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Protecting future generations from FGM
STAND WITH BRAVE GIRLS AGAINST FGM
Meet the girls working to protect future generations from female genital mutilation
In communities around the world, girls remain at risk of female genital mutilation (FGM) – a risk that has increased with the coronavirus crisis. The World Health Organisation defines FGM as the partial or total removal of external female genitalia, or other injury to the female genital organs for non-medical reasons.
FGM is a violation of a girl's human rights that enforces gender inequality. It has no health benefits and leaves girls and young women at risk of emotional and physical trauma, including severe bleeding, infections, complications during childbirth and a greater risk of newborn death.
In countries such as Sierra Leone, Mali and Ethiopia, we're working with girls who want to make sure future generations don't have to undergo FGM. We're supporting them as they educate their communities on the harmful effects of the practice and working with governments and community leaders to increase legal protection for girls and women against FGM.
Infancy to 15 is when most girls are made to undergo FGM
More than three million girls are estimated to be at risk of FGM each year
More than 200 million girls and women globally have been through FGM
2 million more girls could undergo FGM by 2030 as a result of the pandemic
FGM AND THE CORONAVIRUS CRISIS
Coronavirus is having a devastating impact on rates of FGM around the world, with the UNFPA (United Nations Population Fund) estimating that by 2030, an additional two million girls could undergo FGM as a result of the pandemic.
The current crisis means girls are spending more time at home and less time at school, increasing the risk of gender-based violence, including FGM. Lockdown restrictions are also forcing awareness-raising programmes to be scaled back or stopped altogether.
What is female genital mutilation?
Female genital mutilation (FGM) involves the partial or total removal of a girl or young woman's external genitalia, or other injury to the female genital organs for non-medical reasons. It has no health benefits.
How does FGM impact girls and women?
FGM carries the risk of infection and even death. Long-term, girls may face an increased chance of complications during childbirth and stillbirth, increased susceptibility to infection and psychological trauma.
Why does FGM still happen?
The belief that FGM equates to purity and 'good morals' is one reason. In many cultures where the practice happens, it's believed to be required for a girl to become a woman and get married. Those who don't undergo FGM may be ostracised and thought of as promiscuous.
Our work to end FGM
We're supporting young people and their communities to end FGM by:
Working with our partners to adapt our work during the pandemic, to continue to raise awareness about FGM – including in Mali and Somalia, where we've been broadcasting radio messages about the devastating impact it can have on girls' health.
Working with girls to make sure their voices are heard, so they can say no to FGM. In Tanzania, we're training girls as peer educators, establishing girls' clubs and setting up football tournaments to promote conversations about FGM and other issues girls face, as well as training health workers, teachers and parents to support girls' choices.
Working with girls and women, as well as boys and men, to make sure they're aware of the harmful effects of FGM. This not only empowers girls to make choices, it also educates the women who carry out the procedure. Because boys and men tend to have greater power and influence in cultures that practice FGM, working with them to change their attitudes is also important in creating change.
Encouraging community conversations to support changes in harmful social norms such as FGM.
Increasing legal protection. Part of our work involves engaging with governments and community leaders to put legal restrictions in place around FGM and making sure they're enforced.
Supporting survivors. Those who have been through FGM often need help and support, so we work with local health workers and the wider community to provide psychological and medical support to survivors.
Isatu's story
There is no benefit. It only causes us pain.
Isatu was 16 when she went through FGM in Sierra Leone. She shares her experiences and the long-term impact the practice has had on her life.
Stand with brave girls everywhere as they take on the fight for equal rights
Generations of change in Mali
"Many girls of 14 or 15 are determined that when the time comes, their daughters will not be cut." – Sanaba
In one village in Mali, ideas surrounding FGM are changing – and it's mothers and grandmothers, like Sanaba and Fatoumata, who are ending the silence surrounding the practice.
Giving girls back their futures in Sierra Leone
Zainab is speaking out against FGM in her community in Sierra Leone
'It's very important to raise awareness'
Zainab was 13 when she joined the anti-FGM club in her school, which is supported by Plan International. Four years later, she leads the club and uses the radio show she hosts to make sure girls are aware of their rights and know how to get help if they need it.
"Now we know the negative effects. It's very important to raise awareness," Zainab explains. "As well as the danger of death and bleeding, FGM also causes girls to drop out of school – which in turn leads to early marriage and to teenage pregnancy."
Zainab's story
'I thought it was a tradition that was done to protect me'
"I want to help girls believe in themselves and to see that there are a lot of opportunities out there for them." – Sewanatu
Sewanatu and Isha* were both forced to go through FGM when they were growing up. Today, they're determined other girls won't have the same experience they did – and are raising their voices for girls' rights and an end to FGM.
*Name has been changed to protect identity
FGM in the UK
While the practice is concentrated in Africa, the Middle East and Asia, FGM isn't just a problem overseas: the issue is a global one. In the UK the practice is illegal but girls remain at risk – in England, one case of FGM is newly recorded every 92 minutes.
Are You at Risk of FGM?
If you think you or someone you know is in immediate danger of having to go through FGM, or of being taken abroad to undergo the practice, you can call the police by dialling 999.
If you're concerned that a child's welfare is at risk because of FGM, you can call the NSPCC's free helpline on 0808 800 5000. The helpline offers advice, information and support. Though callers can choose to remain anonymous, any information that could protect a child at serious risk may be passed to the police or social services.
Visit the NSPCC website
Help change the future for girls
Sponsor a girl


The Learning Disabilities Mortality Review (LeDeR) Programme was established as a result of one of the key recommendations of the Confidential Inquiry into premature deaths of people with learning disabilities (CIPOLD). A major part of the LeDeR Programme is to support local areas in England to review the deaths of people with learning disabilities.
The training will enable reviewers to identify potentially avoidable factors that may have contributed to a person's death and develop plans of action that individually or in combination, will guide necessary changes in health and social care services in order to reduce premature deaths of people with learning disabilities.


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Uranium Mining: Opportunities Exist to Improve Oversight of Financial Assurances
GAO-12-544 Published: May 17, 2012. Publicly Released: May 24, 2012.
Skip to Highlights
What GAO Found
The Bureau of Land Management (BLM), the Forest Service, and the Department of Energy (DOE) are the key agencies that oversee uranium exploration and extraction on federal land, but GAO identified three areas where their oversight processes differ. First, these agencies have different processes for notification of uranium exploration or extraction activities on federal land. Second, the agencies require operators to have in place financial assurances to cover the full estimated cost of reclaiming a uranium operation, but they differ in who estimates the value of the financial assurance and the frequency of their reviews of the assurances. Third, under existing authorities, DOE can collect royalties or rents for uranium extraction, but BLM and the Forest Service cannot. DOE has collected about $64 million in rents and royalties from its leasing program since the 1940s.
As of January 2012, a total of 221 uranium operations were on federally managed land, but only 7 were actively extracting uranium and all of these were on BLM land. An additional 29 uranium operations were awaiting federal approval. Of the 202 operations on BLM land, the majority were engaged in either reclamation or exploration activities, according to BLM field officials. In addition, 3 uranium operations were on Forest Service land, and 16 operations were on lease tracts that DOE manages, none of which were actively extracting uranium.
As of January 2012, BLM, the Forest Service, and DOE reported having $249.1 million in financial assurances, and these assurances were generally adequate to cover the estimated reclamation costs for uranium operations on federal land. Nearly all of these assurances ($247.6 million) were for authorized uranium operations on BLM-managed land, with the remaining $1.5 million for authorized operations on Forest Service land and for DOE's lease tracts. BLM and the Nuclear Regulatory Commission (NRC), which is responsible for overseeing some aspects of uranium operations on federal land, do not coordinate efforts to establish and review financial assurances for in situ recovery operations, which use a series of wells to extract uranium. Such operations account for a large percentage of the total financial assurances held by the agencies.
Federal agencies do not have reliable data on the number and location of abandoned uranium mine sites on federal land or a definitive cost for their cleanup. There are likely thousands of abandoned uranium mine sites on federal land, but GAO identified significant limitations in agencies' data that make their databases generally unreliable. For example, these databases do not have complete data and do not use a consistent definition of an abandoned mine site. Agencies do not know how many sites will need cleanup, and they do not have information on the total cost to clean up these sites. Based on agencies' experiences with cleanup at some sites, cleanup costs could vary significantly from thousands to hundreds of millions of dollars, depending on site-specific conditions and the amount and type of work required at each site.
Why GAO Did This Study
From 2005 through 2007, uranium prices increased from about $20 a pound to over $140 a pound, leading to renewed interest in uranium mining on federal land. This interest has raised concerns about the potential impacts that more uranium operations could have on the environment. GAO was asked to (1) compare key agencies' oversight of uranium exploration and extraction operations on federal land, (2) determine the number and status of uranium operations on federal land, (3) identify the coverage and amounts of financial assurances for reclaiming current uranium operations on federal land, and (4) examine what is known about the number and location of abandoned uranium mine sites on federal land and their potential cleanup costs. GAO reviewed agency reports and regulations, surveyed relevant agency field staff on the status of these operations, and examined federal data on uranium operations, financial assurances, and abandoned uranium mine sites.
Skip to Recommendations
GAO recommends, among other things, that federal agencies better coordinate their efforts when establishing financial assurances and develop a consistent definition for abandoned mine sites. The Departments of the Interior, Agriculture, and Energy, along with NRC and the Environmental Protection Agency (EPA), concurred with these recommendations. In addition, Interior and EPA provided technical comments, which GAO incorporated as appropriate.
Recommendations for Executive Action
Agency Affected
Department of the Interior To help better ensure that financial assurances are adequate for uranium mining operations on federal land, the Secretary of the Interior and the Chairman of the Nuclear Regulatory Commission should enhance their coordination on financial assurances for in situ recovery (ISR) operations through the development of a memorandum of understanding that defines roles and promotes information sharing.
Closed – Implemented Closed – Implemented

Actions that satisfy the intent of the recommendation have been taken.

Based in part upon our work, the Nuclear Regulatory Commission (NRC) and the Bureau of Land Management signed a memorandum of understanding (MOU) in February 2013 to improve interagency communication and share their respective expertise with one another. One of the areas highlighted in the MOU is coordinating on financial assurances for uranium operations. Specifically, the MOU states that NRC and BLM will coordinate and share information on financial assurances and conduct periodic joint meetings involving staff or senior management.
Nuclear Regulatory Commission To help better ensure that financial assurances are adequate for uranium mining operations on federal land, the Secretary of the Interior and the Chairman of the Nuclear Regulatory Commission should enhance their coordination on financial assurances for ISR operations through the development of a memorandum of understanding that defines roles and promotes information sharing.
Department of the Interior To enhance data collection efforts on abandoned mines, the Secretaries of the Interior and of Agriculture and the Administrator of the Environmental Protection Agency should work to develop a consistent definition of abandoned mine sites for use in data-gathering efforts.
Through the Federal Mining Dialogue, an interagency group consisting of officials from the Department of the Interior, Department of Agriculture, and the Environmental Protection Agency met on June 26, 2012 and November 14, 2012 to discuss and develop a consistent definition of an abandoned mine site. In January 2013, a unified federal agency definition was appproved for implementation. Subsequently, on September 20, 2013, BLM issued an instruction memo to field staff that provided the consistent definition of abandoned uranium mines and said this definition is to be used when communicating with other federal agencies on abandoned uranium mines.
Department of Agriculture To enhance data collection efforts on abandoned mines, the Secretaries of the Interior and of Agriculture and the Administrator of the Environmental Protection Agency should work to develop a consistent definition of abandoned mine sites for use in data-gathering efforts.
Through the Federal Mining Dialogue, an interagency group consisting of officials from the Department of the Interior, Department of Agriculture, and the Environmental Protection Agency met on June 26, 2012 and November 14, 2012 to discuss and develop a consistent definition of an abandoned mine site. In January 2013, a unified federal agency definition was appproved for implementation. On February 4, 2014, the U.S. Forest Service issued an instruction memo to regional foresters that provided the consistent definition of abandoned uranium mines and said this definition was to be used for program management, project planning, and inventory purposes.
Environmental Protection Agency To enhance data collection efforts on abandoned mines, the Secretaries of the Interior and of Agriculture and the Administrator of the Environmental Protection Agency should work to develop a consistent definition of abandoned mine sites for use in data-gathering efforts.
In its FY2016 Superfund Program Implementation Manual, EPA included in its discussion of mining impacts a new definition for an abandoned uranium mine. This definition was derived as part of the Federal Mining Dialogue, which included input from Interior, Agriculture, and EPA, among other agencies. The definition EPA included in the FY16 update to the manual was consistent with the definition that was agreed to by the members of the Federal Mining Dialogue and that was subsequently incorporated into BLM and Forest Service guidance. As a result, we consider this recommendation to be closed as implemented.
Department of the Interior To help better ensure that financial assurances are adequate for uranium mining operations on federal land, and to improve oversight of financial assurances, the Secretary of the Interior should direct the Director of the Bureau of Land Management to (1) include information on expired mine operations in the annual Bond Review Report process, and (2) develop guidance to ensure accurate and prompt data entry in LR2000.
Based in part on our work, BLM has issued its Surface Management Handbook with updates clarifying and reiterating guidance that data be entered in LR2000 within 5 working days of an event. BLM has also incorporated expired uranium mining operations into its Bond Review Report.
See All 6 Recommendations
Highlights Page (1 page)
Full Report (72 pages)
Accessible Text
Anu K. Mittal
mittala@gao.gov
Chuck Young
youngc1@gao.gov
Auditing and Financial Management
UraniumExplorationDatabase management systemsBid protest regulationsFederal agenciesGroundwaterRemediationRoyalty paymentsEnvironmental assessmentAgricultural commodities

redpajama_set_name: RedPajamaCommonCrawl


QMS NZ's digital expansion is showing no signs of slowing down, with the leading outdoor media company this week launching 'Courtenay Place,' a landmark digital billboard in the heart of Wellington.
Located at the iconic intersection of Taranaki Street and Courtenay Place, this large-scale digital billboard captures both pedestrian and vehicle traffic travelling throughout Wellington's business precinct.
The launch of 'Courtenay Place' further cements QMS NZ's coverage of this key metropolitan market with the company last year unveiling 'The Quay,' also situated centrally in Wellington city.
We are committed to providing our clients with more flexible and immediate dynamic advertising opportunities as we expand our digital portfolio throughout the nation's Capital.
Inaugural advertisers on 'Courtenay Place' include Prime Television, ASB, Trade Me, Coca Cola and Sofitel.


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A new type of immersive exhibition
Picasso presented in "Image Totale"
La Sucrière: an exceptional venue
Educational space
Annabelle Mauger
Julien Baron
Rudy Ricciotti
Androula Michael
Imagine Van Gogh
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Winner of the Grand Prix National d'Architecture, and recipient of a Gold Medal from the Fondation de l'Académie d'Architecture, Rudy Ricciotti is one of the greatest contemporary architects who designed the MUCEM in Marseille and the Islamic Arts department at the Louvre in Paris. Imagine Picasso is the third project he has undertaken in collaboration with Annabelle Mauger and this is no coincidence. Ricciotti boldly combines the brutality of the structures with the sensuality of the material better than anyone else. It was in this spirit that he previously designed the Cathédrale d'Images Saint-Priest project, in collaboration with Annabelle Mauger, and the renovation of the Chaufferie de l'Antiquaille a few years later.
THE SCENOGRAPHIC PROJECT
The staging of the Imagine Picasso exhibition sprang from the story of a decade-long friendship with Annabelle Mauger and Cathédrale d'Images. I'm an architect, not a scenographer. If I had been guided by logic I should have declined this proposal, but a whiff of adventure on an avant-garde path made me throw caution to the wind.
The Imagine Picasso exhibition is not just another commercial regurgitation of a selected accumulation of Picasso's works. We've been there before: the repeated exhibitions of the master's work have become a commercial product, stamped with the seal of commissioners and insurers… little more than a money-making scheme.
This essential exhibition, conceived by Annabelle Mauger and Julien Baron, does not show a single original Picasso piece. What it does do is demystify the relationship between the work and its price, showing Picasso's works as a chain of successive experiments rather than just a few links. This is the greatest virtue of an exhibition which showcases the work of a man who has carried out more than 60,000 "experiments": it shows the sequences, the joints, the jumps, the circular movements of thought. In other words, it shows the journey rather than the destination.
In Carrière des Baux-de-Provence in the 1970s Albert Plécy, a pioneer of removing pictures from their frames, invented the notion of 'image totale' and set up the Cathédrale d'Images. He fiddled with his first projectors, found new angles and cleared the caves for the first experiments with gigantic, enveloping and "sculpted" images on the blocks of rock in the belly of the Alpilles mountains. The images were projected at heights of 15 to 17 metres on a single block. The Cathédrale d'Images was constructed from limestone and clay. Then came the sting, the eviction. The Cathédrale was exiled, Annabelle became a migrant with art in tow. I myself have gypsy origins: we met and it was a good match.
The Imagine Picasso exhibition took to the road. Some places were particularly limited in height and the notion of vertical scale (inherent to Les Baux and the roots of Cathedrale d'Images) became obsolete. La Sucrière, the first exhibition venue, had a low ceiling: how could such giant artworks survive in spaces lower than 3.25 metres? The projection of the image for Imagine Picasso would no longer be vertical, the oblique appeared — here I give a nod to my late friend Claude Parent. The sloping projection and inclined supports are a key characteristic of the staging system chosen to maintain the scale of the images. It gives the show a new topography — the image is no longer projected onto the walls, nor on orthogonal planes in a horizontal/vertical direction: the image, still magnified, becomes fleeting in its perception and dynamic in its delivery. Imagine Picasso is a wide-awake wandering in a landscape that comes from a cyclopean bending. The images of Picasso's works bend, telescope and collide. The brilliant works take their meaning from this telescoping and juxtaposition: Picasso worked not in a linear way, but by going back and forth, by inter-related principles. Each "experiment" he created does not exist specifically as such but rather in relation to a general and gargantuan corpus. The scenography I created is an organic, thrilling disruption. The first thing to remember is that Picasso was an ogre, whose work is deeply driven, carnal, irrigated by sex and death. The very principle of the exhibition Imagine Picasso is perhaps, from a sensory point of view, pictorial and metaphysical, based on the notion of orgy
Grand Prix national d'architecture
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Most EHR systems can be configured to organize needed information for a particular patient or condition so that it is presented in a clear and concise way. Some templates actually integrate treatment goals or guidelines and provide highlights or reminders when the patient's parameters are out of range. For example, if you are seeing a diabetic patient whose BMI or blood pressure is high or whose LDL level is above the recommended target, you would get a prompt to modify the treatment plan. When help is needed about what test might substantiate a suspected diagnosis, the computer should be able to assist. Treatment plans and follow-up recommendations can be printed, transmitted, and tracked over time and provide reminders as needed for both patients and office staff.


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Carmelitas de Compiègne ou Mártires Carmelitas de Compiègne ou Mártires de Compiègne, ou, na sua forma portuguesa, de Compienha, são dezesseis religiosas do Carmelo de Compiègne assassinadas por revolucionários franceses do Comitê de Salvação Pública que as levaram à guilhotina por ódio à religião, no segundo período do Terror da Revolução Francesa, no dia 17 de julho de 1794, no local hoje denominado "Place de la Nation", na época "Place du Trône Renversé".

Religiosas carmelitas
Antes de serem executadas ajoelharam-se e cantaram o hino Veni Creator, após o que todas renovaram em voz alta os seus compromissos do batismo e os votos religiosos. A execução teve início com a noviça e por último foi executada a Madre Superiora Madeleine-Claudine Ledoine (Madre Teresa de Santo Agostinho) (Paris, 22 de setembro de 1752), professa em 16 ou 17 de maio de 1775. Durante as execuções reinou absoluto silêncio. Seus corpos foram sepultados num profundo poço de areia em um cemitério em Picpus. Como neste areal foram enterrados 1298 vítimas da Revolução, é pouco provável a recuperação de suas relíquias. Foram solenemente beatificadas em 27 de maio de 1906 pelo Papa São Pio X.

O Papa João Paulo I sobre elas disse: Durante o processo ouviu-se a condenação: "À morte por fanatismo". E uma, na sua simplicidade, perguntou: — "Senhor Juiz, se faz favor, que quer dizer fanatismo?". Responde o juiz: — É pertencerdes tolamente à religião". — "Oh, irmãs!" — disse então a religiosa — "ouvistes, condenam-nos pelo nosso apego à fé. Que felicidade morrer por Jesus Cristo!". Fizeram-nas sair da prisão da Conciergerie, meteram-nas na carreta fatal e elas, pelo caminho, foram cantando hinos religiosos; chegando ao palco da guilhotina, uma atrás doutra ajoelharam-se diante da Prioresa e renovaram o voto de obediência. Depois entoaram o "Veni Creator"; o canto foi-se tornando, porém, cada vez mais débil, à medida que iam caindo, uma a uma, na guilhotina, as cabeças das pobres irmãs. Ficou para o fim a Prioresa, Irmã Teresa de Santo Agostinho; e as suas últimas palavras foram estas: "O amor sempre vencerá, o amor tudo pode". Eis a palavra exacta: não é a violência que tudo pode, é o amor que tudo pode.O grupo de religiosas carmelitas lideradas por Madre Teresa de Santo Agostinho era composto por 16 mulheres:  10 freiras, 1 noviça, 3 irmãs leigas, 2 irmãs rodeiras:

Representação nas artes
 Literatura e teatro: A respeito deste fato Gertrud von le Fort, escritora e romancista alemã (1876-1971), escreveu o romance histórico "A última ao cadafalso" posteriormente adaptado para o teatro, por Georges Bernanos, sob o título de "Diálogo das Carmelitas", publicado postumamente (em 1949).

 Música: Em 1957, Francis Poulenc lançou uma ópera intitulada Dialogues des carmélites sobre este evento.

 Cinema: O texto da peça de Bernanos foi adaptado para o cinema sob o nome de Diálogo das Carmelitas.

Bibliografia
 Le Fort, Gertrud Von. A última ao cadafalso. São Paulo: Quadrante. 152 p. (Título original: Die Letzte am Schafott, 1931).
 Le Fort, Gertrud Von. A última ao cadafalso. Salvador, Ed. Mensageiro da Fé, 1957. 114 p.
 Bernanos, Georges. Diálogos das carmelitas (segundo a novela de Gertrud von Le Fort e o cenário de R. P. Bruckberger e de Philippe Agostini). Rio de Janeiro: Agir, 1960. 144 p. Tradução de Marna Telles de Menezes Rochas.
 Bernanos, Georges. Dialogues des carmélites. Neuchatel: Ed. de la Baconnière, 1949. 236 p.

Ligações externas

Beatos da França
Beatos carmelitas
Mártires católicos
Pessoas guilhotinadas durante a Revolução Francesa
Compiègne

redpajama_set_name: RedPajamaWikipedia


Enchantment Chamber Music, with violinist Ellen Chávez de Leitner, and guitarists Lynn McGrath and Genevieve Leitner, will present a concert of music meant for light-hearted enjoyment, as traditionally celebrated in Europe with social balls and parties before the forty days of Lenten fasting and penance observed by the Church. Included in the concert are New Mexican and Venezuelan waltzes, Austrian ländlers, Brazilian modhinas, New Mexican polkas, and tangos by Piazzola.
February 1st, 2019, 5:30 PM: Ellen Chavez de Leitner, violin, performs with Claire Detels, piano, for the TGIF concert at First Presbyterian Church in Santa Fe, NM. On the program is Franz Schubert's Sonata Op. 162/D.574, and the Adagio from Sonata No. 3, Op. 108 by Johannes Brahms. Claire will also play African-American composer Florence Price's award-winning Sonata in E Minor, movement 2.
Come join us for beautiful music and good company!
Bring wine, cheese, or whatever you would like to share!
ELLEN CHÁVEZ DE LEITNER, violin, GENEVIEVE LEITNER, guitar, AND CECILIA LEITNER, voice, will perform music of Villa-Lobos, Paganini, Atahualpa Yupanqui, Astor Piazzolla, and more at the lovely new Sunflower Theatre in beautiful Cortez, Colorado.
Advance tickets are no longer available for tonight's concert. Please bring cash to pay at the door. Thank you!
8:00 PM October 29, 2016 San Miguel Chapel, Santa Fe, NM 401 Old Santa Fe Trail, Santa Fe, NM 87501 Chapel Series Concert: Duo Guadalupe Plays Music for Violin and Guitar Come and enjoy music by Bach, Piazzola, Paganini and Barrios, in the oldest church in the USA! We're so happy to be playing as a duo again, and hope you enjoy some of our favorites. Tickets are $20 at the door.
Genevieve, Carlos and I plan to perform again, and I hope often.
March 5, 2016 at 3:00PM: Music for violin and guitar, with Ellen Chavez de Leitner, Carlos Perez and Genevieve Leitner, playing solos and duos. To reserve your seats click on BUY at the top of this page. Be sure to select the amount of tickets you want from the drop down button, then the yellow "Buy now" button.
The "Schubertiade" , a benefit house concert for the Taos Community Chorus on Sunday was a great success! Claire Detels invited me to play the Variations on "La ci darem la mano" by Beethoven, for trio (two violins and viola), and there were lots of singers and pianists who also played music of Schubert and other composers of his era. Great fun! Such an appreciative audience too! The house was packed, and I knew it would be, which is why I didn't help out with the promotion. I will, however, be sure to tell you about my next house concert soon!
Come hear Marin Marais' Sonnerie de Ste. Genevieve, "The Soft, Complaining Flute" from Haydn's Mass for St. Cecilia, Richard Strauss' "Allerseelen" (All Souls), and more beautiful music in honor of All Saints and All Souls Days!
Come see the "retablos", or paintings of the saints, by Ellen Chavez de Leitner, Cecilia, Genevieve, and Rose Leitner!
Come buy CD's, retablos, and other items as gifts or something for yourself!
Enchantment Chamber Music presents music and art to commemorate All Saints Day and All Souls Day (also known as Day of the Dead). The concert will include music for the occasion (a couple of weeks early) from Medieval and Baroque to comtemporary, for violin, cello, harpsichord, piano, voice, and flute. Includes Chant from Liber Usualis, music of H.I.F. Biber, Nicola Matteis, Marin Marais, J.S. Bach, J. Albrechtsberger, F. Schubert, R. Strauss and Rev. Fr. J.M. Blanch. Northern New Mexico style santos painted by violinist/artist Ellen Chávez de Leitner and her daughters Genevieve, Cecilia, and Rose will adorn the IHM Chapel, and some will be also available for purchase.
Carlos Perez, virtuoso guitarist, will join the Leitner Trio with music of Antonio Lauro, Fernando Sor, Heitor Villa-Lobos, Marcelo Coronel, Astor Piazzola, Nicolo Paganini, and traditional Chilean songs arranged by Carlos Perez.
You can now make reservations to the Concert on July 14 and buy your tickets using PayPal. (Click on BUY.) Tickets will be held at "Will Call" at the door unless mailing is requested.
Carlos Perez will join The Leitner Trio for another delightful concert at the Immaculate Heart of Mary Chapel.
On the program are Classical, Spanish, and Latin American selections.
Click on BUY to order.
For more information about Carlos Perez and Genevieve, click on "Links".
Competitive rates on private lessons!
Do you want to improve your technique? Need help with a new piece? Or start as a beginner?
Plans are in the making for another concert in July featuring the Leitner family and Carlos Perez.
The Leitner Trio concert was a great success. We had a large, appreciative audience which gave us a standing ovation! Genevieve's guitar solos were amazing. Cecilia's singing was so beautiful that half the audience was crying. All the music was fun and enjoyable, for the audience and us too!
Don't forget to sign our guestbook, and get on the email list to be informed of future concerts.
Genevieve Leitner, guitar, Cecilia Leitner, soprano and Ellen Leitner, violin will present music of J.S. Bach, Joaquin Rodrigo for guitar, solo violin by Georg Philip Telemann, a guitar and violin duo by Fernando Carulli, and traditional Christmas carols from Spain and Latin America.
Tickets available through Ellen until Dec. 3, 2011 or at the door by check or cash.
For more information please contact Ellen Leitner by email or phone at ellenleitner@gmail.com or 505-920-9728. Tickets available through Ellen until Dec. 3, 2011 or at the door by check or cash.


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Fading in the Land of the rising Sun. 5 top players who finish playing in Japan
27/08/2021 1,226 Views
Iniesta Urges Barca To Focus Before Facing Real Madrid
USA Vs Japan 5–2 Video Highlights Women's World Cup Final
Sergi SAMPER
Thomas VERMAELEN
Bojan KRKIC
According to the responses of authoritative observers and experts, the first division of the Japanese J‑league is not such an exotic football championship in terms of the quality of the game, as, for example, the championships of the United Arab Emirates, Saudi Arabia or China. However, it is no secret that good football players move to the Land of the Rising Sun mainly at the end of their career and because of good economic support in the form of wages. Plus, life in Japan itself is a much more acceptable phenomenon for a European or a person who has spent a lot of time on the Old Continent than the countries already mentioned above, where there is much more local colour and differences from Western civilization.
However, the departure to the J‑League for almost anyone, even the once most famous football player, is the beginning of the end in terms of media popularity in Europe. Why this is so, we will follow the examples of five serious-level football players who went to Japan, and many of our readers probably had time to forget about them.
Citizenship: Spain
Club: Vissel Kobe
26-year-old Spanish central midfielder Sergi Samper is the only relatively young player on our list, about whom, perhaps, it is too early to say that he went to Japan to finish playing. But, on the other hand, Samper has been staying at Vissel Kobe for two and a half years, and in general, he is almost satisfied with everything at the club and the country, which is why the parties may soon extend the contract, the validity of which is calculated until the end of January 2022.
Sergi Samper was never able to become a real star of European football, although he was given phenomenal advances at a young age. He was called the second Xavi, and Barcelona expected that the midfielder would reach a similar level of play. However, at some stage of his career, things did not go well for Samper. He began to be bothered by injuries, returning after which Sergi could not mentally reconfigure himself and begin to demonstrate a high level on the field. As a result, in March 2019, after playing only 13 matches for the first team of Blaugranas, Sergi Samper terminated his contract with Barcelona and soon moved to Vissel Kobe as a free agent.
In Japan, Samper has already played 84 matches for Vissel Kobe, in which he scored one goal and gave seven assists. He managed to win the Cup and the Super Cup of the country, and in general, is in good standing. However, remaining in the J‑League, Samper is practically deprived of the chances of being called up to the Spanish national team. However, Sergi still has several years of his career ahead – in fact, its peak, and soon we will see where the midfielder decides to play his best years.
Citizenship: Belgium
Thomas Vermaelen disappeared from the radar of European fans in the summer of 2019, when he moved from Barcelona to Vissel Kobe as a free agent. However, this summer, Vermaelen again found himself in the spotlight when he took part in the final part of Euro 2020 as part of the Belgian national team, having played five matches at the tournament, three of which were in the starting line-up.
In Japan, Vermaelen is holding its third season. He is a critical football player of the foundation of Vissel Kobe, but this does not help Thomas to often find himself in the focus of attention of the European football media. Nevertheless, like Sergi Samper, Vermaelen managed to win two trophies in the Japanese team-the Cup and the Super Cup of the country, and in total, he played 45 matches for Vissel Kobe, in which he scored one goal and one assist.
Vissel Kobe may become the last club in Vermaelen's career. The Belgian's contract with the Japanese expires on January 31, 2022. So far, there is a high probability that the parties will agree on its extension for another season, and then Thomas will finish his career. What is true, in recent weeks, other information has appeared in the media on this score – that North American MLS clubs are interested in Vermaelen's services, where they wanted to drag the Belgian back in the summer of 2019. Still, then he chose the Land of the Rising Sun.
Another incredibly talented pupil of the Barcelona academy was predicted to have a crazy future but never managed to justify even half of his advances. Bojan Krkic played for the first team of "Blaugranas" from 2007 to 2011, having managed to play 163 matches, in which he scored 41 goals and gave 19 assists. Subsequently, Barcelona sold the delayed striker to Roma but soon repurchased him, although it is unclear why. Finally, after a series of leases at Ajax and Stoke City, the Catalans permanently released Krkic to the Potters ' camp for 1.8 million euros.
In the summer of 2019, Boyan left the English club, signing as a free agent a contract with the Canadian club "Montreal Impact", playing in the MLS. Krkich spent a year and a half there, and at the beginning of 2021, he received another"free". Thus, for more than six months, the once very talented striker remained without a club. Still, on August 9, the Japanese "Vissel Kobe", where they love to bet on age-related and well-known representatives of world football (in particular, European), announced the signing of Krkic.
Bojan's contract with Vissel Kobe is calculated until January 31, 2023. So far, the Spaniard with Serbian roots has not even made his debut in the J‑League, and therefore it is too premature to talk about how much he will be able to restart his career in the Land of the Rising Sun. Although in Europe, Krkich has probably already been wholly forgotten, given his one-and-a-half-year adventure in Montreal Impact and a six-month search for a new job.
Citizenship: Brazil
Club: Kawasaki Frontale
Once upon a time, this Brazilian forward was hunted by almost all the giants of European football and those clubs that are well oriented in the South American market – in particular, Porto and Shakhtar. However, the management of Internacional managed to convince Damiao to sign a new contract, which may have somewhat undermined the player's motivation for more rapid progress. As a result, having previously refused offers of 30–40 million euros, Internacional sold Leandro Damiao to Santos in January 2014 for 13 million euros, but this deal was disastrous for Pisces.
In Santos, Damiao failed (only six goals scored in 26 matches), as well as with a similar "success", he later played on loan for Cruzeiro, Betis and Flamengo. More or less, it was possible to find the former Damiao only during the loan period in his native Internacional in 2017–2018, but Leandro did not want to stay in Brazil. Thus, at the beginning of 2019, when the striker's contract with Santos expired, he left the club as a free agent and soon signed an agreement with the Japanese club Kawasaki Frontale, where he plays to this day.
In Japan, Damiao managed to become the leading player in his team. He demonstrates exemplary performance and generally receives good feedback about his game. This season, in 23 matches, the Brazilian has already recorded 13 goals scored and eight assists. As a result, Kawasaki Frontale is confidently leading in the standings and is close to defending the championship title won a year earlier.
The 2010 world champion and two-time European champion Andres Iniesta does not need any other introduction. This football player, with energetic performances, became an absolute legend of Barcelona. Therefore, when in the summer of 2018 it became known about his departure from the capital of Catalonia, many fans of Blaugranas did not hide their tears.
Whatever it was, Iniesta has not yet finished his career and pleases fans of Japanese football with his subtle understanding of football, transparent and timely passes, and almost logarithmic thinking on the field. It seems that nothing is impossible for Iniesta in football and Vissel Kobe appreciates this very much. In May of this year, the Japanese club took care of the extension of the contract with Andres, which was valid from the summer of 2018. Iniesta's current employment agreement with Vissel Kobe is calculated until January 31, 2024. At that time, the Spanish maestro will be almost 40 years old.
It should be noted that despite the presence of many well-known players in Europe, Vissel Kobe can not please Iniesta with the "gold" of the Japanese championship in any way. So this season, Andres ' team is still only the fifth and has lost real chances to compete for the tournament, as it lags behind Kawasaki Frontale by 21 points. Well, there will still be new draws ahead, and perhaps Iniesta will still get the title of champion of Japan.
Tags Andres Iniesta Bojan KRKIC J-league Japan Leandro DAMIAO Sergi SAMPER Thomas VERMAELEN
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text:
The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity
Marina Modrić1 ; Marin Božičević2; Ilijana Odak3; Stanislava Talić3; Danijela Barić4 ; Milena Mlakić5 ; Anamarija Raspudić3; Irena Škorić5
1 Chemistry, Fidelta Ltd., Prilaz baruna Filipovića 29, HR-10 000 Zagreb, Croatia
2 Department of Polymer Engineering and Organic Chemical Technology, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000 Zagreb, Croatia
3 Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice hrvatske bb, 88 000 Mostar, Bosnia and Herzegovina
4 Group for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia
5 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000 Zagreb, Croatia
Comptes Rendus. Chimie, Volume 25 (2022), pp. 267-279.
In our previous research, some screened 1,3-thiazole fragments were found to be potent by inhibiting LPS-induced TNFα and IL-8 release with IC50 values in the μM range without cytotoxic activity. In the current study, 1,3-thiazole fragments were further investigated as potent cholinesterase inhibitors prompted by the previously documented anti-inflammatory effect of AChE inhibitors. Molecular docking enabled insight into stabilizing interactions between the selected thiazoles and the active site of AChE and BChE. According to these experimental results, the cholinesterase inhibitory and anti-inflammatory activity of 1,3-thiazoles were correlated and confirmed that the same compounds inhibited LPS-stimulated TNFα cytokine production in PBMCs and enzymes cholinesterases.
Supplementary Materials:
Supplementary material for this article is supplied as a separate file:
crchim-201-suppl.pdf
Received: 2022-04-08
Revised: 2022-06-10
Accepted: 2022-06-15
DOI: 10.5802/crchim.201
Keywords: Cholinesterases inhibitory activity, Library design, Small chemical fragments, 1,3-Thiazole, Molecular docking, Density functional theory
Author's affiliations:
Marina Modrić 1; Marin Božičević 2; Ilijana Odak 3; Stanislava Talić 3; Danijela Barić 4; Milena Mlakić 5; Anamarija Raspudić 3; Irena Škorić 5
License: CC-BY 4.0
Copyrights: The authors retain unrestricted copyrights and publishing rights
@article{CRCHIM_2022__25_G1_267_0,
author = {Marina Modri\'c and Marin Bo\v{z}i\v{c}evi\'c and Ilijana Odak and Stanislava Tali\'c and Danijela Bari\'c and Milena Mlaki\'c and Anamarija Raspudi\'c and Irena \v{S}kori\'c},
title = {The structure{\textendash}activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity},
journal = {Comptes Rendus. Chimie},
publisher = {Acad\'emie des sciences, Paris},
doi = {10.5802/crchim.201},
AU  - Marina Modrić
AU  - Marin Božičević
AU  - Ilijana Odak
AU  - Stanislava Talić
AU  - Danijela Barić
AU  - Milena Mlakić
AU  - Anamarija Raspudić
AU  - Irena Škorić
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%A Marina Modrić
%A Marin Božičević
%A Ilijana Odak
%A Stanislava Talić
%A Danijela Barić
%A Milena Mlakić
%A Anamarija Raspudić
%A Irena Škorić
%T The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity
%J Comptes Rendus. Chimie
%I Académie des sciences, Paris
%U https://doi.org/10.5802/crchim.201
%R 10.5802/crchim.201
%F CRCHIM_2022__25_G1_267_0
Marina Modrić; Marin Božičević; Ilijana Odak; Stanislava Talić; Danijela Barić; Milena Mlakić; Anamarija Raspudić; Irena Škorić. The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity. Comptes Rendus. Chimie, Volume 25 (2022), pp. 267-279. doi : 10.5802/crchim.201. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.5802/crchim.201/
The great interest in heterocyclic core thiazole in the research of new drugs stems from the fact that there are already a variety of drugs with a thiazole ring, such as antibacterial drugs, antihistamines, vitamin B1 (thiamine), antifungal drugs, gout drugs, and drugs for the inhibition of cholinesterases [1, 2, 3]. Acotiamide (Figure 1, structure I) [4, 5, 6, 7], the drug used to treat functional dyspepsia, acts as a selective acetylcholinesterase inhibitor and is a 1,3-thiazole derivative that has stimulated the development of biologically active compounds with a thiazole nucleus with the aim of inhibiting cholinesterases. From the structure of Acotiamide (I), it can be seen that at position 2 on the thiazole, there is an amide group which was the basis for the synthesis of new compounds in this paper, which are translated into amides, amines, and imines. The need for new drugs that could be used to inhibit cholinesterases in patients with Alzheimer's disease is high due to the various side effects of currently available drugs and the fact that as the disease progresses, more cells fail and less acetylcholine is available; hence the effectiveness of available inhibitors decreases over time. Among the active compounds containing a thiazole nucleus are also the 1,3-thiazolylimine (Figure 1, structure II) [6], 1,3-thiazolylhydrazones (Figure 1, structure III) [4], and the 1,3-thiazole-piperazine derivatives (Figure 1, structure IV) [7].
Examples of thiazole-bearing cholinesterase inhibitors.
Some of the mentioned compounds show promising activity and selectivity to acetylcholinesterase, while a small number of them showed some binding and inhibition of butyrylcholinesterase. Thus, 1,3-thiazolylhydrazones (Figure 1, structure III) show very selective activity against acetylcholinesterase, but only two of them show any activity against butyrylcholinesterase. As it is known, acetylcholinesterase has much higher catalytic activity towards the hydrolysis of acetylcholCine and is present in much larger quantities than butyrylcholinesterase, which is why the results of such compounds are promising. Hydroxynaphthalenyl thiazole II (Figure 1) achieves powerful inhibition of acetylcholinesterase (IC50 1.78 ± 0.11 μM), and also, it can inhibit butyrylcholinesterase in a certain extent (IC50 11.9 ± 0.43 μM) [6]. Thiazolylhydrazones III (Figure 1) showed significant acetylcholinesterase inhibition but slight inhibition of butyrylcholinesterase [4]. The best inhibition of acetylcholinesterase was achieved with the following substituents at positions R1 and R2: R1, R2 = H, IC50 0.0496 ± 0.002 μM; R1 = H, R2 = OCH3, IC50 0.0317 ± 0.001 μM and R1 = H, R2 = CF3, IC50 = 0.2158 ± 0.010 μM. As a reference, Donepezil was used as an acetylcholinesterase inhibitor (IC50 = 0.0287 ± 0.005 μM) [4]. The results on thiazolylhydrazones III showed that the structure with the methoxy substituent (R2) at the para-position is the best acetylcholinesterase inhibitor with the inhibitory activity very close to the values of donepezil.
In order to ensure the diversity of new possible acetylcholinesterase inhibitors, the approaches of different papers are based on different types of molecules and include the introduction of different substituents to the thiazole scaffold. Thus, some 1,3-thiazole-piperazine derivatives (Figure 1, structure IV) [7] proved to be very effective acetylcholinesterase inhibitors almost without any butyrylcholinesterase inhibition activity (R = 2-pyridyl, IC50 0.051 ± 0.002 μM; R = benzyl, IC50 0.011 ± 0.001 μM; R = 2-furoyl, IC50 0.27 ± 0.001 μM). Donepezil was used again as a standard (IC50 0.054 ± 0.002 μM) [7]. Those results showed that inhibition by 2-pyridyl and benzyl derivatives was even better than by donepezil, which gives them great importance in further development and research.
In our previous study concerning the newly synthesized 1,3-thiazoles 1–17 (Figure 2) and their anti-inflammatory characteristics [8], amide 7 with quinoxaline system showed the best activity. Additionally, some other screened compounds were found to be potent in the series by inhibiting LPS-induced TNFα and IL-8 release with IC50 values in the μM range. Amide 2 with para-methoxyphenyl substituent was also beneficial for TNFα inhibition. On the other hand, amide 3, which was inactive, by methylating gave amide 17 with higher activity toward the inhibition of TNFα. Benzyl amine analogues 11–14, with variously substituted benzyl units, were also active, indicating the importance of rotatable bonds for activity. What is very important is that the evaluation of compounds 1–17 by screening in vitro cell viability assays did not show a cytotoxic effect [8].
Investigated thiazole derivatives 1–17.
In the current study series of 1,3-thiazole fragments 1–17 (Figure 2) were further investigated as potent cholinesterase inhibitors prompted by the results on anti-inflammatory activity without cytotoxic activity. Some of these compounds (Figure 2), as well as those from the literature (Figure 1), especially with secondary amines as linkers might be cations at physiological pH. While performing in vitro assays we haven't observed issues with solubility at the measured concentrations. Our aim in this fragments library design was to follow rule of 3, considering the MW, clogP, number of hydrogen donors and acceptors including rotatable bonds. Obtained results are just preliminary data that can lead to conclusions of developing of existing compounds to drug-like compounds. The anti-inflammatory effect of AChE inhibitors was documented previously [9, 10, 11, 12]; it appears that this neuro-immunomodulation comes as the result of the protection of ACh from being split by the AChE enzyme, enhancing the cholinergic pathway. According to the experimental results in this research, the cholinesterase inhibitory and anti-inflammatory activity of 1,3-thiazoles 1–17 will be correlated to see if the same compounds inhibited LPS-stimulated TNFα cytokine production in PBMCs and enzymes cholinesterases. Molecular docking is employed to visualize the possible conformations of thiazoles as cholinesterases inhibitors and to obtain insight into the stabilizing interactions present within the docked active site of AChE and BChE.
2.1. Chemistry
Thiazole derivatives 1–17 (Figure 2) synthesized earlier have been investigated for cholinesterase inhibitory activity due to their evidenced potential as anti-inflammatory agents [8].
Breafly, the amides 1–10 were synthesized from 2-aminothiazole and various carboxylic acids (Figure 2) activated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexa-fluorophosphate (HATU), along with diisopropylethylamine (DIPEA). All amines 11–14 (Figure 2) were synthesized by a reductive amination reaction starting from 2-amino thiazole [13]. Reductive amination was carried out at 80 °C on a stirrer with a heating element overnight. Reductive amination is a reaction in two steps; in the first step, imines are formed, also isolated and characterized in the previous study of the anti-inflammatory activity of 1,3-thiazoles 1–17. The corresponding amines 11–14 were obtained with NaBH4 as a reducing agent. To assess the influence of the NH group as an H-bond donor on cholinesterase inhibitory activity, amide 2 and amine 14 are N-methylated and gave amide 15 and amine 17, respectively. For this purpose, iodomethane with NaH was used as the base.
2.2. Cholinesterase inhibitory activity
Structures of tested 1,3-thiazole derivatives 1–17 (Figure 2) can be grouped into four different sets of compounds. Compounds 1–10 are amides with various substituents at acyl part. The second set of tested 1,3-thiazoles were four amines 11–14, reduced analogs of amides with the same substituent. One amide (2) and two amines (13, 14) were methylated in order to examine the influence of the –NH group on biological activity, as mentioned above.
Presented compounds were screened for acetylcholinesterase and butyrylcholinesterase inhibition activity (for details see Section 3.2). The results are given in Table 1 and reported as maximal inhibition of AChE and BChE at the maximal concentration tested and, where achieved, the IC50 value was calculated. Final concentrations of compounds in tested solutions are expressed in μM values. Maximal tested concentrations were not the same for all compounds due to the problems with solubility in the applied system. Compounds were tested in a wide range of concentrations and adjusted to the solubility of the individual compound.
Inhibition of AChE and BChE by 1,3-thiazoles 1–17 and calculated IC50 values
AChE IC50 (μM)
AChE % Inhibition∗
BChE IC50 (μM)
BChE % Inhibition∗
1 — 31.8 ± 3.6 (500) — 39.1 ± 3.6 (500)
3 621 56.7 ± 3.8 (800) — 45.2 ± 3.9 (1000)
4 — 47.4 ± 1.2 (1000) — 53.1 ± 3.7 (1000)
5 — 35.0 ± 3.1 (1000) 304 71.5 ± 3.0 (1000)
7 91 56.3 ± 2.1 (100) — 19.5 ± 4.1 (100)
8 765 54.8 ± 1.1 (1000) — 26.1 ± 2.1 (1000)
9 502 57.4 ± 4.4 (1000) — 47.0 ± 4.1 (800)
10 — 18.9 ± 6.9 (1000) — 33.7 ± 2.1 (1000)
12 — 36.4 ± 1.3 (800) — 49.5 ± 1.3 (800)
14 — 39.8 ± 2.7 (500) 385 66.1 ± 2.9 (800)
∗Numbers given in parentheses represent maximal concentrations tested in μM.
Among the 17 tested 1,3-thiazoles, all the compounds showed some inhibitory activity on both enzymes. IC50 values were calculated for compounds 3, 7, 8, and 9 for the AChE (Figure 3) and 5, 6, 14, 15 for the BChE (Figure 4). Compound 7 showed the most potent inhibition of AChE with an IC50 value of 91 μM and three times more selective toward AChE over BChE (Table 1). The lead inhibitor for BChE is compound 6 with an IC50 value of 195 μM.
Dose-inhibition curves for inhibition of AChE by compounds 3, 7, 8 and 9. Data are mean ±stdev (n = 3).
Dose-inhibition curves for inhibition of BChE by compounds 5, 6, 14, and 15. Data are mean ± stdev (n = 3).
Each of amides 1–10 has a different substituent; among them, four derivatives achieved IC50 for enzyme AChE. Of these four, derivatives 7, 8, and 9 possess N-heterocyclic substituent at acyl part, while compound 3 bears electron-withdrawing group o-trifluoromethylbenzene. The most potent inhibitor of AChE is compound 7, containing a quinoxaline system. The strongest inhibitors of BChE among amides were 5 with 4,4-difluorocyclohexane and 6 with phenyl substituent. Although these compounds differ only in the substituent on the acyl moiety, this structural difference cannot be easily related to IC50 values. Furthermore, all active amides are selective inhibitors with the inhibition preference only for one enzyme. Among the four tested amines, only 14 with o-trifluoromethylbenzene as a substituent showed selective inhibition against BChE.
Comparison of analogously substituted amides and amines leads to the conclusion that there are no significant differences except for phenyl substituted compound 6 and benzyl substituted 11, with amide 6 showing a more positive effect on BChE inhibition.
Four 1,3-thiazole derivatives contain 4-metoxybenzene substituents: amide 2, amine 13, and their N-methylated counterparts amide 15 and amine 16. In this series, the only compound that showed inhibitory activity is amide 15 (only against BChE). It seems that the possibility of hydrogen bonding due to the presence of –NH group (as in amide 2) does not play a role in the inhibitory activity toward BChE. However, in the case of amines, N-methylation had the opposite effect: compound 14 was active against BChE, while in its methylated counterpart 17, the activity was drastically reduced [8].
2.3. Molecular docking studies
To obtain insight into the structures of the complex between the active site of cholinesterases and selected thiazole derivatives, we used molecular docking. According to experimental results shown in Table 1, among all tested thiazoles, molecule 7 (containing quinoxaline) stands out as the best potential inhibitor of acetylcholinesterase, with the lowest IC50 value. Weaker but still promising inhibitory potential toward AChE is observed for compounds 9, 3, and 8. Therefore, we performed docking of molecules 3, 7, 8, and 9 into the empty active site of AChE (coordinates taken from PDB structure 2ACE [14]) using the Autodock program suite [15]. The number of requested genetic algorithm dockings was 10, resulting in ten different conformations of the thiazole within the active site. According to the roughly estimated energies obtained by docking, molecule 7 again shows better inhibitory potential than other tested thiazoles, with the lowest value of estimated free binding energy and inhibition constant (Table 2). The other three thiazoles have mutually comparable values of estimated free energies of binding and Ki, as already found by the experiment.
Results of molecular docking of selected thiazoles into the active site of AChE
Estimated free energies of binding (lowest/highest)
Estimated inhibition constants, Ki (lowest/highest)
Number of distinctive conformational clusters
Distribution of conformations within clusters
3 −4.93 −4.79 242 308 5 5, 2, 1, 1, 1
7 −5.52 −5.47 90 97 1 10
8 −4.42 −4.32 572 680 3 5, 3, 2
9 −4.24 −4.05 782 1040 2 8, 2
Free energies of binding given in kcal⋅mol−1, inhibition constants in μM.
More importantly, compound 7 takes ten mutually similar poses; all conformations belong to the same conformational cluster with quinoxaline "anchored" to the acyl pocket, where it is stabilized by residues Phe288 and Phe290. The remaining investigated molecules show more variety in taking poses within the active site. Again, the range of estimated values of binding free energy and Ki is the smallest for compound 7. To scrutinize the results suggested by molecular docking, we performed additional geometry optimizations of the active site docked with selected thiazoles, utilizing a quantum mechanical cluster-continuum approach [16]. We used the procedure we applied earlier to test potential AChE and BChE inhibitors [17]. For each investigated system, the structure with the lowest estimated free energy and Ki was chosen and prepared for QM optimization. During the optimization, the α-carbon atoms of residues in the active site were held fixed, enabling the active site's architecture in the enzyme to be preserved [16] (details in Supporting Information). The Gaussian 16 program package was used [18], and structures were optimized at the CPCM/B3LYP/6-31G(d) level of theory, with the dielectric constant 𝜀 = 4. The estimate of the relative thermodynamical stability of investigated systems was assessed by calculating the final energy at CPCM/B3LYP+D3/6-311+G(2df,p)//CPCM/B3LYP/6-31G(d) model, where D3 stands for empirical dispersion correction (the Grimme's D3 atom pairwise dispersion correction [19]). The optimized structure of the complex [7-AS] formed between molecule 7 and the active site of AChE is presented in Figure 5. It is visible that the quinoxaline moiety strongly interacts with aromatic residues in the active site: the π–π stacking is observed with Phe288, Phe290, Tyr121, Phe330, and His440. Each of these five residues is placed in proximity of quinoxaline, within a distance from 3.9 to 4.8 Å. Additional stabilizing interaction is the hydrogen bond between the H-donating –NH group of the 7 and the oxygen of Tyr121. The length of this hydrogen bond in the optimized structure of [7-AS] is 2.19 Å, as shown in Figure 5.
Optimized structure of the complex between the active site of AChE and molecule 7, [7-AS] Hydrogen atoms of residues are not shown for clarity.
The steric placement of compound 7 enables additional favorable stacking between the thiazole part of the molecule and remaining aromatic residues: Tyr334, Tyr70, Trp84, and Trp 279. All these amino acids are placed within the ∼4 Å from the thiazole moiety of 7. These interactions are responsible for the relative thermodynamic stability of the complex: the calculated enthalpy for the formation of the complex is −23.0 kcal⋅mol−1. (This value represents the enthalpy of the complex formation reaction: Molecule 7 + Active site → [7-AS], see Supporting Information for details.)
It must be mentioned that the experimental measurements were performed using the AChE isolated from an electric eel (EeAChE), while the crystal structure of AChE isolated from Torpedo californica (TcAChE) was used for modeling. To verify findings made by molecular docking into TcAChE, we subsequently performed docking of compounds of interest into the active site of AChE from electric eel, using coordinates taken from PDB structure 1EEA [20]. The complex obtained by docking compound 7 into the active site of EeAChE was again more stable than the one docked with 3, with estimated free energies of binding for the most stable conformation of −5.24 and −4.86 kcal⋅mol−1 for 7 and 3, respectively (with the TcAChE, the values were −5.52 and −4.93 kcal⋅mol−1, as shown in Table 2). The structures of active sites of TcAChE and EeAChE docked with 7 are shown in Figure 6, and active sites docked with 3 are presented in Figure 7.
The active site of AChE isolated from Torpedo californica (coordinates taken from 2ACE.pdb) docked with molecule 7 (left), and the active site of AChE isolated from electric eel (coordinates from 1EEA.pdb) docked with the same molecule (right). The starting structure for DFT geometry optimization was taken from the complex obtained with TcAChE.
It turns out that the geometries of TcAChE and eeAChE docked with molecules 7 and 3, respectively, are very similar. Therefore, we feel that using the active site assessed from TcAChE docked with 7 and 3 as the starting geometries for more computationally demanding DFT geometry refinements did not affect the final results.
The optimized structure of the complex [3-AS], formed between molecule 3 and the active site of AChE, shown in Figure 8, is obtained starting from the most stable pose given by the docking. Unlike the positioning of the 7, the thiazole moiety of 3 is oriented toward His440.
Optimized structure of the complex between the active site of AChE and molecule 3, [3-AS] Hydrogen atoms of residues are omitted for clarity.
According to the experimental data (Table 1) and results assessed by molecular docking (Table 2), compound 3 has weaker inhibitory potential toward the AChE than the 7. The computationally assessed enthalpy of complex formation for molecule 3 is −10.8 kcal⋅mol−1, indicating that the [3-AS] is less stable than the complex with quinoxaline compound 7. It should be emphasized that these relative thermodynamic stabilities obtained by QM refinement are not an exact quantitative indicator of inhibitory potential; their primary purpose is to examine the reliability of results assessed by molecular docking. The stabilizing interactions in [3-AS] include stacking between the thiazole part of the molecule with residues Phe288, Phe290, His440, Phe330, and Tyr121, all of them being situated within 5 Å from the thiazole. The trifluoromethylphenyl interacts with Trp279, Tyr70, and Tyr334. As in other structures of the active site of AChE docked with amides, the H-bond between the hydrogen of –NH of amide 3 and the oxygen in Tyr121 is present in [3-AS] (Figure 8).
The experimental testing of the ability of thiazole derivatives to inhibit butyrylcholinesterase showed that the best candidates were compounds 5, 6, 14, and 15. The results of molecular docking of these molecules to the active site of BChE are presented in Table 3.
Results of molecular docking of selected thiazoles into the active site of BChE
5 −4.83 −4.44 286 555 2 9, 1
14 −4.17 −3.71 882 1520 4 3, 4, 2, 1
15 −4.31 −4.17 688 916 2 9, 1
The active site of AChE contains nine aromatic residues, whereas there are six in the active site of BChE. Here, we did not perform additional geometry optimization and refinement of the active site docked with the tested thiazoles. Figure 9 shows the active site of BChE docked with molecule 5; four aromatic amino acids (Trp82, Tyr128, Tyr114, and His438) surround the thiazole subunit, and the difluorocyclohexyl fragment of 5 is positioned within the acyl pocket of the active site, at a distance of 4.3 and 4.4 Å from Leu286 and Val288. The H-bond is observed between the hydrogen of the –NH group and His438.
The structure of the active site of BChE docked with molecule 5. Hydrogen atoms are omitted for clarity.
2.4. Structure–activity relationship
Obtained results of IC50 values of AChE and BChE inhibition were summarized in structure–activity relationship overview (Figure 10) together with our previous study concerning the newly synthesized 1,3-thiazoles 1–17 (Figure 2) and their anti-inflammatory activity on lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNFα) production and causing increased ACh production in human peripheral blood mononuclear cells (PBMCs).
Structure–activity relationship of most active compounds.
It is known that the cholinergic anti-inflammatory system, a part of the vagus nerve system, is a powerful tool by which the organism regulates the inflammation excess to ensure the elimination of the threat and prevent any potential tissue disruption or damage. The key player in this pathway is acetylcholine (ACh), and its actions are mainly bound to receptors α7nAChR and M1AChR [9]. The cholinergic pathway functions by releasing the ACh, which agonizes the α7nAChR receptor and causes Ca2+ influx into cells. Increased calcium levels in cells lead to activation of NFκB transcription factor and suppression of immune response. This mechanism can be interrupted by cholinesterases (ChE)—enzymes that degrade ACh to acetic acid and choline. Therefore, the inhibitors of AChE and BChE enzymes could also have anti-inflammatory effects [21, 22, 23, 24, 25, 26].
It is noteworthy to point out that out of 17 tested thiazoles, compound 7 with fused quinoxaline system (Figure 10) showed the most potent inhibition of AChE with an IC50 value of 91 μM. Selectivity over BChE (Table 1) was three times. Compound 7 also showed inhibition of LPS-induced TNFα with an IC50 value of 8 μM which demonstrates that compound 7 can modulate inflammatory response through inhibition of AChE. Replacing quinoxaline with pyridine AChE inhibition was decreased eight times, selectivity over BChE retained, and TNFα inhibition decreased four times, which led to the conclusion of importance to AChE inhibition of π–π stacking as well as pKa modifying.
By combining computational studies with biological evaluations, compound 14 showed inhibition of BChE with IC50 value of 385 μM, selectivity over AChE, and inhibition of LPS-induced TNFα with IC50 value of 10 μM that is in the range of compound 7. SAR suggests that 1,3-thiazole-2-amino linker with flexible benzyl type of coupled substituent is preferred for BChE selectivity over AChE.
These promising data on the series of small fragments provided us with a good starting point to further design and synthesize 1,3-thiazoles derivatives with computational studies as potent and selective ChE inhibitors with anti-inflammatory activity and acceptable physicochemical properties drug-like compounds.
3.1. General
The amidation test reactions and the reductive amination reactions [8] were carried out on a magnetic stirrer with a heating body, while part of the amidation reactions was carried out on a shaker with a heating body. Chromatographic separations were performed on a Biotage instrument using puriFlash silica gel-filled columns (4 g, 15 μm and 12 g, 15 μm). All products obtained were identified and characterized by ultra-high-efficiency liquid chromatography (UPLC) with mass and UV detectors and NMR. 1H NMR and 13C NMR spectra were recorded on Bruker Ultra Shield 300, Bruker Ultra Shield 400, Bruker Ultra Shield 500, and Bruker Ultra Shield 600, depending on the amount of compound and the desired spectra. Ultra-high performance liquid chromatography monitoring the range of the reaction and determining the purity of the final product was performed on a Waters Acquity Ultra Performance LC with an SQD mass spectrometer (UPLC-MS/UV).
Acetylcholinesterase (eeAChE, E.C. from electric eel), butyrylcholinesterase (BuChE, E.C. from equine serum), Tris-HCl buffer, acetylthiocholine iodide (ATChI), S-butyrylthiocholine iodide (BTChI), and galantamine hydrobromide were purchased from Sigma-Aldrich (St. Louis, MO), 5,50-dithiobis-(2-nitrobenzoic acid) (Ellman's reagent, DTNB) was purchased from Zwijndrecht (Belgium). The AChE/BChE inhibitory potentials of 1,3-thiazoles 1–17 were determined using modified Ellman's method [27]. Briefly, 180 μL Tris HCl buffer (50 mM, pH 8.0), 10 μL of AChE/BChE (final concentration 0.03 U/mL, prepared in 20 mM Tris HCl buffer, pH 7.5), and 10 μL tested solution (final concentrations, depending on solubility, in a range 20–1000 μM) were mixed and pre-incubated for 5 min at 4 °C. The reaction was then initiated with the addition of 10 μL of DTNB (final concentration 0.3 mM prepared in Tris buffer) and 10 μL of ATChI/BTChI (final concentration of 0.5 mM prepared in Tris buffer). AChE/BChE activity was measured using a 96-well microplate reader (IRE 96, SFRI Medical Diagnostics) at 405 nm for 6 min at room temperature. Non-enzymatic hydrolysis was measured as blank for control measurement without inhibitors. The non-enzymatic hydrolysis reaction with added inhibitor was used as a blank for the samples. The enzyme was replaced by an equivalent buffer amount. The experiment was run in triplicate. Percentage enzyme inhibition was calculated according to the equation: Inhibition(%) = [(AC − AT)∕AC] × 100: where AC is the activity of enzyme without test sample and AT is the activity of the enzyme with a test sample, and represented as mean values ± standard deviation. Data were used to calculate IC50 value by a nonlinear fit of compound concentration (log) values vs. response. Samples were dissolved in ethanol. The inhibitory activity of ethanol was measured, and its contribution to inhibition was subtracted.
Thiazole derivatives 1–17 were investigated in order to screen their cholinesterase inhibition activity. Some 1,3-thiazole fragments were found to be potent with IC50 values in the μM range by inhibiting AChE or BChE selectively. The connection of their cholinesterase inhibition and inhibiting LPS-induced TNFα were also detected. Concerning their anti-inflammatory activity in our previous research, amide 7 with quinoxaline system showed the best activity and without cytotoxic effect. In addition, compound 14 showed selective BChE over AChE inhibition with anti-inflammatory activity in the range of compound 7. Encouraged by promising data obtained on small fragments, a new series of 1,3-thiazole derivatives is planned to be developed in drug-like molecules with both anti-inflammatory and cholinesterase inhibition activity aiming IC50 values in the nM range with satisfactory ADME-Tox properties.
Authors have no conflict of interest to declare.
Presented synthetic work has been performed at Fidelta Ltd., Zagreb. We thank the University of Zagreb Computing Centre (SRCE) for granting computational time on the ISABELLA cluster.
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Are you ready to supercharge your social media marketing efforts, but don't know how?
Do you find the creation of valuable content that activates and inspires a thriving community elusive?
The ideas below are designed with you in mind!
Believe it or not, you don't have to spend hours per day formulating your perfect post.
Each one is ready for you to swipe and adopt into your business immediately!
Ready to connect and engage with the right people? Then complete your social media profiles, including an optimized and keyword-rich profile.
Make certain that who you are, what you do and how you can assist potential clients is prominent within your bio.
You also want to make it easy for anyone to connect with you. Include your links to your website and other social profiles.
Want to get found? Then get on Google Plus! There is a direct correlation between Google Plus engagement and your search results. This means that it isn't enough to simply join the social network. You must get involved.
Begin by seeking out business professionals within your industry and adding them to circles. Circles are similar to Facebook or Twitter lists. They will allow you to keep up with a select group of individuals based on the circle (think category) you have placed them in.
Google Plus communities are another great way to make valuable connections and share your content with a group eager to consume it. Check out the "communities" tab and search based on keywords for communities you would find interesting. Then begin to +1, comment and share other members content.
The best rule of thumb in any community is to get involved, create a conversation and interact consistently before you start marketing or pushing your agenda. Allow people to get to know and appreciate you first.
Google Plus hangouts are an excellent way to get face-to-face with those individuals you have connected with and are eager to learn more about. Similar to Skype or Facetime, hangouts are easy to use and simple to access via your Google Plus account.
Take the time to reach out and go deeper with those within your industry. I guarantee it will be time well spent!
A quick way to join the conversation and stay connected with a specific group is to add them to a list. Use Twitter lists to group together people you want to engage with on a daily basis. Then add this list to your favorite third-party management tool and review it daily.
What you will see is a quick snapshot of what each person on that list is talking about. Rather than trying to track each one down, make it easy to stay on top of what is being said. Then comment or retweet their content to begin building relationships.
Creating a custom graphic for your original content and pinning it to Pinterest is an excellent way to get your business in front of a whole new audience.
You spend time on Facebook, but have you made your mark on the social network built for business professionals?
Use LinkedIn to establish rapport with experts within your industry. Make sure to send a custom message including who you are and why you are interested in connecting. Grab this great tip from Viveka Von Rosen, Founder of Linked to Business on how to pump up your LinkedIn marketing efforts!
There are many LinkedIn groups to choose from, so it is important to be picky when identifying where to spend your time.
Do a quick search based on keyword or industry and determine which group might be a good source of leads, referrals or recruits. Then get into the conversation!
If your niche is hot, invite past clients, prospects and other industry professionals to join your Facebook Group.
Explain the benefits and why the group was created. Set expectations and ensure everyone that joins that the group is a safe space, free from any hard sales tactics. You want to be a resource, not an annoying marketer with only your best intentions in mind.
Use Instagram to support all of your marketing efforts.
Have a blog? Post an image with a call-to-action directing followers to your website, share a quote or tip from your post, or simply notify followers that you have a new post up and direct them to your blog.
Stumped when it comes to content creation? Ask people within your niche!
Creating meaningful relationships with other influencers actively creating an online presence is a great way to keep your finger on the pulse of what's hot within your niche or industry.
Though not as popular as it was before, Stumbleupon can still drive a lot of traffic to a website or blog. See one of my posts below; a good reminder to Stumble all of your new content.
Likewise, it is also a great way to find fresh content within your niche. Check out their categories and find content that is timely and relevant for your audience.
I might love technology, but I'm an old school girl in a lot of ways. A notebook is one of them.
Keep a notepad handy to quickly jot down ideas that can be turned into social media posts down the road. Want to take it one step further? Expand upon your notes and turn that single idea into a short blog post, video tip or list on Listly.
Commenting on blogs is a strategy used by many active bloggers to gain visibility, boost awareness and create strategic relationships. It also drives those interested back to your social networks, allowing for further interaction and engagement.
Begin by creating a short list of your favorite bloggers and add commenting as a weekly to-do to your calendar.
Want to create social media magic? Stay consistent! A third-party management tool like Hootsuite can help you use automation in a thoughtful and strategic way.
As you come across content you want to share, add it to Hootsuite and schedule a time to tweet or post your content throughout the day.
Commun.it, has quickly become one of my go-to social media management tools. With it, you can dig deeper into your followers and create more meaningful social media relationships. With you can keep up with what matters most to you and your business.
Use mind-mapping software to flesh out a particular topic, creating multiple posts designed with your target audience in mind.
Brainstorm ideas connected with that topic along with subtopics that can easily be turned into posts or tweets.
Using share buttons on blog posts and websites will allow visitors to easily share the information with their friends and business associates.
Make them easily accessible and simple to use!
No one can deny the power of video!
Share videos or create your own based on customer questions, blog comments or even conversations via social media. Better yet, use Google Hangouts to create your own TV show or interviews.
Did you recently present on a topic relevant to your niche? Upload that presentation to SlideShare!
Easy to use, SlideShare gives your presentation social media juice as others within your niche are actively researching your particular subject and sharing it across their social networks.
As one of Yahoo's big assets, Tumblr can be a perfect resource for inspiration.
Twitter is a powerful tool when used to research and stay on top of your name, business and competitors. Set up Twitter alerts, research keywords and identify opportunities using Twitter Advanced search.
Want to learn more? Check out Susan Gilbert's excellent post on how to put Twitter to work for you!
A social media calendar is one of the best ways to stop wasting your time and stay consistent.
The good news? Creating a social media calendar doesn't have to be hard. You can use something as basic as an excel spreadsheet or more detailed program like Divvy HQ.
Using relevant keywords for your niche and set the delivery option to feed instead of by email, then click create!
Do one for each keyword, keyword phrase, your business name and any unique phrasing that you use on your websites and blogs.
Use an RSS aggregator like Feedly to subscribe to your favorite blogs or news source. Then log in to your account and spend five minutes each day sharing articles to your social networks.
A key ingredient to social media success is sharing other people's content, not just your own. Take time to not only share others content, but tag them whenever you share.
Not only does this bring awareness to their personal brand, it is a great way to build rapport.
Support all of your marketing efforts by cross-promoting your social media networks. Post a great article on Google Plus? Share that along with your Google Plus link to Twitter.
Not everyone follows you on the same social network. Make sure they know where you are and how easy it is to engage with you across multiple channels.
When all else fails, never forget the power of a shared quote. Social media fans and followers of all kinds love a good quote.
Magic Tips for Social Media Tools and Technology – 101 fantastic social media technology tool tips from Ian Cleary that you can use to promote your business on social media.
The 50+ Best Ways to Curate and Share Your Favorite Social Media and News Content – How to quickly find and share the best content on the web.
Leave a comment on a frequented blog, great idea?
But really, great article. You always have such excellent advice!
Before reading this article my knowledge about social media optimization is very limited. But this article has provided me an immense info about to get traffic from social media. Thanks Rebeka.
Great ideas for an overall presence, Rebekah. Would you happen to know anything about using BuzzSumo?
Hello Rebekah! I was reading your article on how to generate massive exposure with G+ and am so happy I clicked over to check out this article WOW> I truly needed loved this one and I am going to implement your idea for the social media calender right now..
What a great way to keep track of what you have done as well as how to track the results. Love It Love it!! Of course there were many more tips here that I am going to implement as well..
I'm so glad I saw mention of this post in my Google+ Stream Rebekah. Having another SMM Pro recommend these 26 social media apps, tools and tactics to create SMM magic is perfect timing.
If its OK by you, I would love to include this article in my upcoming piece on how to manage your social media presence, especially since you reference many of the apps, tools and tactics I use in my SMM efforts. Like you, I'm a huge fan of Commun.it and Feedly is one of my best sources for finding awesome content like this article.
The only thing I would add to your awesome SMM compendium would be the Scoop.it platform. As you reference in Tip #25 Cross promote to your other social channels. This is where Scoop.it shines!
We know that social media is a great source to get instant traffic and build good connections with our audience.
Learned lot from your article .
Awesome list. Will definitely share this with our job seeker list!
That was a fantastic article, Rebekah. Both concise and comprehensive that somehow cleverly disguises how much work you put into it- great job & much appreciation to you. I am looking forward to reading more of your articles in 2014.
Social media is often overwhelming to newcomers (surprisingly, there are still newcomers to SM) so I advise my clients to start slowly and do it properly rather than spreading themselves too thin everywhere, or worse abandoning their platforms. Your list is a great checklist for people to work through as their time allows.
My favourite time-saving advise to all my clients is to integrate their platforms so that they feed each other & hopefully pulls more followers.
Latest list for social contact to build. Thanks to Rebekahradice.
This is such great information.
Would you recommend using the Google calendar?
I like Listly and the way you can embed a list in a blog post and it even gets updated right there on the post when you add to the list.
Very useful, comprehensive list! I tried to subscribe to your blog on my iPad but got a message that the RSS feed does not support email. ?
Thanks for letting me know Robert. I haven't had any trouble with it in the past, so I appreciate the heads up.
Seemed to work today. Stupid computer tricks!
Very nice article. I will share this with my readers.
A fantastic resource and collection!
Anyone looking for some ideas or tips from the pros will certainly be impressed and be able to accelerate their social media awesome-ness in no time!
Great list! Just bookmarked it.
Oh my, a well written one indeed! I like the social media calender. I really have not try yet but certainly looks promising. Oh yes, G+ community. Recently, it exploded my traffic and I am loving it!
Wow! Such a comprehensive list. I know I am doing some of these already but Google+ communities is a place where I have not been very active so far. I think you have pushed me through this post and I am going to start paying attention to some of the items you have listed here.
Thank you for sharing and adding value. Not just sharing, I am going to put this in my list of things to refer to once in a while.
Real cool, easy to follow tips! some of them are basic but worth to keep in mind on our daily basis. Thanx. I will promote this article.
You epitomize social media magic, Rebekah! I love how generous you are with all your suggestions and how you write out all your tips in such an accessible way, which which makes them all seem do-able. I also love how you write all your articles in such a positive way, leaving the reader inspired to go out into the world and take your tips to heart, rather than more confused and even less likely to begin than they were before reading the article, as can often be the case with some authors who talk down to their readers and over-complicate things just to boost their own egos! I can't wait to read Peg's 26 upcoming magical tips 🙂 Happy Friday/weekend, Rebekah and, as always, excellent article!!!
Awesome article. You mentioned a lot of great tips. I pretty much have my social media platforms covered. I can always work on better optimizing my profiles though. I also need to look into some management tools too. Thank you for such a thorough list!
Powerful list of tips. Many of them are already in my arsenal – some are not applicable. For instance Tumblr is for a very young audience and definitely not my target audience. Stumble – I agree it's not quite the powerhouse it use to be, but I still get quite a bit of traffic from there. Looking forward to the rest of the list!
Hi Rebekah. You really have put it all together here! I don't know what's coming next, but one secret I'd add is native advertising. On Facebook, native ads in the News Feed generated 49-times higher click-through rates and a 54% lower cost-per-click than traditional placements. Before investing on native ads, marketers must identify where their audience is first. That goes for the choice of platform, as well as the choice of site where your ads will be shown! What are your thoughts on it?
Excellent point Adella. I have had huge success with native ads on Facebook. In fact, it was for a while the most substantial portion of my marketing budget due to their superior performance.
Commenting is perhaps my best and most favorite strategy. I do have many of these in my collection of strategies, but I don't use them very well. I definitely need to finalize on my social media strategy, before launching the blog (Right now, I am in the process of finding communities to engage with, mostly G+ communities. I haven't found any good ones yet. Hopefully, I will be able to find 1-2 in the coming days).
Anyways, I do appreciate you sharing this – thanks to Peg too 🙂 Have a wonderful weekend!
Hi Jeevan! G+ communities have been a big resource and traffic provider for me. Join me and Peg in our community I mentioned above – Closing the Google+ Gap.
Thank you so much for the link to the Closing the Gap Google+ community, Rebekah! I can't believe I didn't know about it 🙂 Just joined and am excited to read the posts!
These are the basics of social media and yet many of these ways are missed by users. Thank you for listing them down together, hope it creates the desired awareness. Waiting for the next list.
Thanks Dave! There's a lot of to-do's when it comes to social media. Lists are always my favorite way to take the overwhelm out of all of it.
Hi this is pretty much great article , hoosuite is amazing tool for me. I also use buffer for posting posts & other stuffs. Google alerts is also very good to get alerts about your specific needs. Feedly is one stop destination to read your content.
Google alerts are a great tool Jitendra. I use them to keep up with multiple keywords. It's a great way to monitor your name and your business.
Thanks for the advice. I am at a point in my company where I must embrace Social media in order to reach our goals. We have been in the Gourmet Sauce and seasoning business for a little over 8 years now. We have built up somewhat of a name for ourselves but have stayed small. Now though we are faced with some choices do we really go all out or just stop all together.. So here we are going all out. Challenging yes on a shoestring budget so all the advice we can get is much appreciated.
Great advice on using social media. With practice and persistence we will be able to master social media.
Whew! That was a really comprehensive list. And a great tool to check what I'm doing and could be doing with my social media strategy.
Great article to remind people just how much goes into just staying active in the social world. A lot of people thing they can just set these things up and let the sit there unused.


text:
by Clark Groome
Since Bruce Graham made his playwriting debut with "Burkie" at the Philadelphia Festival Theatre for New Plays in 1984, his work has been a regular part of the Philadelphia Theatre scene. Over the last 28 years I've seen 18 of his plays. They have all been unique, and all have a sense of humanity and humor that distinguish them from the works of other equally prolific playwrights.
Graham's latest, "The Outgoing Tide," is making its Philadelphia debut at the Philadelphia Theatre Company, where it will be through April 22. Its production here follows one in Chicago last season, where it garnered the Jefferson Award for Best New Play, the Windy City equivalent of our Barrymores or New York's Tonys.
PTC's superb production affirms the Jeffersons' wisdom. "The Outgoing Tide" is a tough and tender play about the pain a family experiences when its patriarch is facing the long road of oncoming dementia.
Gunner (Richard Poe) is both terrified of and determined to defeat the monster that is slowly destroying him. He figures out a way to do that so that his family — wife Peg (Robin Moseley) and son Jack (Anthony Lawton) — will be taken care of handsomely after he's gone. His scheme, which I won't reveal, troubles them. The two days we spend with them at Gunner and Peg's home on the Chesapeake Bay are revelatory, emotionally draining and exquisitely human.
Graham has always been good at creating characters who are believable. These three are among his most sympathetic and recognizable. As his three fine actors limn them, we see their varying emotions, their devotion and their fears. This remarkable play is receiving a stellar performance, magnificently directed, like so many of Graham's other plays, by James J. Christy.
David Gordon's set, Pamela Scofield's costumes, R. Lee Kennedy's lighting and Bart Fasbender's sound all add immensely to the play's effectiveness.
But it is Graham's characters and his adroit mixture of humor amid sadness that make "The Outgoing Tide" so special.
For tickets to Bruce Graham's "The Outgoing Tide," being presented by the Philadelphia Theatre Company and the Suzanne Roberts Theatre through April 22, call 215-985-0420 or visit www.philadelphiatheatrecompan.org
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