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Holidays ... beach
Our house in Ribadesella
Home / What to do in Asturias / Municipalities and towns of Asturias / Towns of Ribadesella
Villages of Ribadesella
Municipality of Ribadesella
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Dozens of villages dot the municipality of Ribadesella, each with its own idiosyncrasies and unique attractions for the visitor. Go ahead and discover them.
Eastern Shore, muja What to see in Ribadesella,
Silva Brothers 0,03 km
Hnos. Silva is a family company. His beginnings were back in the 70 years, dedicating himself to
Sidrería Carroceu 0,04 km
The Sidrería Carroceu is located next to the pier of Ribadesella, overlooking the beach. On our terrace
Northern Mountains 0,04 km
Montañas del Norte is an Active Tourism company dedicated to providing its clients with experiences
Sidrería El Puerto 0,05 km
El Puerto restaurant has been renovated, from 2016 enjoy this new place in the village of Ribadesella.
El Campanu Restaurant 0,08 km
The restaurant / seafood restaurant El Campanu is run by José Manuel Mori Cuesta 'El Marqués', prestigious
Guided tours through Ribadesella 0,08 km
The guided tours program is organized by the Ribadesella City Council and covers some of the
The International Descent of the Sella 0,08 km
In the first video above you can check the great atmosphere that was in the Sella 2018. With a lot of fun, a
All the festive calendar of Ribadesella 0,09 km
Starting the year with a lot of cold, in the month of February or March -as the Holy Week falls- we have:
The village of Ribadesella 0,10 km
Going around Ribadesella becomes a very dense and entertaining walk, with dozens of
Ribadesella: basic information 0,11 km
The town of Ribadesella is the capital of a municipality surrounded by mountains, beaches and cliffs. Without going more
Map: how to get to Pueblos de Ribadesella
Ribadesella is a municipality of sea and half mountain that keeps natural, ethnographic and architectural treasures at every step. A total 36 villages, organized in 9 parishes, are in charge of putting a vast patrimony to good protection. Knowing these towns, walking through them, photographing their corners and talking with their people is one of the best experiences that tourists and / or hikers can do for this land. In all of them we find rural accommodations, restaurants and ideal scenarios for adventure sports.
We list in alphabetical order a good number of these villages and we add a small review of their main attractions.
Abeo (Abeu)
In the vicinity of this town (5 kilometers west of the capital of Ribadesella) we can enjoy panoramic views of the coast, with the possibility of going down to a pedral (or pedreru) that is part of the Jurassic coast. In the village we discovered a good number of traditional houses, as well as fountains, laundries and drinking fountains; some of them hundreds of years old. The palace of the Argüelles stands out, a superb building built in Caravia la Alta and later transferred to this town stone by stone. Abeo is the transit point of the Camino de Santiago of the coast.
9 km to the Southwest of the caital of the council, is at the foot of the Natural Reserve of the Sierra del Sueve, so it allows a good number of hiking excursions. Here we can admire a Palace of the sixteenth century, with a main body in the form of a tower and two lower sides. On the façade, the cover with a semicircular arch consists of large voussoirs.
Ardines
Located just one kilometer from the town center of Ribadesella, the village extends around the Ardines massif, a geological site that houses the cave of Tito Bustillo and another good number of caverns, like the famous Cuevona. In the upper area of the town is the recreational area of La Moría, the most visited in the municipality, with unparalleled views over the estuary of Sella.
Barredo (Barreu)
Very close to the Vega beach and the natural monument of Entrepeñes, is located in a meadow at 6 kilometers west of the town of Ribadesella, in an area marked by the spain-fluorine mining.
Berbes
A 9 km from the capital, on the westernmost slope of the council, is located in the coastal rasa near the beach of Vega. Through the town passes a stretch of Camino de Santiago known as caleyone or caneyona. In this area there was also a large mining activity related to quartz or florite. In the vicinity of the village is the «La Rasa de Berbes Golf Course«. We discovered in this village several examples of Indian architecture.
It is the entry point to the municipality from the A-8 highway, on the west of the municipality. It is located to 5 kilometers of the capital, next to the neighboring village of Pando, a town this one that allows an underground excursion of hour and means of duration. A speleological route, along the cave of Pando, quite affordable for anyone but always accompanied by the staff of an adventure tourism agency.
Calabrez
A 8 Kilometers from Ribadesella, in the Southwest, on the same slope as Sueve nature reserve, where Asturstur horses live in freedom. Nearby is Cueva Rosa (Cova Rosa), a karst complex south of Cerro de La Florentina. It is a set of cavities whose known development is 3.5 km. Its ecological wealth is given by being the largest refuge of bats in all of Asturias.
Camango (Camangu)
Place of passage of Camino de Santiago through Asturias, 4 kilometers east of Ribadesella on the AS-263 road. It has a good sample of rural accommodation and from here we can enter a path through the cliffs. In the limit of Camangu and Meluerda is the house of Tarabuxín, of the XVIII century, with three floors and three shields adorning its façade, it has its own chapel with an invocation to Santa Ana surrounded by a small forest of yew trees.
Cuerres
It is perhaps the most representative village in Camino de Santiago on its way through the muncipio: with medieval bridge, old water mills, fountain of the Pilgrims and Church of San Mamés. It is located 5 kilometers east of Ribadesella. Very close to the population we can enjoy the unusual beach of Guadamía, like a large estuary that at high tide resembles a swimming pool. Around the beach there is a path along the cliffs and we find an area where, in days of swell, we can admire the jesters or waterfalls. Cuerres is a town famous for its Cheese Fair, held on the day of San Lorenzo.
It is the most inhabited parish of the Ribadesella council, just 2 kilometers east of the urban center. In 1052 the existence of the Monastery of S. Martín de Collera is cited. Currently there is no vestige of it, only some historical detail inside the current church, as four pieces carved in Romanesque stone and a side chapel of the eighteenth century. Collera is a population center with outstanding hotel services and abundant samples of popular architecture. Near the village is the spectacular Arra Beach; to access it you have to go down the cliff by a staircase.
Cuevas del Agua (Caves)
About 5 kilometers southwest of the coastal village. The access to this village is very surprising, since you have to travel by car inside a natural cave: Cuevona de Cuevas. The village itself is one of the most charming in the council, on the banks of the River Sella and with a good number of granaries and traditional houses. In the village there is a classroom-hostel of nature where we can find out about the most characteristic ecosystems of Ribadesella. From Cueves we can also undertake the beautiful route of the mills.
It is one of the most extensive populations of the council, with a good number of smaller and nearby villages such as Fresnu, La Granda or Soto. We can enjoy in this area of Museum of the Territory of Ribadesella, located in a building of 1900 corresponding to an old school of Indian origin. Inside, the complexity and wealth of the Ribadesella council is made known to the public. In El Carmen we find a good sample of Indian architecture and large houses.
On the banks of the Sella River, halfway between Ribadesella and Arriondas, the Molín de Fríes built in 1890 stands out, with only one rodezno with six injectors or nozzles.
Junco (Xuncu)
A village located on a privileged promontory, with panoramic views everywhere. About 3 kilometers south of Ribadesella, here is the famous chapel of Santa María de Junco. A small rural temple, of late Romanesque, built at the beginning of the 13th century. Near this church, and without leaving the town, there are two old palaces, both built by the Ruiz de Junco family. One is the Torre de Junco, probably the oldest civil building in the council, erected in the 15th century as a defensive bastion. The other is the Villabuena Palace, from the 17th century, also from the Ruiz de Junco and in a state of ruin.
Linares (Llinares)
It is a parish of the council with a population of 150 inhabitants and is located 8,4 kilometers to the Southwest of the capital of the council. In its heart we find the Palace of Galmés, magnificent example of the northern architecture of the late nineteenth century, and the Parochial Church, one of the most beautiful of Ribadesella, with a beautifully paved atrium.
Llovio (Lloviu)
At 2,5 kilometers from the villa, this village is the entry point par excellence to Ribadesella. The Lloviu river runs through here, which goes to the Sella after crossing the cave of Tinganón, in the Santianes mountain range. Nearby we find Los Campos de Ova, a bucolic riverside on the banks of the Sella which is one of the historic sites of the International descent of the Sella, where the picnic takes place and the homage to the champions of the test.
Meluerda
Labyrinthine rural nucleus with hundreds of paths and paths where we encounter a large number of Asturian mansions, native trees, ancestral yews and dreamy farms. Also worth mentioning is the chapel of San Julián, whose construction dates from the 17th century, in front of a manor house (that of the Manjón) where there are several yew trees. Meluerda, about 3 kilometers east of the town, has a wide range of accommodation and restaurants.
Nocedo (Noceu)
Here we find the one that in its time was one of the most splendid parish churches of Asturias: the church of San Salvador de Moro. It was built in the 12th century with extensions of the 14th, 15th, 18th and 19th centuries; It consists of a Romanesque nave with a rectangular floor plan, a Gothic main chapel and a possibly Baroque side chapel. After the studies carried out in 2003, 2005 and 2008 by the Government of the Principality, the restoration work began on some beautiful paintings, located in the presbytery of the church (paintings attributed to the XV-XVI centuries). Noceu is located south of the capital, about 4 kilometers.
It is a neuralgic point of Camino de Santiago since in the old schools, in front of the church, is the hostel of pilgrims (to reach it, the walkers must previously cross the beautiful village of San Pedro). It also highlights the Torre de Leces, one of the stately towers par excellence of the Late Middle Ages. The town is located on a high point, with very good views, at 2 kilometers southwest of the capital.
San Miguel de Ucio
Village through which the river transits, which then enters the Ardines massif and runs through the interior of the famous Tito Bustillo cave, draining in the Sella very close to the village. The village is located 3 km south of the capital of the council.
Santianes
Located at 20 altitude meters on the banks of the Sella River, it is the main access point to the Sierra Riosellana and its highest point, Mount Mofrechu. Surrounded by native forests, the village preserves good examples of traditional architecture, such as granaries, remains of several mills and a church dedicated to San Juan Bautista. It is located 3 kilometers east of Ribadesella.
Sardalla
From here we enjoy unbeatable views of the fishing village. The heart of the village stands out for its traditional aroma. Near the river Sella, on the edge of the protected space of the Mediana, is the Palacio de la Piconera and its annexed houses, an Indiano ensemble built in 1891. The palace has a rectangular floor with classicist reminiscences. The village is 3 kilometers south of Ribadesella.
Sardedo (Sardéu)
5 kilometers to the southwest of the village, at the foot of the popular Peña Pagadín, is this town, scattered in an irregular orography, forming the praos quite steep slopes. The village is famous for hosting several estancias of the Princes of Asturias.
Sebreño (Sebreñu)
2 kilometers to the south of the capital, is a village of Asturian essence, with traditional houses, corradas and hórreos. Surprise the visitor, after a vast prao, the rural Renaissance palace of the sixteenth century reformed in the eighteenth and twentieth centuries. Arranged with a central body with a recent wooden corridor and two lateral bodies flanked by firebreaks. The set is completed with chapel and hórreo.
Tereñes
One of the most visited towns of Ribadesella, especially for its unbeatable views to the sea. It is in full Jurassic coast, and its pedral, the Pedral de Tereñes, is one of the milestones of the research, with numerous samples of ichnites and fossils on the rocks. The Ribadesella Lighthouse also rises in this term, in the so-called Punta Se Somos. Tereñes is the seat of the popular Fiesta del Pez and is located at 2,5 kilometers west of the urban center of Ribadesella.
Toriellu
4 km east of Ribadesella, noted for its coastal strip and proximity to the beautiful cliff of Tomasón. The village extends in a number of twists and turns where we find significant samples of traditional architecture. It is also located here one of the most renowned and traditional restaurants of Ribadesella.
It is located at 5 km west of the capital, in a small valley where the Acebo rivers and its tributary El Castañar meet. Very close to Torre, the natural passage of Entrepeñas opens, giving access to the town and the beach of Vega. A unique building called El Llagarón stands out in the village, with a striking decorated door with the date of 1786. There are some outstanding hórreo and panera in Torre. There is in its term a mining exploitation dedicated to the spar-fluorine, also establishments dedicated to the hotel trade.
Tresmonte
It is a village located at 170 meters high in the foothills of Monte Moro. It conserves some examples of traditional architecture (hórreos and paneras), and a beautiful hermitage dedicated to San Agustín. By Tresmonte the PR AS-58.1 passes. Route of the Mills. This small town, today only inhabited by a family, is known to have been the birthplace of D. Manuel Fernández Juncos, defender of Spanish in Puerto Rico against the advance of English. Tresmonte is located to the South of the capital, at about 6 kilometers.
Registered in full Jurassic coast, 7 kilometers west of the capital, is home to one of the most amazing wild beaches of Asturias. The set formed by the sickles of Entrepeñes and the beach of Vega-Berbes It has been declared a Natural Monument.
Beautiful towns of Asturias Best towns Asturias Ribadesella: basic information Guided tours through Ribadesella


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Our Plan in Support of Immigrant Rights
As your City Council Member, I will fight to make New York City a more equitable and safe home for immigrants:
Support community-based organizations and City agencies to better provide resources and support to immigrants.
Help immigrants get equitable aid, have equal representation, and feel safer in New York City.
Press for stronger immigrant support and protection at the state and federal levels.
Read more below...
The Issues:
New York City's strength lies in its cultural diversity as a city of immigrants. Immigrants comprise nearly 38% of our city's population and 45% of its workforce, with parts of The Bronx having particularly high concentrations of immigrant residents. Immigrants contribute to our local economies, and to richer, local communities. Despite the resilience and strength of our immigrant communities, COVID-19 has deeply hurt and traumatized immigrants, and laid bare pre-existing inequities. In my work with immigrant communities I have seen the devastating impact of anti-immigrant policies and their impacts on families and seniors throughout The Bronx.
Immigrants are facing a disproportionate impact from COVID-19—economically, physically, and emotionally. Immigrant communities have seen a dramatic loss of primary income, a rise in eviction threats, and increased food insecurity. COVID-19 and the Trump Administration's racist rhetoric throughout the crisis have also created a spike in anti-Asian hate crimes, which have caused Asian immigrant communities to fear for their safety, and Asian business owners to see even more drastic losses throughout these intersecting crises.
In terms of support throughout the pandemic, our immigrant communities have been shut out of almost all government stimulus support and cash assistance programs. Many immigrants are not eligible for state unemployment due to their immigration status, and a lack of health care, language access, and digital equity have further deepened the struggles immigrant communities face.
Our Solutions:
In order to build back better and make New York City a place for everyone to thrive, we need to prioritize support for our immigrant communities.
As your City Council Member, I will fight alongside the residents of District 11 to make New York City a more equitable and safe home for immigrants.
Support community-based organizations and city agencies to better provide resources and support to immigrants:
Ensure that community-based organizations that serve and work with our immigrant communities are adequately funded and supported by City Council.
Work to make sure that the Department for the Aging is equipped to address older immigrants' needs and that senior centers have resources to offer culturally- and linguistically-responsive services.
Allocate additional funding to community-based organizations that offer avenues of support for Asian immigrant communities and business owners.
Ensure that special provisions exist for immigrant communities in all essential services provided by the City, prioritizing language access, digital equity, and culturally-responsive offerings.
Expand the role of the Mayor's Office of Immigrant Affairs to provide free or low-cost translation services for community-based organizations, to create jobs and improve language access.
Help immigrants get equitable aid, have equal representation, and feel safer in New York City:
Strengthen anti-harassment laws and resources for immigrant tenants.
Ensure that immigrant business owners are included in grant and loan disbursement throughout COVID relief.
Pass City Council Intro 1876, that would give the right to vote to non-citizen but permanent residents and green card holders in New York City elections.
While it is important to support our immigrants at the city-level, I recognize that support cannot stop there.
As your City Council representative I will use my platform to press for stronger immigrant support and protection at the state and federal levels:
Advocate for state legislation on immigrant health care and support the Coverage for All Campaign that seeks to create a statewide health insurance solution for New Yorkers who are excluded from eligibility for coverage because of their immigration status.
Advocate for federal reforms including:
Expand Special Immigrant Juvenile Status (SIJS) through the inclusion of children who juvenile courts have intervened to protect from domestic violence in the home, reducing the barrier of special findings orders.
Expand pathways to citizenship and support the Biden administration's current plan that would expand pathways to citizenship for 11 million undocumented peoples living in the United States.
Fully rescind the Public Charge Rule.
Protect Deferred Action for Childhood Arrivals (DACA) and Temporary Protected Status (TPS).
Fully include all immigrants in COVID-19 financial assistance and relief programs.
Implement a moratorium on certain deportations.

redpajama_set_name: RedPajamaCommonCrawl


Sport Experience is a major business accelerator based in The Netherlands, which cooperate with the FIFA, NOC, other major relevant to sports organizations, startups and investors. The project provides financial, resource and expert support to the early-stage companies, working specifically in the sports field.
One of the events held by the company is the annual Sports Business Day, which takes place in the beginning of November in Eindhoven, the Netherlands. The biggest sportive startup occasion in Europe is a unique opportunity for progressive companies to demonstrate the proper potential and insights to attract the investment inflow from the European market and extend the business activity abroad. The accelerator is focused on the sports industry development.
The accelerator not only takes on the role of a platform for startup's presentation but also assures of the actual support in finding the sponsorship and cultivating foreign markets.
Last year SmartSport.com™ was involved in the event and had a chance to represent the company to the European business community. SmartSport.com™ is the innovative marketplace for training camps, which offers to choose sports complexes, accommodation, and transfer at a single location. The project has become a revolution in the sports world, offering fast and simple access to the sports facilities worldwide. Currently, the startup deals with over 600 objects in more than 32 countries around the globe which are increasing daily.
Sport Experience calculated the startup's accounting model and declared evaluation in 5 million dollars. The accelerator had attracted a number of enterprisers ready to invest according to the assessed valuation. However, SmartSport.com™ made a choice in favor of the proper capital provider, offering not only financial but also knowledge-based support.
One year passed the parties are going to renew the cooperation. Sport Experience has shown the strong interest in the startup and invited the CEO Ilya Popov to the following business conference to discuss the partnership.
SmartSport.com™ is growing really fast, which is reflected in the site traffic, the number of orders proceeded, the staff increase and business indicators. Currently, the company opens branch offices in Europe and America. Since the startup applies the B2C business model, the presence of offices in different economic territories is very important for the market developing and establishing relationships with international partners.
At this stage the startup's strategy largely depends on the SmartSport's engagement in the American TechCrunch Disrupt Conference, which is expected to raise sizable funding from the transoceanic market, however, Sport Experience is ready to offer the independent cooperation terms. Sport Experience represents expressed a belief that the SmartSport's idea is relevant and unique for the European market, which could serve the development of the industry at large.
The accelerator is ready to offer new investors and to provide all-round support with European affiliated branch opening.


Tom was born and raised in Berks County, PA on a Dairy Farm known as Mat Mar Farms Inc., in West Leesport. Tom went on to manage the farm and held the position of president for 10 years.
As the agricultural economy changed over the years in Berks County, Tom became well-known as the always smiling, ever patient Parts and Service Manager at Manor Equipment in Sinking Spring. He held this position for over 20 years.
Tom began his career in Real Estate after many years of serving customers and clients within his own community. He enjoys working with buyers and sellers of all ages and continues to stay in touch with his clients long after the sale via phone calls, mailings and visits. Past clients are his best source of referrals! Tom works in Berks County and Lancaster County and has offices in both counties as well.
When it comes to working with the senior market, his qualifications are literally unmatched. Tom has earned the national designation of Certified Senior Advisor Realtor in Berks County. He also has the SRES Realtor Designation (Senior Real Estate Specialist) for working with seniors in the mature market.
Tom has also completed the Real Estate e-PRO Designation (enhanced internet and technology professional), the CRS designation (Certified Residential Specialist) and just recently the ABR Designation (Accredited Buyer Representative.) This education has given him the ability to use advanced technology that is necessary to enhance his business and better serve his clients in the ever changing residential and commercial real estate world.
In Tom's "free time" he loves to spend time with his grandchildren and golfing. Having golfed in many different states one of his favorite courses remains Willow Hollow Golf Course in Leesport. He also loves watching sports, football being the favorite. Another hobby is camping, and spending time with family and friends.
Tom believes there has to be a balance between business, family and God. He loves to give back and is an active member of the following organizations.
information about real estate in your area, contact Tom today.


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Bukit Batu Lawi map
Bukit Batu Lawi
3.871493 N 115.386298 E
Batu Lawi is a twin-peaked mountain in the Kelabit Highlands of Sarawak, Malaysia (Borneo) that has played important roles in both ancient mythology and modern history. The taller 'male' peak is 2046 metres above sea level, while the female summit is at 1850 metres. It is one of the highest mountains in the state of Sarawak.
By elevation Bukit Batu Lawi is
# 42 out of 5270 in Malaysia
# 7 out of 1148 in Sarawak
By prominence Bukit Batu Lawi is
# 97 out of 1148 in Sarawak
Bukit Batu Lawi model
7.3 km E
3.88 N 115.451667 E
Mount Murud - 13.9 km ENE
6.9 km SE
Unnamed Summit - 6.9 km SE
Check out a downloadable 3D model of Bukit Batu Lawi area. A higher resolution model can be found in the PeakVisor mobile app.
Do you have photos of Bukit Batu Lawi or know something about it? Please let us know!
Loading Bukit Batu Lawi panorama


text:
/**
 * Autogenerated by Thrift
 *
 * DO NOT EDIT UNLESS YOU ARE SURE THAT YOU KNOW WHAT YOU ARE DOING
 *  @generated
 */

#include <src/gen-py3/extend/clients_wrapper.h>

namespace cpp2 {
ExtendTestServiceClientWrapper::ExtendTestServiceClientWrapper(
    std::shared_ptr<cpp2::ExtendTestServiceAsyncClient> async_client) :
    HsTestServiceClientWrapper(async_client),
    async_client(async_client) {}

folly::Future<folly::Unit> ExtendTestServiceClientWrapper::disconnect() {
  return folly::via(
    this->async_client->getChannel()->getEventBase(),
    [this] { disconnectInLoop(); });
}

void ExtendTestServiceClientWrapper::disconnectInLoop() {
    async_client.reset();
    cpp2::HsTestServiceClientWrapper::disconnectInLoop();
}

folly::Future<bool>
ExtendTestServiceClientWrapper::check(
    cpp2::HsFoo arg_struct1) {
 return async_client->future_check(
   arg_struct1
 );
}

} // namespace cpp2

redpajama_set_name: RedPajamaGithub


Dang Weather and a slow part time mechanic are holding me up from getting my lude back home where I can start adding all my goodies that I have stockpiled.
So since there aint no where to go and its snowing like a mofo, might as well photoshop.
I photo shopped the height of the car and colored in the primer. HA!
Last edited by bukolo; 01-30-2014 at 06:22 PM.
Gives you insight on the final product. Nice.
Clone tool or what to get it red?
Did you photoshop a cover half on it? Or is that Montana snow?
My black car took a few weeks to fix at one point. It happens.
A little here, a little there, dude eventually fixed it.
Any-hoo, I covered it every evening upon returning home from work and uncovered it upon leaving for work every day he had it 'cept weekends... he kept it indoors on the weekend as a 'thanks for not being sore at me for taking so long' gesture.
He wanted it fixed as much as I did. For differing reasons though.
I wanted it home, he wanted to know wtf kept both fans from working so he could finally fix it.
Yeah a little bit of clone tool and cropping. Exactly my thoughts for doing this is to give me an idea of finished product.
Yep and thats MT snow. And more snow to come, already 3 more inches today.... BOOOOOOOOOOOOOOOOOOOO!
Last edited by bukolo; 01-30-2014 at 08:43 PM.
I was thinking to myself that from what I've seen on tv, Montana usually has a harsh winter.
ie it seems like you'd have photo shop-ed a red 4th into a gigantic snow bank.
AND SAVED! NEW SCREEN SAVER!
someone photoshop me in a Lambo?
Gives a good perspective of whats to come. I have no photoshop or paint skills lol.
Ohh Gawd! I almost died when I seen Godzilla with Mac and cheese! ROFLMAO!
I didn't know the Biebs was part of this group! HA!
LMAO!!!!! FUKC YOU!!! BUT STILL LMAO!!!!


Patients remain at the center of everything we do at GlycoMimetics. Through collaboration with our investigative partners, we are conducting clinical studies that explore the use of product candidates developed by our scientists in different hematological and oncologic settings. Our central goal is to obtain the data required for review and approval by regulatory authorities, such as the U.S. Food and Drug Administration.
Learn more about the RESET study at resetsicklecell.com.
To learn more about other clinical trials involving our product candidates, please visit ClinicalTrials.gov. ClinicalTrials.gov is a registry of publicly and privately supported clinical studies involving human participants conducted around the world. To find information on trials run by GlycoMimetics, our development partners, or by independent investigators, use the "Search for Studies" function and enter the product candidates name (e.g., uproleselan).


Similar to a Bridezilla, a Momzilla is highly controlling of the many elements to a wedding. Everything must be perfect for her child's day. This child is often the bride, but may sometimes be the groom. The excuse for being controlling and overbearing is usually that the Momzilla has paid for a large amount of the wedding expenses. Common conflicts in which Momzilla may attack include last-minute changes to plans, guests/party members who she does not like, and the bride and groom declaring that they do not like her ideas.
1. The mother-of-the-bride turned into Momzilla when her daughter said she wouldn't wear her grandmother's dress.
2. My friend's mother was upset that her ex-husband appeared at the wedding. Fortunately, a few drinks were enough to soothe Momzilla.
Get a momzilla mug for your dad Callisto.
"Did you see how Tammy cut up my meat for me and tell me how to save money by using coupons? She is such a momzilla!!!"
Get a momzilla mug for your cousin Julia.
Essentially a 'new mom' who is so baby focused they are obsessive, and could develop into control freaks; basically the ones who go on and on and on about their kids and carry a few albums of pictures with them.
Jenny was a bit of the momzilla of the group, and dominated the conversatiosn talking about her kids.
Get a Momzilla mug for your cousin Riley.
Get a Momzilla mug for your sister Sarah.


text:
Potamogeton richardsonii is a species of aquatic plant known by the common name Richardson's pondweed. It is native to much of northern North America, including all of Canada and the northern and western United States. It grows in water bodies such as ponds, lakes, ditches, and streams. This perennial herb grows a narrow, mostly unbranched stem from a mat of rhizomes in the substrate. It reaches about a meter in maximum length. The leaves are up to 13 centimeters long and about 3 wide with crinkly pointed or rounded tips. The inflorescence is a spike of flowers arising from the water surface on a peduncle.

References

External links
Jepson Manual Treatment
Washington Burke Museum

richardsonii

redpajama_set_name: RedPajamaWikipedia


text:
import { OnInit } from '@angular/core';
import { ControlValueAccessor, NgModel } from '@angular/forms';
export interface TimepickerConfig {
    hourStep: number;
    minuteStep: number;
    showMeridian: boolean;
    meridians?: any[];
    readonlyInput: boolean;
    mousewheel: boolean;
    arrowkeys: boolean;
    showSpinners: boolean;
    min?: number;
    max?: number;
}
export declare const timepickerConfig: TimepickerConfig;
export declare class TimepickerComponent implements ControlValueAccessor, OnInit {
    cd: NgModel;
    hourStep: number;
    minuteStep: number;
    readonlyInput: boolean;
    mousewheel: boolean;
    arrowkeys: boolean;
    showSpinners: boolean;
    min: Date;
    max: Date;
    meridians: Array<string>;
    showMeridian: boolean;
    onChange: any;
    onTouched: any;
    private _selected;
    private _showMeridian;
    private meridian;
    private hours;
    private minutes;
    private selected;
    private invalidHours;
    private invalidMinutes;
    constructor(cd: NgModel);
    ngOnInit(): void;
    writeValue(v: any): void;
    registerOnChange(fn: (_: any) => {}): void;
    registerOnTouched(fn: () => {}): void;
    protected updateHours(): void;
    protected hoursOnBlur(): void;
    protected updateMinutes(): void;
    protected minutesOnBlur(): void;
    protected incrementHours(): void;
    protected decrementHours(): void;
    protected incrementMinutes(): void;
    protected decrementMinutes(): void;
    protected toggleMeridian(): void;
    private refresh();
    private updateTemplate();
    private getHoursFromTemplate();
    private getMinutesFromTemplate();
    private pad(value);
    private noIncrementHours();
    private noDecrementHours();
    private noIncrementMinutes();
    private noDecrementMinutes();
    private addMinutesToSelected(minutes);
    private noToggleMeridian();
}


text:
NEWSFLASH : Keel ram problem on SMA
This afternoon at 1415 UTC, Paul Meilhat contacted his team to inform them of a problem with his keel ram. The ram has a 40 cm (16 inch) crack and this has led to the keel canting leeward of the boat. Paul is in the process of blocking the system to try to get the keel in the middle. To carry out this operation, he bore away and is heading towards the north.
It was after hearing an unusual noise early this afternoon that the skipper of SMA went to inspect his keel housing. He immediately realized that oil from the hydraulic circuit had flooded the ram compartment. He thought first of all that it was a pipe that had burst in the hydraulic circuit, but then noticed a 40 cm crack in the ram itself.
SMA is currently in the middle of the Pacific Ocean, 2000 miles east of New Zealand.
More information to follow...
HOW TO FOLLOW THE RACE
All of the pictures and programs will also be available on the video server www.vendeeglobe.tv
Web SailingBreezes.com
Video of Dragonsbane, a globe-trotting 43-foot Sceptre, at the 35th Heineken Regatta in St. Maarten, March 2015.
About Sailing Breezes Magazine
Please send us your comments!!


The BCT (A) is an international, standardized exam in Chinese language proficiency that focuses on testing non-native Chinese speakers' abilities to use the Chinese language in real business or common working environments, and that evaluates the language tasks they are able to complete. Following the principle of practicality, oriented towards speaking and listening, and emphasizing abilities in the workplace, this test aims to recreate actual situations in the workplace and takes practical content for communications as the method of examining test takers' abilities to use Chinese to meet their needs in a working environment.
The BCT (B) score report records a test taker's sub-test scores and total score, without setting any passing score. The report will also provide competence descriptions for all levels of test takers.
Promote learning through examination: encourage Chinese language learners' interest and confidence, and further broaden the scope of the test in accordance with the actual demands of overseas Business Chinese learners and Chinese speakers in a general working environment.
Promote teaching through examination: provide teachers and self-learners with graded, task-based teaching resource sand suggestions related to business Chinese, and help teaching and training institutions systematically and effectively improve business Chinese learners and speakers' abilities to use the Chinese language in real business or common working environments.
Provide positive feedback for test takers: evaluate test takers' ability to complete various language tasks by asking them to carry out a series of typical business language tasks and provide positive feedback for Chinese language learners to plan their future studies.
The BCT (B) is an international, standardized exam in Chinese language proficiency that focuses on testing non-native Chinese speakers' abilities to use the Chinese language in real business or common working environments, and that evaluates the language tasks they are able to complete. Following the principle of practicality, oriented towards speaking and listening, and emphasizing abilities in the workplace, this test aims to recreate actual situations in the workplace and takes practical content for communications as the method of examining test takers' abilities to use Chinese to meet their needs in the working environment.
Promote teaching through examination: provide teachers and self-learners with graded, task-based teaching resource sand suggestions related to business Chinese, and help teaching and training institutions systematically and effectively improve business Chinese learners and speakers' Chinese language communicative competence in a realistic business environment.
Provide positive feedback: evaluate test takers' ability to complete various language tasks in a business environment by asking them to carry out a series of typical business language tasks and provide positive feedback for Chinese language learners to plan their future studies.


You or your declaring agent can apply for an online refund and be notified of the outcome through the Refund Module in TradeNet.
Rejection: This could include requiring the taxable importer to claim from the Inland Revenue Authority of Singapore (IRAS).
Approval: All successful refunds will be credited directly into the Inter-Bank GIRO (IBG) accounts of the payers who maintained IBG accounts with Singapore Customs.
If the GST was deducted via IBG from the taxable importer's bank account registered with Singapore Customs, (i.e. payment permits with the permit conditions "GF" & "TX"), the importer is advised to claim the GST as input tax from IRAS during the company's accounting period. The same applies if the GST was paid by the taxable importer at the bank.
However, if the claim for refund is due to stating the wrong importer's name or UEN, the importer can apply for a GST refund from Singapore Customs.
You may log in to TradeNet to check the status of your refund application.


text:
Q: scanf Getting Skipped I am trying to make a simple C program for a class and one of the requirements is that I'm required to use scanf/printf for all input and output. My question is why is it that my scanf after the for loop in the main gets skipped and the program just terminates.
Here is my code
#include <stdio.h>

void main() {
    int userValue;
    int x;
    char c;

    printf("Enter a number : ");
    scanf("%d", &userValue);
    printf("The odd prime values are:\n");
    for (x = 3; x <= userValue; x = x + 2) {
        int a;
        a = isPrime(x);
        if (a = 1) {
            printf("%d is an odd prime\n", x);
        }
    }
    printf("hit anything to terminate...");
    scanf("%c", &c);
}

int isPrime(int number) {
    int i;
    for (i = 2; i < number; i++) {
        if (number % i == 0 && i != number)
            return 0;
    }
    return 1;
}

I was able to "fix" it by adding another identical scanf after the first one, but I would prefer to just use the one.

A: The new-line character present in stdin after the previous int was entered will not have been consumed by the last call to scanf(). So the call to scanf() after the for loop consumes the new-line character and continues without the user having to enter anything.
To correct without having to add another scanf() call you could use format specifier " %c" in the scanf() after the for loop. This will make scanf() skip any leading whitespace characters (including new-line). Note it means the user will have to enter something other than a new-line to end the program.
Additionally:

*

*check the result of scanf() to ensure it actually assigns a value to the variables passed in:
/* scanf() returns number of assigments made. */
if (scanf("%d", &userValue) == 1)

*this is an assignment (and will always be true):
if (a = 1){ /* Use == for equality check.
               Note 'a' could be removed entirely and
               replace with: if (isPrime(x)) */

redpajama_set_name: RedPajamaStackExchange


Weekly Angel Card Magical Mermaids and Dolphins by:Doreen Virtue Treasure Chest! I don't want to sound Too excited, but this is my favorite angel card! This card offers you the assurance that your prayers for financial assistance have been heard and assistance is here for you, NOW! Believe it to receive it! Remain grateful, no matter how things may appear. This is the card of unforeseen windfall, a windfall that is well deserved. Gratitude proceeding what you desire is faith in action. You must believe it is yours to have for it to show up in the material world. Do You Believe? Affirm often "Thank you for all of the support, supply, abundance, and money that you bring to me. I AM Grateful for these riches, which I use in Divine Ways to bring blessings to the earth." Your abundance my reveal itself as actual money, a new opportunity, promotion, creative ideas or gifts from others. Bless and honor all gifts from God as true heavenly gifts, no matter how they show up. Your gratitude ensures continual, overflowing abundance in your life. Get excited! I sure am! Thank you so much for reading the angel card of the week. I hope you are blessed this week and this month with more abundance than you can imagine. Come back and share your story. You never know who you may help.


Susan has a Bachelor of Science degree in Interior Design with a minor in Architecture and has been working in Real Estate since January 2004. Susan has a passion for helping her buyers find that dream home using her talent to either help them see the potential of an existing home or helping design and build their dream home. She is equally talented in using her skills and knowledge in design to help her sellers stage and get their homes ready to list, assisting them to get the most value for their home. If you are thinking about buying or selling a home, but Susan's passion and skills to work for you and Call Her Today!


How to create a self-signed certificate with a specific hostname for evaluations, when configuring SSL for Knox.
In order to continue to use self-signed certificates for larger evaluation deployments, a certificate can be generated for a specific hostname. This will allow clients to properly verify the hostname presented in the certificate as the host that they requested in the request URL.
>Create a certificate: where $gateway-hostname is the FQDN of the Knox Gateway: cd $gateway bin/knoxcli.cmd create-cert --hostname $gateway-hostname.
Export the certificate in PEM format: keytool -export -alias gateway-identity -rfc -file $certificate_path -keystore $gateway /data/security/keystores/gateway.jks.
cURL option accepts certificates in PEM format only.
Restart the gateway: cd $gateway bin/gateway.sh stop bin/gateway.sh start.
After copying the certificate to a client, use the following command to verify: curl --cacert $certificate_path -u $username : $password https:// $gateway-hostname : $gateway_port /gateway/ $cluster_name /webhdfs/v1?op=GETHOMEDIRECTORY.


More and more experts are saying global warming is as grave a threat to our national security (PDF) as terrorism and nuclear proliferation. Some in the media are coming to the same view.
Picture Japan, suffering from flooding along its coastal cities and contamination of its fresh water supply, eyeing Russia's Sakhalin Island oil and gas reserves as an energy source … Envision Pakistan, India and China – all armed with nuclear weapons – skirmishing at their borders over refugees, access to shared river and arable land.
And if nuclear power plants take center stage in the drive to cut carbon dioxide emissions and therein lead to nuclear weapon proliferation, you can see why the Bulletin of Atomic Scientists moved the Doomsday Clock forward two minutes in anticipation of potentially unwise climate solutions.
There is no telling what consequence of global warming will be the most devastating — refugees, spurred terrorism, sea level rise, food and water shortages — but we must bear them all in mind. The national security threat posed by global warming will only grow if we continue our do-nothing policy.


text:
Nusia är ett släkte av svampar. Nusia ingår i divisionen sporsäcksvampar och riket svampar.

Källor

Sporsäcksvampar
Nusia


Sky's the limit. The Wave Sky 2 takes it to the next level in premium, luxurious, cushioned running. The all new upper with AeroHug technology works to provide the most comfortable fit possible, working with the foot in achieving the perfect balance of stretch, hold and breathability. Running has never felt so comfortable.


text:
The β2-Adrenoceptor Agonist Formoterol Stimulates Mitochondrial Biogenesis
Lauren P. Wills, Richard E. Trager, Gyda C. Beeson, Christopher C. Lindsey, Yuri K. Peterson, Craig C. Beeson and Rick G. Schnellmann
Lauren P. Wills
Richard E. Trager
Gyda C. Beeson
Christopher C. Lindsey
Yuri K. Peterson
Craig C. Beeson
Rick G. Schnellmann
Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β3-AR agonist), and formoterol (selective β2-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β2-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of β2-AR ligands for therapeutic MB.
Mitochondrial dysfunction is associated with the etiology of multiple diseases including Alzheimer's disease, Parkinson's disease, and diabetes, as well as renal, liver, and myocardial injury (Hagen et al., 2002; Baloyannis, 2006; Civitarese and Ravussin, 2008; Seo et al., 2010; Tran et al., 2011). Mitochondrial dysfunction is also a common cause and consequence of ischemia/reperfusion, trauma, and drug/toxicant-induced organ injury. In ischemic/reperfusion and lipopolysaccharide-induced acute kidney injury there is a persistent loss of mitochondrial function (Funk et al., 2010; Tran et al., 2011). Mitochondrial damage may hinder critical energy-dependent repair mechanisms and lead to irreversible cell injury, limiting restoration of organ function. Thus, the development of therapies to promote mitochondrial biogenesis (MB) has the potential to treat multiple pathologies and restore organ function after injury.
Mitochondria are constantly being renewed through the processes of biogenesis, fusion, fission, and mitophagy (Seo et al., 2010). MB occurs under homeostatic conditions and can be induced as an adaptive response initiated by cells to meet energetic demands resulting from injury and genetic, metabolic, and dietary events, thereby affecting health and disease (Medeiros, 2008). MB is a complex process requiring the coordination of both nuclear DNA and mitochondrial DNA (mtDNA) that encode for mitochondrial proteins. A primary regulator of MB is the nuclear transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). PGC-1α interacts with cAMP response element-binding protein and nuclear respiratory factors 1 and 2 to regulate the transcription of multiple genes (Wu et al., 2006). PGC-1α provides a direct link between external physiological stimuli and the regulation of MB and is inducible both physiologically and pharmacologically.
There are a limited number of chemicals known to induce MB. The Spiegelman group conducted a high-throughput screen that examined the effects of 3000 compounds in skeletal muscle cells, and 82 compounds (2.5%) increased PGC-1α mRNA (Arany et al., 2008). Our laboratory has reported that isoflavones, a 5-hydroxytryptamine type 2 agonist [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride] (DOI), and a silent mating type information regulation 2 homolog 1 activator (N-[2-[3-(piperazin-1-ylmethyl)imidazo [2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide; SRT1720) induce MB in renal proximal tubular cells (RPTC) (Rasbach and Schnellmann, 2008; Funk et al., 2010; Rasbach et al., 2010). Furthermore, we determined that the stimulation of MB after the initiation of cellular injury accelerates cell repair and regeneration. For example, after t-butylhydroperoxide-induced oxidant injury, exposure of primary cultures of RPTC to 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride or SRT1720 or overexpression of PGC1-α accelerated the recovery of mitochondrial and ATP-dependent cellular functions (Rasbach and Schnellmann, 2007; Funk et al., 2010; Rasbach et al., 2010). Therefore, targeted stimulation of MB may be a valuable approach in the development of new therapies for the treatment of injury and disease characterized by mitochondrial impairment (Funk et al., 2010).
Agonists for the β2-AR have been reported to modulate oxidative metabolism, energy expenditure, lipolysis, glucose transport, and glucose oxidation (Agbenyega et al., 1995; Hagström-Toft et al., 1998; Pearen et al., 2008). Pearen et al. (2009) found that mice dosed with the β2-AR agonist formoterol showed a 5-fold mRNA induction of PGC1-α in skeletal muscle. In addition, exercise-induced increase in PGC-1α mRNA was inhibited by pretreatment with the β2-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551) and the β-AR antagonist propranolol, suggesting that β-AR activation mediates exercise-induced increases in PGC-1α in skeletal muscle (Miura et al., 2007; Sutherland et al., 2009). Thus, the stimulation of the β2-AR signaling pathway may regulate mitochondrial function in multiple tissues.
β-AR receptor agonists are approved therapeutic agents for the management of asthma and other diseases. The β2-AR has been successfully targeted for drug discovery by using a ligand-based approach, resulting in the creation of multiple receptor-specific drugs (Wishart et al., 2006). Kolb et al. (2009) used the X-ray structure of the β2-AR to conduct a structure-based screen of nearly one million commercially available molecules. Using the β2-AR crystallized in complex with the inverse agonist carazozol, the researchers identified 25 novel compounds that fit the receptor, and six of the compounds were confirmed as inverse agonists. However, the therapeutic potential of β2-AR agonists as inducers of MB has not fully been explored (Ortega and Peters, 2010).
In this study, we used a unique phenotypic approach developed by Beeson et al. (2010) to examine the potential of β2-AR agonism to induce MB in both the kidney and heart. The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to evaluate the effects of β2-AR agonists on maximal mitochondrial respiration in primary cultures of RPTC and cardiomyocytes, two cells highly dependent on aerobic metabolism. In vivo and ligand-based in silico studies were then used to integrate the effects of β2-AR agonists on mitochondrial function and gene expression, with detailed analysis of chemical structure. These data were used to develop a discrete pharmacophore model capable of predicting novel compounds with MB properties.
All experiments were performed in accordance with national and institutional guidelines for animal welfare, adhering to protocols approved by the institutional subcommittee on research animal care.
All solvents and reagents, unless otherwise stated, were supplied by Sigma-Aldrich (St. Louis, MO) and used as supplied.
(±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344), (R*,R*)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide fumarate (formoterol furmarate dihydrate), and (R)-3,4-dihydroxy-α-(isopropylaminomethyl)benzyl alcohol hydrochloride (isoproterenol hydrochloride) were purchased from Sigma-Aldrich and confirmed to be 98% pure by HPLC. The Library of Pharmacologically Active Compounds (LOPAC) was purchased from Sigma-Aldrich, and the compounds were confirmed to be 95% pure by HPLC. The ChemBridge DIVERSet 50,000-compound library was purchased from the ChemBridge Corporation (San Diego, CA), and the compounds were confirmed to be 95% pure by HPLC.
Biological Evaluation of Compounds
Isolation of Proximal Tubules.
Female New Zealand white rabbits (1.5–2.0 kg) were purchased from Myrtle's Rabbitry (Thompson Station, TN). Rabbit renal tubules were isolated by using the iron oxide perfusion method as described previously (Nowak et al., 1995). The resulting proximal tubules were plated on 100-mm tissue culture-grade plastic Petri dishes constantly swirled on an orbital shaker at 80 rpm. The culture medium was a 50:50 mixture of Dulbecco's modified Eagle's essential medium and Ham's F12 (lacking glucose, phenol red, and sodium pyruvate; Invitrogen, Carlsbad, CA) supplemented with 5 μg/ml human transferrin, 5 ng/ml selenium, 50 nM hydrocortisone, and 10 nM bovine insulin. After 3 days the de-differentiated cells were trypsinized and replated onto XF-96 polystyrene cell culture microplates (Seahorse Bioscience) at a concentration of 18,000 cells/well and maintained in a 37°C incubator for 2 days before experimentation (Beeson et al., 2010).
Isolation of Primary Adult Feline Cardiomyocytes.
Adult feline cardiomyocytes (AFC) were isolated to 95% purity as described previously (Mann et al., 1989). In the present study, we used glass-bottom dishes (MatTek, Ashland, MA) coated with laminin for culturing cardiomyocytes in Piper's medium, which was prepared in M199 cell culture medium (Invitrogen) containing the following additional ingredients: 2% bovine serum albumin, 5 mM creatine, 2 mM l-carnitine, 5 mM taurine, 0.25 mM l-ascorbate, 10 μM cytosine arabinoside, 200 units/ml penicillin, and 200 mg/ml streptomycin (Invitrogen). The freshly isolated adult cardiomyocytes were plated into XF-96 polystyrene cell culture microplates and maintained in a 37°C incubator for 2 days before experimentation.
Respirometry Assay.
The oxygen consumption rate (OCR) measurements were performed by using a Seahorse Bioscience XF-96 instrument according to the protocol outlined in Beeson et al. (2010). Each experimental plate was treated with vehicle controls (DMSO <0.5%), a positive control (SRT1720, 10 μM), blank controls, and the appropriate concentration of the compound of interest. The XF-96 protocol consists of five measurements of basal OCR (1 measurement/1.5 min), injection of p-trifluoromethoxyphenylhydrazone (FCCP) (0.5 μM), and three measurements of uncoupled OCR (1 measurement/1.5 min). The consumption rates were calculated from the continuous average slope of the O2 partitioning among plastic, atmosphere, and cellular uptake (Gerencser et al., 2009). Quality-control evaluations considered the basal and uncoupled rates of the vehicle control, positive control, and variances between duplicate treatment wells. Based on preliminary studies the positive threshold value was >1.15 for the mean ratio of chemical treatment FCCP-OCR/vehicle control FCCP-OCR. This threshold is ≥1 S.D. above the historic mean for the vehicle control.
Dosing of C57BL/6 Mice.
Male C57BL/6 mice (National Cancer Institute, Bethesda, MD) were between 6 and 8 weeks old. The mice were housed in groups of three in a temperature-controlled room under a 12-h light/dark cycle. Mice were randomly assigned to either saline control or formoterol-treated groups (n = 3–6 mice/group). Treated mice received daily intraperitoneal injections of formoterol for up to 72 h (100 μg/kg/day), and control mice received an equivalent volume of sterile saline.
Real-Time Reverse Transcription-PCR.
Total RNA was isolated from renal cortex and heart by using TRIzol reagent (Invitrogen). cDNA was synthesized from 2 μg of RNA template by using a SuperScript II Reverse Transcriptase kit (Invitrogen). PCR products were amplified from 5 μl of cDNA template in a 25-μl reaction containing 12.5 μl of 2× SYBR Premix (Agilent Technologies, Santa Clara, CA) and 400 nM of each primer (Integrated DNA Technologies, Inc., Coralville, IA) (Supplemental Table 1). The average fold induction was calculated by comparing the CT (threshold cycle) of the target gene to that of tubulin (the reference gene). The gene expression of the reference gene remained consistent throughout each treatment. The CT of each of the technical replicates was averaged, and that average was used in the following formulas:
Mitochondrial DNA Content.
Real-time PCR was used to determine relative quantities of mtDNA content in both RPTC and mouse kidney and heart tissues. Genomic DNA was extracted by using the DNeasy Blood and Tissue kit (QIAGEN, Valencia, CA). PCR products were amplified from 25 ng of cellular DNA in a 25-μl reaction containing 12.5 μl of 2× SYBR Premix and 400 nM of each primer. For estimation of mtDNA in RPTC the NADH dehydrogenase subunit 6 (ND6) gene was amplified. The nuclear-encoded tubulin gene was used for normalization (Supplemental Table 1). For estimation of mtDNA in mice the control region (D loop) of mouse mtDNA was amplified. The nuclear-encoded apolipoprotein B gene was used for normalization (Supplemental Table 1) (Fuke et al., 2011).
Computational Procedures
Molecular Modeling of Potential Mitochondrial Biogenic Compounds.
Modeling, simulations, and visualizations were performed by using MOE version 2010.10 (Chemical Computing Group Inc., Montreal, Canada). The Sigma LOPAC and the ChemBridge DiverSet were searched by using the Tanimoto score with MACCS structural keys (166 keys) fingerprinting (Maccs II; Molecular Design Ltd., Memphis, TN). Using tables of the compounds represented as Simplified Molecular Input Line Entry System strings were imported into MOE as an mdb database. Molecules were rigidly aligned manually, and then subjected to MOE flexible body refinement (configuration limit 100, α1, gradient test 0.01, RMSD tolerance 0.5, maximum steps 500). The ChemBridge DIVERSet conformers were a stochastic force field-based library generated by using MOE conformation import with no import filters. The total number of possible conformations per molecule was 50 and used default settings including a strain limit of 4 kcal/mol, RMSD test for structural diversity of 0.15, and an energy minimization gradient test of 0.01 kcal/mol. Transconformations were enforced. Consensus pharmacophores were calculated by using a distance parameter (tolerance) maintained at the default value of 1.2 Å and a threshold of 100%. Pharmacophore feature projections including aromatic ring projections (PiN), H-bond acceptor projections (Don2), and H-bond acceptor projections (Acc2) were not included in the analysis.
Statistical Analysis.
Data are presented as means ± S.E.M. and were tested for normality. Data that were confirmed to have a normal distribution were subjected to one-way analysis of variance. The respiration data failed a normality test; therefore, a Kruskal-Wallis one-way analysis of variance on ranks was conducted. Multiple means were compared by using Dunn's post hoc test and considered statistically different at P < 0.05. RPTC and AFC isolated from a single animal represented an individual experiment (n = 1) and were repeated until n ≥ 4 was obtained. Rodent studies were repeated until n ≥ 3 was obtained.
β2-Adrenergic Agonist Induces MB In Vitro.
Kidney proximal tubules require aerobic metabolism to maintain high levels of ATP for transport processes. The primary cultures of RPTC used in this study were grown under improved culture conditions with optimized glucose-free media supplemented with 6 mM sodium lactate and increased oxygen supply (Nowak and Schnellmann, 1995, 1996). RPTC grown under these conditions remain polarized, maintain their differentiated functions, and exhibit respiration and gluconeogenesis rates comparable with in vivo renal proximal tubule cells. The primary culture of AFC used in the study also maintained differentiated function and exhibited mitochondrial respiration similar to that observed in vivo (Mitcheson et al., 1998).
Primary cultures of RPTC and AFC have been optimized for use with the Seahorse Biosciences 96-well extracellular flux analyzer (XF-96), a multiwell plate-based assay platform that addresses the need for higher-throughput cellular respirometric measurements (Ferrick et al., 2008; Beeson et al., 2010). The XF-96 instrument uses fluorescent detectors to measure OCRs and can be used to identify compounds that alter mitochondrial respiration. Injection of the proton ionophore carbonylcyanide FCCP uncouples the mitochondrial membrane potential from the production of ATP, increasing the OCR. We determined that this maximum respiratory capacity could be used as a measure of MB (Beeson et al., 2010).
The FCCP-OCR increased in RPTC after a 24-h exposure to formoterol (30 nM) relative to the vehicle control (Fig. 1A). The FCCP-uncoupled OCR was also increased in AFC after a 24-h exposure to formoterol (10 and 30 nM) (Fig. 1B). No significant changes in FCCP-OCR were observed after exposure to isoproterenol (nonselective β-AR agonist; 10, 100, and 1000 nM) or BRL 37344 (selective β3-AR agonist; 100, 300, and 1000 nM). The catecholamines dopamine, epinephrine, and norepinephrine are nonselective agonists for all three β-adrenoceptors (Hall et al., 1990). No significant changes in FCCP-OCR were observed in the RPTC after exposure to dopamine, epinephrine, or norepinephrine (30 and 100 nM) (Fig. 1C).
Formoterol exposure increases uncoupled OCR and mtDNA copy number in RPTC and AFC. A, RPTC were exposed to isoproterenol (nonspecific β-AR agonist), BRL 37344 (β3-AR agonist), and formoterol (β2-AR agonist) for 24 h and evaluated for changes in FCCP-OCR. B, AFC were exposed to isoproterenol (nonspecific β-AR agonist), BRL 37344 (β3-AR agonist), and formoterol (β2-AR agonist) for 24 h and evaluated for changes in FCCP-OCR. C, RPTC were exposed to the nonspecific β-AR agonists dopamine, epinephrine, and norepinephrine for 24 h and evaluated for changes in FCCP-OCR. D, RPTC were exposed to 30 nM formoterol for 24 h and evaluated for changes in mtDNA copy number relative to DMSO controls. Data are represented as mean ± S.E.M. of four biological replicates. *, P < 0.05.
To further document that the increased OCR values were the result of MB, mtDNA copy number was assessed. Relative mtDNA copy number was determined by using quantitative real-time PCR and the ratio of a mitochondrial-encoded gene (ND6) to a nuclear-encoded gene (tubulin). Formoterol (30 nM)-treated cells exhibited a significant 2.5-fold increase in mitochondrial copy number (Fig. 1D). These results provide strong evidence that β2-adrenergic receptor activation induces MB in RPTC and AFC and formoterol is a potent agonist.
β2-Adrenergic Agonist Induces MB In Vivo.
To determine whether β2-AR agonism in vivo produces MB, male C57BL/6 mice were dosed intraperitoneally with 100 μg/kg formoterol every day for 1 or 3 days. Kidney and heart tissues were collected from the animals, and MB was determined by assessing mtDNA copy number and the mRNA levels of multiple mitochondrial proteins.
Twenty four hours after formoterol exposure, mRNA levels of multiple genes involved in mitochondrial regulation and function increased in kidneys. PGC-1α was induced 2.5-fold and mitochondrially encoded ATP synthase F0 subunit 6 of transmembrane F-type ATP synthase (ATP6), ND1, and ND6 were induced 2.5-, 4-, and 2.5-fold, respectively (Fig. 2A). The kidneys of formoterol-exposed animals also showed 2-fold induction of the nuclear-encoded mitochondrial protein NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8 (NDUFB8). After repeated daily exposure to 100 μg/kg formoterol for 72 h, the kidneys exhibited 1.5-fold induction of PGC-1α, as well as a 2-fold induction of NDUFB8 and ND1 (Fig. 2B). The mtDNA copy number was increased in the kidneys of mice 72 h after repeated daily formoterol exposure (Fig. 2C).
Formoterol exposure induced the expression of mitochondrial genes and mtDNA copy number in the kidney cortex of CB57BL/6 mice. A, mRNA expression was evaluated in the kidney cortex of CB57BL/6 mice 24 h after a single intraperitoneal injection with 100 μg/kg formoterol. B, mRNA expression was evaluated in the kidney cortex of CB57BL/6 mice 72 h after daily repeated intraperitoneal injections with 100 μg/kg formoterol. C, mtDNA copy number was evaluated in the kidney cortex 24 and 72 h after daily repeated intraperitoneal injection with 100 μg/kg formoterol. Values indicate fold change relative to DMSO controls. Data are represented as mean ± S.E.M. of three to six biological replicates. *, P < 0.05.
The hearts of mice exposed to 100 μg/kg formoterol for 24 h exhibited a marked induction of PGC-1α, ATP6, ND1, ND6, and NDUFB8 (3-, 1.5-, 2-, 2-, and 2-fold, respectively) (Fig. 3A). After a repeated daily exposure to 100 μg/kg formoterol for 72 h, the hearts of formoterol-exposed animals exhibited a 2-fold induction of PGC-1α, a 4-fold induction of mitochondrially encoded ND1, and a 2-fold induction of nuclear-encoded NDUFB8 (Fig. 3B). The mtDNA copy number was increased in the hearts of mice 24 and 72 h after daily formoterol exposure (Fig. 3C). These results provide strong evidence that β2-adrenergic receptor activation induces MB in the kidney and heart.
Formoterol exposure induced the expression of mitochondrial genes and mtDNA copy number in the hearts of CB57BL/6 mice. A, mRNA expression was evaluated in the hearts of CB57BL/6 mice 24 h after a single intraperitoneal injection with 100 μg/kg formoterol. B, mRNA expression was evaluated in the hearts of CB57BL/6 mice 72 h after daily repeated intraperitoneal injections with 100 μg/kg formoterol. C, mtDNA copy number was evaluated in the heart 24 and 72 h after daily repeated intraperitoneal injection with 100 μg/kg formoterol. Values indicate fold change relative to DMSO controls. Data are represented as mean ± S.E.M. of three to six biological replicates. *, P < 0.05.
Formoterol-Based Pharmacophore Identifies Novel Mitochondrial Biogenics.
Using formoterol as a basis for chemical similarity and pharmacophore analysis, we explored chemical space that would otherwise be impractical to explore given the current limitations in biological assay techniques. Pharmacophores are defined as a collection of steric and electronic features required for molecular interactions with a specific biological target structure, resulting in the activation or deactivation of its biological response (Horvath, 2011). Pharmacophore models have been developed to identify biologically active chemicals responsible for therapeutic activity (Ebalunode et al., 2011). The resulting structures can be used to predict potential pharmacology based on the assumption that compounds containing the same pharmacophore are likely to cause similar effects by targeting the same active site (Horvath, 2011). Currently, there are no known pharmacophores associated with MB. We used formoterol in a ligand-based approach to identify novel compounds with a similar chemical structure and determine whether they induced MB.
We used formoterol to conduct a similarity search of the 1280-compound Sigma LOPAC. Similarity was measured by using the Tanimoto Coefficient (TC). TC is a similarity metric of one-dimensional chemical descriptors that identifies the presence of molecular elements and facilitates rapid initial comparisons (Willett, 2006). A TC similarity search of LOPAC found 23 compounds 60% similar to formoterol. RPTC were treated with the 23 identified LOPAC compounds (5 μM) for 24 h and examined for changes in FCCP-uncoupled OCR. This assay revealed that nisoxetine increases FCCP-uncoupled OCR above vehicle control (Table 1). A subsequent concentration response evaluation determined that nisoxetine increased FCCP-uncoupled OCR in a concentration-dependent manner with a minimum effective dose of 30 nM (Fig. 4A).
Formoterol pharmacophore extraction of the 1280-compound Sigma LOPAC
Chemical fingerprints defined within the MOE software package were used to cluster compounds based on molecular similarity as measured from the TC. Analysis of the data using a TC of 60% identified 23 compounds of 1280 (or 1.8%) compounds from LOPAC that matched formoterol based on chemical similarity. RPTC were treated with the 23 identified LOPAC compounds (5 μM) for 24 h and examined for changes in FCCP-OCR. This assay identified nisoxetine, which increases FCCP-OCR 15% above vehicle control.
Cheminformatic analysis of formoterol identified nisoxetine, which induces MB in RPTC. A, RPTC were exposed to formoterol and nisoxetine (10–300 nM) for 24 h and examined for changes in FCCP-OCR. Values indicate a percentage of fold change relative to DMSO controls. Data are represented as mean ± S.E.M. of four biological replicates. B, pharmacophore based on the alignment of formoterol and nisoxetine. Formoterol and nisoxetine aligned with superimposed chemical features. F1 is a proton acceptor, F2 and F3 are hydrophobic, F4 is a mixed feature with a cationic and proton donor, and F5 and F6 are mixed features with aromatic or hydrophobic characteristics. F1 and F4 were marked as essential while requiring that at least five features matched the model. C, formoterol aligned with superimposed pharmacophore.
To confirm the specificity of formoterol on β2-AR, we pretreated cells for 1 h with the β-AR antagonist propranolol (5 nM) or the β2-AR inverse agonist ICI 115,881 (3 and 10 nM) before a 24-h treatment with formoterol (30 nM). As seen in Fig. 5, both propranolol and ICI 115,881 attenuated the formoterol-induced increase in FCCP-OCR in RPTC. Nisoxetine is a norepinephrine reuptake inhibitor, and there are no direct published data suggesting nisoxetine activates β2-AR. Nevertheless, because there is a report that some effects of nisoxetine are blocked by propranolol (Springer et al., 1994), we determined whether propranolol and ICI 115,881 blocked the MB effects of nisoxetine. Propranolol (5 nM) and ICI 115,881 (3 and 10 nM) blocked the increase in FCCP-OCR produced by nisoxteine (Fig. 5).
The effects of formoterol and nisoxetine are inhibited by β2 antagonism. A, RPTC were pre-exposed to the β-AR antagonist propranolol (5 nM) 1 h before exposure to 30 nM formoterol or nisoxetine and evaluated for changes in FCCP-OCR. B, RPTC were pre-exposed to the β2-AR inverse agonist ICI-118,551 (3 and 10 nM) 1 h before exposure to 30 nM formoterol or nisoxetine and evaluated for changes in FCCP-OCR. Values indicate a percentage of fold change relative to DMSO controls. Data are represented as mean ± S.E.M. of four biological replicates. *, P < 0.05.
Formoterol and nisoxetine were aligned in first two and then three dimensions based on the presence of consensus chemical features within 100% of the compounds. This alignment resulted in a pharmacophore containing six features of conserved chemical similarity (Fig. 4, B and C). F1 is a proton acceptor, F2 and F3 are hydrophobic, F4 is a mixed feature with a cationic and proton donor, and F5 and F6 are mixed features with aromatic and hydrophobic characteristics. Distances of the model are: F1–F2, 2.53 Å; F2–F4, 2.02 Å; F4–F3, 1.77 Å; F3–F5, 4.55 Å; F5–F6, 6.56 Å, and F6–F4, 4.76 Å.
The six-point pharmacophore model was used to search the ChemBridge DIVERSet for similar compounds. This library contains 50,080 unique drug-like compounds that represent a wide range of chemical diversity. These compounds were used to create a 1,420,467-entry conformer library. An in silico search identified 16 compounds containing all six chemical features with a RMSD <1 Å. No compounds with an RMSD >1 Å were identified, but this was expected because each feature was only ∼1 Å in diameter and six features were absolutely required, leading to a minimum possible RMSD. Note that the TC search and pharmacophore search of ChemBridge had no overlapping compounds.
RPTC were exposed to the 16 identified ChemBridge compounds (5 μM) for 24 h and examined for changes in FCCP-OCR. This assay identified three novel compounds (CB1, CB2, and CB3) that increase FCCP-OCR above the vehicle control (Table 2). In a previous study, our laboratory tested 480 random compounds from the ChemBridge DIVERSet on the XF-96. From these 480 random compounds, 13 were determined to be biogenic (unpublished data). We extrapolate that the spontaneous hit rate of the entire data set would be approximately 2.7%. Our pharmacophore performed with a hit rate of 18.8% of the compounds it chose. Using the enrichment factor equation from Pearlman and Charifson (2001), our pharmacophore selected a subset of the database 6.9 times richer in biogenic compounds than the original database:
The six-point formoterol pharmacophore model was used to search the ChemBridge DIVERSet for similar compounds
The ChemBridge DIVERSet contains 50,080 unique drug-like compounds that cover pharmacophore diversity. These compounds were used to create a 1,420,467-entry conformer library. An in silico search identified 16 compounds (or 0.03%) containing all six chemical features with a RMSD < 1 Å to the pharmacophore model for all features. RPTC were exposed to the 16 identified ChemBridge compounds (5 μM) for 24 h and examined for changes in FCCP-OCR. This assay identified three novel compounds (CB1, CB2, and CB3) that increase FCCP-OCR 15% above the vehicle control.
RPTC were exposed for 24 h to 10 to 3000 nM of CB1, CB2, and CB3 to determine potency in increasing FCCP-OCR. CB2 and CB3 increased FCCP-OCR in RPTC with maximal effects at 30 and 100 nM, respectively, whereas CB1 was not effective at this concentration range (Fig. 6A). These data were incorporated into the original model and used to further refine the pharmacophore. Formoterol, nisoxetine, CB2, and CB3 were aligned in both two and three dimensions and matched all six of the original features, suggesting the model accurately described all of the essential features (Fig. 6B). Analysis of the final alignment revealed a unique hydrophobic feature (F7) found in nisoxetine and CB2 (Fig. 6C; Table 3).
Formoterol pharmacophore identified two ChemBridge compounds that induce MB in RPTC. A, RPTC were exposed to ChemBridge compounds 1, 2, and 3 (10–300 nM) for 24 h and evaluated for changes in FCCP-OCR. Values indicate a percentage of fold change relative to DMSO controls. Data are represented as mean ± S.E.M. of four biological replicates. B, refined pharmacophore based on the alignment of formoterol, nisoxetine, CB2, and CB3. In this alignment, F1 is a proton acceptor, F2 and F3 are hydrophobic, F4 is a mixed feature with a proton donor and a cationic or proton acceptor, and F5 and F6 are mixed features with aromatic or hydrophobic characteristics. F7 is a unique hydrophobic feature found in nisoxetine and CB2. F1, F2, F4, F5, and F6 are essential features. C, nisoxetine aligned with superimposed pharmacophore.
Formoterol, nisoxetine, and (CB2) ChemBridge 5144525
The original pharmacophore was built by using formoterol and nisoxetine. CB1, CB2, and CB3 were found by using the original pharmacophore from a search of the ChemBridge DIVERSet 50,000 small-molecule conformational library. CB2 and CB3 were confirmed to be biogenic; however, CB2 was the only compound to add features to the pharmacophore model.
The mitochondrion is an intricate organelle, with components derived from both the nuclear and mitochondrial genomes, whose activity must be carefully coupled to cellular metabolism and signaling (Wagner et al., 2008). Mitochondrial health is essential for cell and organ function. Multiple diseases are characterized by mitochondrial impairment including diabetes, Alzheimer's disease, Parkinson's disease, and diet-induced obesity. Ischemia/reperfusion injury of the kidney, heart, and liver all show deleterious consequences on mitochondrial function. Therefore, the development of novel pharmaceuticals that induce MB may have broad usage in diverse diseases.
Despite the potential for treating disorders characterized by mitochondrial impairment, very few therapies target the mitochondria to promote its function (Funk et al., 2010). Likewise, there are no current databases matching mitochondrial biogenic activity to chemical pharmacophores or specific chemotypes. Those studies that have focused on MB as a therapeutic target have used skeletal muscle cells and assay systems using surrogate markers of MB (e.g., PGC-1α mRNA). Surrogate markers may suffer from false positives and negatives, and the use of cell lines that are highly glycolytic with limited aerobic capacity may not be sensitive to MB. The use of primary cultures of primary RPTC grown under improved conditions resolves the cell line issue, and the use of a phenotypic respirometric assay minimizes the limitations of surrogate markers.
We demonstrate that formoterol, a potent and selective agonist for the β2-AR, stimulates MB in both RPTC and AFC within 24 h of a 30-nM exposure (Fig. 1). Neither a selective β3-AR agonist (BRL 37344) nor nonselective β-AR agonists (dopamine, epinephrine, norepinephrine, or isoproterenol) stimulate MB in RPTC. In addition, the ability of formoterol to increase FCCP-OCR was inhibited by the β-AR antagonist propranolol and the β2-AR inverse agonist ICI 115,881. These data provide further evidence that specific stimulation of the β2-AR induces MB in vitro.
Researchers have shown that exercise-induced increases in PGC-1α mRNA in skeletal muscle is blocked by the β2-AR inhibitor ICI-118,551 and the β-AR inhibitor propranolol (Miura et al., 2007; Sutherland et al., 2009). In addition, PGC-1α in skeletal muscle 24 h increased after injection of formoterol (100 μg/kg) (Pearen et al., 2009). In our studies, the same dose of formoterol induced MB in the kidney and heart of male mice as indicated by increased mRNA expression of multiple mitochondrial proteins that are both nuclear and mitochondrially encoded (NDUFB8, AT6, ND1, and ND6) (Figs. 2 and 3). Furthermore, PGC1-α, the master regulator of MB, was induced both 24 and 72 h after formoterol exposure. Using the aforementioned markers of MB, these data suggest that formoterol does induce MB in vivo and in both the kidney and heart.
We used the chemical structure of formoterol to search the Sigma LOPAC of 1280 compounds to find current pharmacological compounds that were similar in structure to formoterol and therefore may induce MB. We identified 29 compounds that were tested for their ability to increase the FCCP-OCR in RPTC after a 24-h 5-μM exposure. We identified nisoxetine as a potent inducer (30–300 nM) of MB. Nisoxetine is reported to be a potent and selective inhibitor of noradrenaline uptake with little or no affinity for a range of other similar neurotransmitter receptors (Wong and Bymaster, 1976; Cheetham et al., 1996; Mochizucki, 2004). Currently there are no data suggesting a role for nisoxetine in inducing MB. It is noteworthy that nisoxetine was aligned with formoterol, and a preliminary pharmacophore was developed with six features in common (Fig. 4B). In addition, propranolol and ICI-118,551 blocked the MB effects of both compounds (Fig. 5). These data provide strong evidence that nisoxteine is an agonist at the β2-AR receptor.
In addition to finding pharmacologically active compounds with MB activity, we used the formoterol-based pharmacophore to probe diverse chemical space. The pharmacophore designed from formoterol and nisoxetine was used to screen the 50,000 small-molecule ChemBridge DIVERSet. The in silico screen identified only 16 compounds that matched all six chemical features that defined the pharmacophore. When tested using RPTC, three of the compounds (19% accuracy in prediction, enrichment factor of 6.9) increased FCCP-OCR 24 h after a 5-μM exposure. A concentration response curve for the three compounds revealed CB2 and CB3 increased MB at 30 nM, whereas CB1 had no effect at concentrations below 5 μM. The positive compounds were aligned, resulting in the development of a refined pharmacophore with six features present within 100% of the compounds (Fig. 6B). Negative data are not included, because no clear consensus to exclusion space was reached. This improved pharmacophore can be used to search libraries such as the World Drug Index to find other compounds that match the pharmacophore and induce MB. In addition, future studies will attempt to identify a broader range of novel agonists for β2-AR-mediated MB by using a structure-based approach of the β2-AR as outlined by Kolb et al. (2009).
There is an abundance of evidence showing that exercise induces MB in skeletal muscle, and data suggest that β-AR agonism is required for exercise-mediated alterations in mitochondrial function (Miura et al., 2007; Higashida et al., 2008; Sutherland et al., 2009; Little et al., 2011). However, the potential use for β2-AR agonists for the treatment of mitochondrial dysfunction and injury has not yet been explored. Although evidence suggests that chronic exposure to formoterol decreases oxidative capacity in the heart, acute exposures to β2-AR agonists have the potential to activate MB after insult with limited detrimental effects (Ortega and Peters, 2010; Léger et al., 2011). Agonists for the β2-AR are promising therapeutics to treat mitochondrially related organ dysfunction found in diseases, including diabetes, and to promote recovery after injury, including acute kidney injury. We have identified a role of formoterol in the induction of MB in both the kidney and heart. In addition, we have used the chemical structure of formoterol to identify four new mitochondrial biogenic compounds. Future studies will focus on the potential of formoterol exposure to promote recovery of kidney and heart mitochondrial function in both disease and injury models.
Participated in research design: Wills, Peterson, C. C. Beeson, and Schnellmann.
Conducted experiments: Wills, Trager, and G. C. Beeson.
Contributed new reagents or analytic tools: Peterson.
Performed data analysis: Wills, Trager, Lindsey, Peterson, C. C. Beeson, and Schnellmann.
Wrote or contributed to the writing of the manuscript: Wills, Trager, Peterson, and Schnellmann.
We thank the staff at the Medical University of South Carolina Drug Discovery Core for access to the ChemBridge DIVERSet and the Medical University of South Carolina/Seahorse Biosciences Academic Core Facility.
L.P.W. is funded by the National Institutes of Health National Cancer Institute [Grant T32 CA119945-04] and the National Institutes of Health National Institute of Environmental Health Sciences [Grant F32 ES020103-01]. R.G.S. is funded by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK062028, DK071997], the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES012878], the National Institutes of Health National Institute of General Medical Sciences [Grant GM084147], and the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs. Animal facilities were funded by the National Institutes of Health National Center for Research Resources [Grant C06 RR-015455].
http://dx.doi.org/10.1124/jpet.112.191528.
mitochondrial biogenesis
adult feline cardiomyocytes
F0 subunit 6 of transmembrane F-type ATP synthase
β-AR
β-adrenoceptor
ChemBridge
threshold cycle
FCCP
carbonylcyanide p-trifluoromethoxyphenylhydrazone
high-performance liquid chromatography
LOPAC
Library of Pharmacologically Active Compounds
ND1
NADH dehydrogenase subunit 1
NDUFB8
NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8
oxygen consumption rate
PGC-1α
peroxisome proliferator-activated receptor γ coactivator 1-α
RMSD
root mean square deviation
RPTC
renal proximal tubule cells
SRT1720
N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide
Tanimoto Coefficient
BRL 37344
(±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate
ICI-118,551
3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride.
Received January 5, 2012.
U.S. Government work not protected by U.S. copyright
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You are at:Home»Uncategorized»Celebrating Windmills
Celebrating Windmills
By Elizabeth Normen on	 July 2, 2019 Uncategorized
By Donna Baron
(c) Connecticut Explored Inc. Spring 2019
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Connecticut farmers used small windmills for years, primarily to pump water for livestock and for household use. Information about where these windmills once stood, however, is often hard to come by. In Lebanon, there was a windmill at Redwood, the historic home on the southwest corner of West Town Street and Exeter Road. According to the Norwich Bulletin, in April 1913 a fire threatened Redwood when the house next door burned to the ground. Redwood's kitchen roof was badly burned, but the house was saved because of its windmill. More than 100 men responded to the fire alarm and formed bucket brigades to bring water from the windmill's storage tank to douse the flames.
In 1978 dairy farmer Clayton Williams (1899 – 1981) recalled in an oral history interview in the archives of the Lebanon Historical Society that there was a windmill-driven water system on his farm at 105 West Town Street when his parents moved there about 1902. The windmill tower was 60 to 65 feet tall and had a 1,500- to 2,000-gallon storage tank about 30 feet above the ground. A pump was buried underground to keep it from freezing. The gravity system fed water through pipes laid to the barn and the house. Williams also recalled windmills at 234 Trumbull Highway in the Liberty Hill section of Lebanon, 688 Trumbull Highway, just north of the Baptist Church, 15 West Town Street, and 1035 Trumbull Highway, one mile south of the town green.
The last remaining windmill is located on the McCaw farm between the houses at 812 and 820 Trumbull Highway. Although the blades or sails are missing, the tower is a striking landmark on the east side of the green.
Learn more about the impact of water on Lebanon at the Lebanon Historical Society's new exhibition "Working Water," on view through September 1, 2019.
Donna Baron is director of the Lebanon Historical Society Museum. This story is based on Alicia Wayland's "Windmills,"Lebanon Provisions, Summer 2015.
Working Water
On view March 1 to September 1, 2019 this exhibition investigates the history of water-powered businesses, the development of resorts and camps on old millponds, and the impact that weather has had on the water resources of Lebanon, Connecticut.
Lebanon Historical Society Museum, 856 Trumbull Highway, Lebanon
860-642-6579; HistoryofLebanon.org


Facebook is has the capability to keep photos you showed your friends, follower, even with those you shared on your timeline. How To Delete An Album Off Facebook - Sometime you attempt to produce album for your pictures, this gives you fast access to what you carry your account. On the other hand, you may want to erase pictures album from your Facebook account.
May be you have tried different means, however you can not remove album at once, just what you do is erasing pictures in the album together.
At the same time you are lucky today as you are about to learn just how you could delete photos album at one click on your Facebook account.
If you really wish to delete Photos album from your account, then the complying with steps will certainly lead you with.
Step 4: Then click Albums to see all your Facebook picture albums. The number of pictures in an album is displayed listed below the name of the album, I believe this is excellent.
Tip 5: On any kind of album you wish to erase, click the three dots to view option to delete. On the other hand you could open the album as well to locate the setups symbol on the page, click the symbol to see delete alternative.
Action 7: Finally click erase album to complete your activity.
Deleting an album erases all its pictures permanently; removed albums can not be recuperated. So prior to you remove photo album, reconsider as you remove can not be recoup.


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