSE students, in just over 3 years.
Robert Chapman, CEO, says: Firebrand Training is proud to say we have seen the 3000th qualified student on our training course for MCSE over Windows Server 2003. Our examination based course gives delegates accreditation at MCP, MCSA and MCSE levels.
The Microsoft Certified Systems Engineer (MCSE) certification proves your expertise in designing and implementing the infrastructure for business solutions based on the Windows Server 2003 platform. The MCSE is the UK's de facto standard of skills and knowledge for Server and Network Administration. One of the most effective ways to grasp the skills required for to pass an MCSE is through Accelerated Learning.
Our 14 day accelerated Microsoft MCSE 2003 training course provides information technology professionals with the knowledge and skills necessary to install, configure, support, and troubleshoot Microsoft Windows 2000- and 2003-based networks, with a focus on information security in the enterprise. This is an accelerated, residential, fully-immersed MCSE course, designed for computer professionals that require effective, real-world skill-building and timely certification. You will live, learn, and test on-site to become an MCSE."
The Accelerated Learning pioneer Firebrand Training say the latest MCSE boot camp is designed to incorporate the requirements of existing users and to enhance knowledge to Windows Server 2003 and Windows Vista operating systems.
The Firebrand Training MCSE bootcamp details how to install and configure Windows XP and Windows Vista, manage a Windows Server 2003 environment, understand Active Directory, and also to design security for a Windows Server 2003 network.", Robert Chapman explains.
He says the IT training course builds on the delegates knowledge of Windows Server 2003 networks and environments, and ensures that the students leaves the MCSE course with both the skills and knowledge to implement and manage a Windows Server 2003 infrastructure.
About the Firebrand Training MCSE.
Firebrand Training's Accelerated Learning MCSE course:
Helps students grasp complex project management concepts more easily by identifying and catering to individual student learning styles through a mixed visual, auditory and kinaesthetic-tactual delivery system
Enhances retention by employing accelerated learning techniques focused on committing information to long-term memory
Is not like other bootcamps where just the exams are taught. In fact our PRINCE2 training courses is delivers more case based scenarios than traditional training or boot camps
About Firebrand Training (www.firebrandtraining.co.uk)
Firebrand Training is challenging the way in which professional training is delivered.
Firebrand Training, formally known as The Training Camp, has pioneered Accelerated Learning courses for busy IT professionals. The organisations innovative approach to course delivery has led to its status as the Institute of IT Trainings IT Training Company of the Year for the three years something no other IT Training company has achieved.
Students are totally immersed in the subject matter, receiving an average of 12 hours intense tuition per day at a residential training site. Subject experts implement a range of teaching methodologies designed to fit with how we best understand and retain information during different periods in the day.
Accelerated Learning is an attractive proposition for contractors, whose time commands very high premiums, and employers who need to minimise staff absence. Firebrand Training has an above average pass rate of 85% - confounding critics claims that Accelerated Learning fails to produce results.
Firebrand Training was founded by Robert Chapman and Stefano Capaldo in Summer 2001 as The Training Camp. Stefano was a former student in the US and rated the companys approach so highly that he decided to launch a programme of courses in the UK.
The organisation has since been recognised by Microsoft as a Gold Partner for Learning Solutions (MCPLS) and over 15,000 students have been trained in the UK to date. The success of the company enabled the management team to relaunch as Firebrand Training, which is focused on delivering training courses specifically designed for a European market.
Firebrand Training offers a range of courses covering all major vendors such as Microsoft, Cisco, Oracle, Sun, and Novell, as well as specialist certifications in the areas of security, business intelligence, project and business process management.
Press Contact:
Nick Wells
Firebrand Training
4 Gt Portland Street
London, UK


text:
Don't Miss the Boat, Go Visit the Ark Encounter! (Part 1 of 2)
Outdoor Opportunities By COL(Ret.) Grey D. Berrier II
Our 2019 PA Spring turkey season opens tomorrow, Sat., April 27, and I can't wait to head to the woods in pursuit of a bearded bird. However, I had one of those experiences less than a month ago that was so awe-inspiring, it keeps coming to my mind and I just have to share it with as many people as I possibly can! Let me provide you with a little backstory for context. I have always had a lifelong fascination with wildlife. As a young child, I loved when someone read me a story about animals and my favorite TV show (back in the days of only four TV stations: ABC, NBC, CBS, & PBS) was Mutual of Omaha's "Wild Kingdom". Growing up, I spent as much time as possible out-in-the-woods and it was a natural progression to major in Wildlife Science when I earned my Bachelor's degree at Penn State. My passion for wildlife persists and it serves as a primary motivation for writing my outdoor column each week. It should come as no surprise then that I have always been enthralled by the story of Noah and the Flood found in The Bible in Genesis, Chapters 6-9. When I was young, my thoughts immediately focused on the wonder of all those animals brought together in one place; while as an adult, I've often pondered the extensive details of constructing such a massive vessel and the overwhelming logistics of housing, feeding, watering, and cleaning the pens of all those animals. About two and a half years ago, when I first learned the nonprofit organization, Answers in Genesis, had constructed a life-sized replica of Noah's Ark, based on Biblical dimensions, in the Greater Cincinnati Area of Northern Kentucky, I knew I had to go see it for myself. Back on March 29 & 30, my wife and I made the relatively quick and painless 5+ hour drive from Lawrence County, PA down to the Greater Cincinnati Area. Based on good advice from my uncle, who had been there on a bus trip with my aunt within the past year, we initially went to the Creation Museum (which answersingenesis.org opened in Petersburg, KY in 2007) and then headed down to the Ark Encounter (which opened to the public on July 7, 2016 in Williamstown, KY) on Saturday morning. It's roughly 42-miles between the Creation Museum and the Ark Encounter, and the most direct route takes you right past the Greater Cincinnati Airport in Northern Kentucky, where there are literally hundreds of options for food and lodging, just off the interstate. The Ark Encounter opens at 9 AM, Mon. – Sat., and 12 PM on Sundays. Since my wife and I are both morning people, we were only the third vehicle to arrive at 8:20 AM in the ample 4,000 space parking lot and we caught the very first shuttle bus that morning heading back the limited access shuttle road to the Ark. Now, I've personally visited Denali National Park, the Grand Canyon, and Mount Rushmore; and I honestly can tell you, you get the same sense of overwhelming awe and blown-away "Wow" factor when you first encounter the Ark up close. Before they even finished building the Creation Museum in 2007, answersingenesis.org started planning on building the Ark Encounter. Why build an Ark? Independent surveys found, when people worldwide were asked, "What major historical place or thing would you like to see archaeologists discover within your lifetime?", an overwhelming majority (43%) responded, "Noah's Ark". Surprisingly, cultures and people groups from around the world, some not even reached until the 20th century, have the common denominator of a world-wide flood story in their past. Further independent research indicated 63% of Americans (roughly 200 million people), from all walks of life, both Christians and Non-Christians, would be inclined to come visit a family-friendly, themed attraction centered on Noah's Ark. Built on 800-acres just off I-75 (the second busiest North-South interstate in the U.S. running from Florida to the Canadian Border) it's located within a one-day's drive of two-thirds of the entire U.S. population. Next week, we'll explore the details of this one-of-a-kind marvel. God Bless, Be Safe, and Great Outdoors! ©WBB 2019


text:
Product View
CamelBak M.U.L.E.
Shipping Information
Product Information
The CamelBak® M.U.L.E. bike pack combines 12 liters total storage with a 3-liter Crux™ reservoir with Quicklink™. The Air Director™ back panel and ventilated harness work to keep you cool and comfortable.
- Air Director™ Back Panel: Channels air flow to keep you cool
- Removeable Stability Belt: For additional fit and stability
- Ventilated Harness: Lightweight and breathable
- Adjustable Sternum Strap: Offers a range of adjustments for a custom fit and increased stability
- Secure Phone Pocket: Keep essentials safe and easy to access
- Stretch Overflow Pocket: Quickly stash or shed an extra layer
- Magnetic Tube Trap™ Management: Keeps your tube secure and accessible when you need it
- Partially made with post-consumer recycled materials
- Brand : CamelBak
- Country of Origin : Imported
- Style : 2245001000
- DSG Pro Tips
- Web ID: 20CBKAMLXXXXXXXXXHYD