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Karol Szymanowski's Stała matka bolejąca (Stabat mater dolorosa), Op. 53, was composed in 1925 and 1926. Scored for soprano, alto and baritone soloists, SATB choir and orchestra, it sets Jozef Janowski's Polish translation of the Marian hymn in six movements. His first composition to a liturgical text, it is characteristic of his late period in being partly based on Polish melodies and rhythms; a stay in the Tatras mountains, at Zakopane, in 1922 had led him to describe Polish folk music as "enlivening [in] its proximity to Nature, [in] its force, [in] its directness of feeling, [in] its undisturbed racial purity." Indeed, Szymanowski's use of Polish musical elements together with the Polish translation here is unique.

Origin and performances
In 1924 Princess Edmond de Polignac requested "a piece for soloists, choir, orchestra (perhaps with Polish text): a kind of Polish Requiem." Teresa Chylińska indicates Szymanowski's intentions for the piece in response to the request: "a type of peasant Requiem, something peasant and ecclesiastical, naively devotional, a sort of prayer for souls, a mixture of simple-minded religion, paganism and a certain austere peasant realism." But Szymanowski and the princess lost touch.

Late the same year, however, thoughts about such a composition were revived when Warsaw industrialist Bronisław Krystall asked Szymanowski for a work in memory of his late wife. Circumstances in the composer's own life also served as an catalyst. Upon the death of his niece, Alusia Bartoszewiczówna, in January 1925, the composer spent time consoling his sister, subsequently choosing to set the Stabat mater text, reflecting as it does the "grieving mother." External factors served as motivation too, including financial need, although there is no evidence of the composer receiving compensation for this work.

The Stabat mater was premiered on January 11, 1929, in Warsaw, conducted by Grzegorz Fitelberg. Its American premiere came two years later at Carnegie Hall, performed by Berthe Erza, Hugh Ross, Nelson Eddy, and others. The score was published by Universal Edition in Vienna.

Instrumentation
Soprano, alto, and baritone soloists; SATB choir; and orchestra consisting of 2 flutes, 2 oboes (2nd doubling cor anglais), 2 clarinets in A, two bassoons (2nd doubling contrabassoon), 4 horns, 2 trumpets, timpani, bass drum, triangle, suspended cymbal, tam-tam, tubular bells, harp, organ (ad lib), and strings consisting of 8 first violins, 8 second violins, 6 violas, 6 cellos, and 4 contrabasses.

Movements

 Stała matka bolejąca (Stabat mater dolorosa, verses 1–4) for soprano, SA choir and orchestra
 I któż widział tak cierpiącą (Quis est homo qui non fleret, verses 5–8) for baritone, SATB choir and orchestra
 O matko źródło wszechmiłości (O eia mater fons amoris, verses 9–12) for soprano, alto, SA choir and orchestra
 Spraw niech płaczę z tobą razem (Fac me tecum pie flere, verses 13–14) for soprano, alto and SATB choir unaccompanied
 Panno słodka racz mozołem (Virgo virginum praeclara, verses 15–18) for baritone, SATB choir and orchestra
 Chrystus niech mi będzie grodem (Christe cum sit hinc exire, verses 19–20) for soprano, alto, baritone, SATB choir and orchestra

Polish Text
Szymanowski chose to set Jozef Janowski's (1865–1935) Polish translation of the Latin Stabat mater text. Though the 13th-century text is already inherently dramatic, this translation is especially raw; Kornel Michałowski suggests that the composer's attraction to it resulted from its "unusually primitive, almost 'folk-like' simplicity and naivety".

The score includes the Latin original for reference only and it notes that the work should always be sung in Polish when performed in Poland. An English translation and commentary on the Polish translation is given in: Belland, Douglas Keith.  An examination of the Persichetti, Poulenc, and Szymanowski Stabat Mater settings with pertinent information on the text.  Dissertation:  University of Cincinnati, 1992.

Influence of Early Music
Coinciding with his setting of the Stabat mater was Szymanowski's study of early music, encompassing pre-Palestrinian and Palestrinian periods as well as old Polish religious music. Early-music devices used in the score indicating this study include: parallel movement between voices; modal pitch organization; and strongly patterned rhythms such as ostinati. Also incorporated into the Stabat mater are melodic elements of two Polish Hymns: Święty Boże [Holy God] and Gorzkie żale  [Bitter Sorrows].."

Nationalism and folk music
Influenced by composers such as Stravinsky and Bartók, Szymanowski began to incorporate folk music into the work of his late period (after 1922). In the years preceding his setting of the Stabat mater, he kept a notebook of highlanders' melodies or devices encountered in his visits to the Tatra Mountains and later incorporated into his compositions. For example, his use of the Podhalean mode, an ancient Polish folk mode characterized by its raised fourth-scale degree (Lydian), can be heard in the Stabat mater.

References

Bibliography

 Belland, Douglas Keith. An examination of the Persichetti, Poulenc, and Szymanowski Stabat Mater settings with pertinent information on the text.  Dissertation:  University of Cincinnati, 1992.
 Chylinska, Teresa.  John Glowacki, trans.  Karol Szymanowski : his life and works.  Los Angeles: University of Southern California, School of Music, 1993
 Howard, Luke.  Pan-Slavic parallels between Stravinsky and Szymanowski.  Context: A journal of music research,  Issue 13, Winter 1997, pp. 15–24. Melbourne: University of Melbourne. .
 Jeffers, Ron.  "Stabat Mater", Translations and Annotations of Choral Repertoire.  earthsongs, Corvallis, Oregon: 1988.
 Maciejewski, B. M. Karol Szymanowski: his life and music.  London: Poets & Painters' Press, 1967.
 Saffer, Bernard Agnes, Sister.  A stylistic analysis of Stabat mater for solo voices, mixed chorus and orchestra by Karol Szymanowski.  Dissertation: University of Rochester, 1965.
 Samson, Jim.  The music of Szymanowski.  New York : Taplinger, 1981.
 Samson, Jim.  "Szymanowski, Karol (Maciej)", Grove Music Online ed. L. Macy (Accessed 2/1907), http://www.grovemusic.com
 Szymanowski, Karol.  Wightman, Alistair, ed.  Szymanowski on music : selected writings of Karol Szymanowski.  London: Toccata, 1999.
 Szymanowski, Karol.  Karol Szymanowski and Jan Smeterlin; correspondence and essays. London, Allegro Press, 1969.
 Wightman, Alistair.  Karol Szymanowski : his life and work.  Brookfield, Vermont : Ashgate, 1999.
 Zielinski, R.  "Karol Szymanowski (1882–1937): The father of contemporary Polish choral music." Choral Journal No. 46 September 2005, 8–24.
 Karol Szymanowski's "Stabat Mater". Spanish Radio and Television Symphony Orchestra. Thomas Dausgaard, conductor. Live concert.

Compositions by Karol Szymanowski
Szymanowski, Karol
Music for orchestra and organ
1926 compositions


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We're giving away The Square on DVD, so come cringe along
Katie Rife
Filed to: FilmFiled to: Film
Photo: Magnolia Films
"The Square is a sanctuary of trust and caring. Within it we all share equal rights and obligations." It's also Swedish director Ruben Östlund's celebrated followup to Force Majeure (2014), a dry and incisive satire of bourgeois art-world pretension to rival Force Majeure's pointed skewering of toxic masculinity. The Square has been on a major winning streak, from the Palme D'Or at Cannes to Golden Globe and Oscar nominations to—most flattering of all, of course—a spot on The A.V. Club's list of the 20 best films of 2017, where we called it a "super-sized cringe comedy, awkward enough to get Larry David hot under the collar."
If that sounds like a fine evening of cringeworthy entertainment, we're giving you the opportunity to squirm along with The Square on DVD. We're giving away 10 copies of the film to readers along with our friends at Magnolia Home Entertainment, and to enter to win your copy, email us at avcontests@theonion.com with your name and U.S. mailing address (no P.O. boxes, please) with the subject line "Bang" by Friday, January 26. We'll pick winners that afternoon, and send your information to our partners for shipping on the DVD's street date of Tuesday, January 30.
You can watch a trailer for The Square below.
The Square wins the Palme D'Or and Nicole Kidman gets a special award at Cannes
Cannes winner The Square is a scathingly funny art-world satire from the director of Force Majeure
Elisabeth Moss asks a tough question in this exclusive clip from Cannes winner The Square
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Creepshow comes home for an exclusive poster reveal
Sorry, Darlin', but Pollyanna McIntosh's directorial debut doesn't quite work
I Love You, Now Die questions everything we thought we knew about the case against Michelle Carter

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RxDB itself is not a self-contained database. It uses adapters that define where the data is stored. Depending on which environment you work in, you can choose between different adapters. For example in the browser you want to store the data inside of indexeddb but on NodeJs you want to store the data on the filesystem.
This page is an overview over the different adapters with recommendations on what to use where.
With RxDB you can also use adapters that implement abstract-leveldown like the memdown-adapter.
The IndexeDb adapter stores the data inside of Indexeddb use this in browsers environments as default.
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Sixteen-year old Peyton Jones had it all: straight A's in school, the perfect boyfriend, and nothing to worry about but keeping her GPA up. Then one night her perfect world is suddenly ripped away from her. Everything she has ever known changes and she goes from having a perfect plan to watching her world crumble around her.
Steve Gibbons was the quarterback of his high school football team...until the new guy showed up and stole his spot, causing him to lose his chance at a scholarship. Football was his life and now he feels like he has nothing.
Drawn together after losing hope for their futures, Peyton and Steve become best friends, but as they grow closer, a colossal secret is revealed changing everything. Will Peyton be left to face her inevitable future alone, or can she trust enough to let someone else in?
Kelsie Blanton is a fun-loving young woman from a small town in Kentucky. Writing has always been her passion and when she's not working at her full-time job, she is at home writing on something. Her hobbies include reading, writing, singing (poorly), dancing (again, poorly), and talking…a lot.
Surrounded by amazing friends and family that support her, Kelsie is following her dreams. Happy reading!
I froze, too afraid to move. The steps began to get louder as each second passed. My heart was pounding to its own quick rhythm. A hand grasped my shoulder and I squeezed my eyes shut expecting the worse. I began to quiver uncontrollably, wanting to scream, to run as hard as I could, but my feet were frozen. I could only stand there as my tears mixed with the rain pouring over me.
The grip was released, and suddenly an arm snaked around my back turning me in the opposite direction. I couldn't muster up the courage to look at the person helping me. I could only assume it wasn't Aaron. Whoever it was had too gentle of a touch. Yet instead of feeling relief a sense of nausea washed over me. Granted, I was momentarily safe, but the emotions coursing through me had made it—for a brief moment—feel like it was happening all over again.
I didn't want to be vulnerable in front of anyone who could take advantage of me. With my heart going 100 miles per hour in my chest, I tried to push away from the person and nothing happened. They didn't budge and their grip around me was too strong. After many deep breaths, I got the courage to glance up into eyes the color of emeralds—eyes filled with concern. My legs gave out and I sagged in his arms. Steve didn't hesitate. He slowly lowered me to the wet asphalt and sat there while I sobbed into his already wet shirt.


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Q: pre-compiling long document preamble I have several long documents (500-1000+ pages), where the pre-amble is itself rather lengthy (say, 15-25 packages being loaded, with multiple option tweaks, lots of custom functions, etc, etc). When compiling (I normally use MikTeX, but observe the same with TeXlive), a fair chunk of time comes from reading in the pre-amble, before getting to contents of the document itself.
In browsing around it seems there are methods for pre-compling the preamble (e.g., Ultrafast PDFLaTeX with precompiling), but everything I've found applies to PDFTex or LuaTex, but I haven't found anything that might work with my normal build sequence: .tex -> .dvi -> .ps -> .pdf.
Perhaps it isn't possible, but it would be a major time saver if I could pre-compile the preamble for these big docs, since the preamble isn't changing (typically) between compiles.
Any options?

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text:
Stay Safe. Stay Home.
Human coronaviruses are common and are typically associated with mild illnesses, similar to the common cold.The corona virus COVID-19 is affecting 210 countries & territories around the world and 2 international conveyances.
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Learn Methods
Don't Touch Face
Social Meetup
Drink Much Watar
Use Face Mask
Dry Dough
Continuous coughing a lot for more than an hour, or 3 or more coughing episodes in 24 hours.if you usually have a cough, it may be worse than usual.
Older people, and those with underlying medical problems like high blood pressure, heart and lung problems, diabetes, or cancer.
People of all ages who experience fever and/or cough associated with difficulty breathing/shortness of breath.
Fever you feel hot to touch on your chest or back (you do not need to measure your temperature). It is also may appear in 2-10 days.
Headache is a key symptom, experts say. Don't fixate on a relaxation, but know it's really danger until your headache reaches at maximum.
Around 1 out of every 6 people who gets COVID-19 becomes seriously ill and develops difficulty, causes motion sickness and vomiting.
viastudy June 09, 2020 viatimes
This document provides advice on the use of masks in communities, during home care, and in health care settings in areas that have reported…
The Health Ministry on Thursday, 4 June, issued the SOPs on preventive measures to be taken in hotels, shopping malls, restaurants and places of …
by viastudy June 09, 2020
This document provides advice on the use of masks in communities, during home care, and in health care settings in areas that have reported cases of COVID-19. It is intended for individuals in the community, public health and infection prevention and control (IPC) professionals, health care managers, health care workers (HCWs), and community health workers. This updated version includes a section on Advice to decision makers on the use of masks for healthy people in community settings. Corrigendum - Advice on the use of masks in the context of COVID-19: Interim guidance, 5 June 2020 Previous guidance: Advice on the use of masks in the context of COVID-19: interim guidance, 6 April 2020 Download PDF 519 kB Get a link Publication details Number of pages: 16 Publication date: 5 June 2020 Languages: English WHO Reference Number: WHO/2019-nCov/IPC_Masks/2020.4
Here You Will Find The Answers Of Your Most Asked Questions
1. What is novel corona virus?
Coronaviruses are a large family of viruses which may cause illness in animals or humans. In humans, several coronaviruses are known to cause respiratory infections ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The most recently discovered coronavirus causes coronavirus disease COVID-19.
2. What is COVID-19?
COVID-19 is the infectious disease caused by the most recently discovered coronavirus. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019.
3. What is Quarantine?
separates and restricts the movement of people who were exposed to a contagious disease to see if they become sick. These people may have been exposed to a disease and do not know it, or they may have the disease but do not show symptoms.
4. What is Isolation?
The separation of a person or group of people known or reasonably believed to be infected with a communicable disease and potentially infectious from those who are not infected to prevent spread of the communicable disease. Isolation for public health purposes may be voluntary or compelled by federal, state, or local public health order.
5. What are the symptoms of COVID-19?
The most common symptoms of COVID-19 are fever, tiredness, and dry cough. Some patients may have aches and pains, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are usually mild and begin gradually. Some people become infected but don't develop any symptoms and don't feel unwell. Most people (about 80%) recover from the disease without needing special treatment. Around 1 out of every 6 people who gets COVID-19 becomes seriously ill and develops difficulty breathing. Older people, and those with underlying medical problems like high blood pressure, heart problems or diabetes, are more likely to develop serious illness. People with fever, cough and difficulty breathing should seek medical attention.
6. Is there any treatment of coronavirus disease (COVID-19)?
There is no specific medicine to prevent or treat coronavirus disease (COVID-19). People may need supportive care to help them breathe.
6. Is there anything I should not do?
The following measures ARE NOT effective against COVID-2019 and can be harmful: Smoking, Wearing multiple masks. In any case, if you have fever, cough and difficulty breathing seek medical care early to reduce the risk of developing a more severe infection and be sure to share your recent travel history with your health care provider.
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Currently, the source of SARS-CoV-2, the coronavirus (CoV) causing COVID-19 is unknown. All available evidence suggests that SARS-CoV-2 has a natural animal origin and is not a constructed virus. SARS-CoV-2 virus most probably has its ecological reservoir in bats. SARS-CoV-2, belongs to a group of genetically related viruses, which also include SARS-CoV and a number of other CoVs isolated from bats populations. MERS-CoV also belongs to this group, but is less closely related.
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The virus that causes COVID-19 is mainly transmitted through droplets generated when an infected person coughs, sneezes, or speaks. These droplets are too heavy to hang in the air. They quickly fall on floors or surfaces. You can be infected by breathing in the virus if you are within 1 metre of a person who has COVID-19, or by touching a contaminated surface and then touching your eyes, nose or mouth before washing your hands.
Water & Soap
Rub Fingers
Rub Thumbs
Back of Hands
Rub Wrists


text:
Doctor Advice
Mbrace Aligners In Singapore – 7 Tips By a Dentist
This author doctor has chosen to stay anonymous.
This product is no other than Mbrace!
Introducing Mbrace
Basic Cost Inclusions
Other Items Affecting Mbrace Costs
Mbrace Treatment Package
Under the Private Hospitals and Medical Clinics Act, doctors can be warned, fined or suspended if they position themselves as an expert above their peers. Doctors also cannot use before/after photos in the article or state their preferences towards specific methods or techniques. The strict laws help uphold the repute of Singapore's private healthcare scene and we strongly support it. Due to this, some doctors choose to stay anonymous so they can write more informative pieces.
Click To Check Cost of Mbrace treatments in Singapore
As compared to Invisalign, Mbrace is remarkably cheaper by approximately $1,500 to $2,000. The average cost of a complete treatment of Mbrace clear aligners is $5,000 to $7,000.
Clear aligners have recently gained a popular following from Singaporeans who want straighter teeth without the inconvenience of traditional (and a bit more painful!) metal braces. There are a lot of brands available in the market, however, there are two most prominent ones that are usually chosen by dental patients. You will be surprised to know that one of them is locally sourced in the country!
A lot of people mistake Invisalign and Mbrace as one for the other. To set the records straight, here are facts about Mbrace that differentiates it from the imported brand.
Mbrace is a brand of clear aligners that are designed, developed, and produced in Singapore. Dr Keith Wong and Prof. The Bin Tean of Dentalthon Medtech Pte founded it in 2014. Ltd.
Although Mbrace is very recent in the dental seen as compared to Invisalign, the company has seen an expansion of its clear aligners in other countries like Indonesia, Hong Kong, and Malaysia.
As mentioned at the start of the article, compared to Invisalign, Mbrace is remarkably cheaper by approximately $1,500 to $2,000. The average cost of a complete treatment of Mbrace clear aligners is $5,000 to $7,000.
You may have noticed the significant disparity between the pricing of the two braces. Why is Mbrace cheaper than Invisalign? You wonder.
Mbrace is much cheaper compared to Invisalign because the clear aligners, as said, are fabricated locally. A big chunk of the cost savings when choosing Mbrace over Invisalign is credited to Mbrace's laboratories that are located in Singapore. This means that the mapping out of a patient's full course of treatment does not have to be shipped off and be developed overseas.
An Invisalign treatment, on the other hand, will have to pass through two countries (Mexico and Costa Rica) for the production of the clear aligners.
When scouting for an Mbrace accredited clinic for treatment, do note that each clinic will offer different rates for pricing. Always inquire about what is included in the packages being offered and payment options as well.
A regular Mbrace package quotation should include pre-treatment bite registration and patient's photograph for profiling, dental x-rays, and your teeth's moulds.
As you may have noticed, the cost of Mbrace is based on a price range and not on a specific amount. There are several reasons for this.
First, the laboratories where the clear aligners are developed and manufactured belong to Mbrace. The dentists are paying for all the materials and equipment used in the labs; therefore they follow the company's given rates. If the company decides to multiply on costs, then these price adjustments trickle down to the charges of the dental practitioners.
Next, the number of aligners needed for the treatment relies solely on the intricacy of a patient's dental condition. If the misalignment is severely complicated, then expect that more aligners and extended time will be needed for your treatment. Of course, extended time would mean more trips going back to the clinic for follow-up appointments, which will entail you to shell out more cash.
Often times, the dentist may note additional requirements or enhancements to your treatment plan, such as interproximal reduction. This process is done to improve a patient's jaw bite, as well as create enough space for teeth movement when the aligners are set in place.
In addition, the type of dental practitioner you choose may contribute to your treatment's expense. Both dentists and orthodontists can practice Mbrace treatment as along as they have successfully finished the course required by the company. However, do note that orthodontists may charge higher compared to general dentists as they have taken additional years of learning and specializing in the structure and function of the teeth's mechanical movement.
I am afraid that there are no options available when it comes to greatly lessening the costs of Mbrace's treatment. Medisave only covers medical procedures relating to surgeries, which Mbrace is obviously not. On the other hand, dental insurances normally do not include cosmetic or orthodontic treatments in their coverage.
This is what you can anticipate once you have found the right doctor to do your Mbrace treatment:
During the consultation, your dentist should be able to evaluate you based on the basic inclusions mentioned earlier (e.g. dental x-rays, pre-treatment patient photographs and bite registration, teeth moulds).
Treatment Plan. After the evaluation, the dentist will formulate your Mbrace treatment plan. The plan should be presented to you and your approval to the proposal is needed to proceed with the production of Mbrace clear aligners that are to be used in sequence.
Use of Mbrace Aligners. As soon as you receive your first pair of Mbrace aligners, use them at least 20 to 22 hours daily for 2 weeks before moving on to its replacement. During this period, patients will need succeeding appointments to the dentist to monitor the progress of the teeth's movement.
End of Treatment. As soon as you have successfully completed all sets of your Mbrace clear aligners, your dentist will issue you a pair of retainers. The retainers are to be worn in order to avoid relapse that may result in misalignment for a second time.
My advice for patients who want to scrimp on costs is to do research on the different Mbrace packages offered by clinics. This may take a bit of time and effort, but to land on a package that best fits your budget and getting the straight teeth that you want are great rewards in the end. Likewise, it is vital to find a dentist that looks after the welfare of the patient more than focusing on profit. Dentists that are honest when it comes to their competencies and those that are able to recommend better alternatives, such as getting traditional braces if need be or recommending a colleague more well-versed on your condition, are your best bet in getting optimal Mbrace treatment results.
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Begin your tulip season cruise in Amsterdam. Cruise to Arnhem and tour its WWII Airborne Museum commemorating the brave battle of 1944. Join your ship in Nijmegen and visit the lovely forest setting of 's-Hertogenbosch to sample decadent Dutch chocolate desserts. Perhaps visit a fruit and flower farm to visit with the miller there to hear the history of a 15th-century windmill. A carriage ride takes you through the nearby nature reserve to watch for herons, storks, birds of prey, and wild horses. If you prefer, take a guided bike ride along the Rhine River banks of Arnhem. In Maastricht, choose a sightseeing tour of the old cobblestoned university town, or visit a working mill to make your own Limburg pie. On to Belgium for a sightseeing tour of medieval Namur and free time to browse its ancient architecture, charming cafes, and bookshops. In Liège, see the ancient quarters of the "Fiery City" as well as its romantic streets, steps, and tiny alleyways. Next, you'll explore the city of Antwerp—birthplace of the master painter Peter Paul Rubens. Stroll its cobbled lanes amid 16th-century guildhall houses and the cathedral's stunning altarpiece paintings by the famous artist. In Brussels, you'll find landmark buildings and a collection of cafes and shops on your guided tour. Visit "The Diamond of Flanders", Ghent, for stunning Flemish artwork in St. Bavo's Cathedral. Explore more of the Flanders area with tours in Bossuit—the In Flanders Fields Museum and moving battlefield memorials and memorabilia.
In Middelburg, explore its grand history in the Dutch East India Company. Tour the Veere Delta Works to see the world's largest flood-protection system. Continue your cruise through Kinderdijk—where windmills built in 1740 for water management helped the iconic structures become a symbol of Holland. See the Erasmus Bridge in Rotterdam, and the quintessential Dutch towns of Zaandam and Haarlem with their signature flower farms, windmills, waterways, and North Sea trading. Your cruise through Holland and Belgium returns to Amsterdam for a guided canal cruise through the iconic city.


It's a choice to manage our stress and truly enjoy the holiday season as we head into the end of the year. It is certainly a busy time for many, and we don't often take time to notice why we do all the things we do. Today we spend a few minutes to stop, breath and be still, while we reflect and discover ways to lessen stress at this time of year.


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Harvard T.H. Chan School of Public Health > Gökhan S. Hotamışlıgil
Gökhan S. Hotamışlıgil
PubMed Articles
Hotamisligil Lab
James Stevens Simmons Professor of Genetics and Metabolism
Director, Sabri Ülker Center for Nutrient, Genetic and Metabolic Research
Department of Molecular Metabolism
Sabri Ülker Center
Associate Member, Broad Institute
Associate Member, Harvard Stem Cell Institute
The major interest of my laboratory is to study the regulatory pathways, which control glucose and lipid metabolism. Our biochemical and genetic studies focus on signal transduction using cultured mammalian cells as well as transgenic animals to identify specific abnormalities in these pathways, which are involved in human metabolic and inflammatory diseases including obesity, diabetes, fatty liver disease, atherosclerosis, and asthma.
Lineage Commitment and Differentiation of Adipocytes and Control of Energy Metabolism
One of the most fundamental questions in biology is how different cell types commit to specific lineages and regulate their terminal differentiation program. To understand this process, we use adipogenesis as a model system and study the molecules, which control early stages of differentiation in these cells. We have recently identified a family of transcription factors, which play a critical role in adipocyte differentiation. The molecular mechanisms underlying their biology are currently being studied using molecular and cellular approaches as well as mouse genetics. Through this line of research, we hope to generate insights into the process of adipocyte differentiation and the integration of positive and negative hormonal and metabolic signals that regulate the program of differentiation, which could assist the development of new tools for prevention and treatment of obesity.
Inflammatory and Stress Pathways and Molecular Basis of Metabolic Disorders
Recent years have witnessed a significant revision of the traditional view of fat cells as simple stores of excess energy. Studies in our lab, as well as many others, have clearly demonstrated that adipocytes produce and regulate many metabolic and hormonal signals, which generate profound effects on systemic endocrine equilibrium. In our earlier studies, we have also demonstrated that these cells exhibit an inflammatory capacity which is abnormal in obesity and key to the pathogenesis of insulin resistance and diabetes. Recently, we identified key molecular mechanisms underlying the link between inflammatory responses and insulin action. These pathways include obesity-related activation of the serine.threonine kinase, JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of a substrate of insulin receptor, IRS-1. In mice lacking JNK genes, there is dramatic protection from obesity and diabetes. There is also genetic evidence that JNK activation is linked to type 2 diabetes in humans. These studies have recently led our group to the discovery of endoplasmic reticulum stress as a central mechanism linking metabolic stress with insulin resistance and type 2 diabetes. The mechanisms leading to ER stress and targeting these pathways for novel therapeutic strategies are also being explored.
Biology of Fatty Acid Binding Proteins
The nutrient content of diet has a profound influence on a number of vital physiological pathways. Furthermore, a strong link exists between the dietary trends and a number of common diseases such as cancer, diabetes and atherosclerosis. We approach the molecular basis of these interactions by focusing on fatty acid-mediated transcriptional regulation in cells and the biological role of fatty acid binding proteins (FABP) as lipid chaperones involved in intracellular lipid trafficking. We have developed several mice models that are deficient in adipocyte/macrophage FABPs and demonstrated that these animals were protected from some of the most detrimental effects of dietary intake of high levels of calories and fatty acids through alterations in the gene expression pattern of adipocytes, macrophages and systemic metabolic responses. We have so far demonstrated that FABPs are central to many components of the metabolic syndrome, including obesity, insulin resistance, type 2 diabetes and cardiovascular disease. These proteins are also proximal to generation of the inflammatory responses, especially upon exposure to lipids. Using FABP-deficient animals and cells as model systems, we are trying to establish the components of the signaling pathway that is controlled by FABPs and the mechanisms by which these pathways are linked to inflammatory and metabolic responses. We hope to generate insights into the mechanisms leading to obesity, diabetes and atherosclerosis and create novel preventive and therapeutic opportunities.
Ph.D., 1994, Harvard University
M.D., 1986, Ankara University
For more information about the our research, members of our team, and the Sabri Ülker Center and Hotamışlıgil Lab, please visit our Website
Building I Room 605
ghotamis@hsph.harvard.edu