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Whether you are running a business or educational seminar or hosting a movie, a big screen can make a long-lasting expression. Usually, for movies and games, the projector offers a much greater size as compared to television on a short budget. If you are leading a business, again it is a very flexible and reliable way to share presentations with groups of large size. This Best cheap projectors buyer guide will help you to learn about various types of portable projects and find the one that perfect fits your needs.
Best Cheap Projectors Comparison
|Best Cheap Projectors
|Image Resolution
|Image Brightness
UO Smart Beam Laser
|2.2x.2.2×2.2 inches/ 500 grams
|60 lumens
|4,200 mAh
|DLNA, Miracast, HDMI
|6 inches/181 grams
|32 lumens
|2 hours' battery
|DLNA, Miracast, HDMI
ZTE SPro 2
|5.3 x 1.2 x 5.2 inches/1.3 pounds
|200 lumens
|6,300 mAh
|Miracast, HDMI, USB port, Wi-Fi
Sony MP-CL1
|5.9 x 3 x 0.5 inches/7.4 ounces
|32 lumens
|USB flash drive, Mini HDMI, MHL cable, Miracast
|ASUS ZenBeam E1
|83 x 29 x 110 mm/307 grams
|150 lumens
|Miracast, HDMI, USB flash drive
JmGO View
|9 inches long with 2.85 inches in diameter/2.2 lb
|250 lumens
|USB port, HDMI
| 3.9 x 5.9 x 1.6 inches/
1.3 lbs
|400 lumens
|60 minutes
|USB drive, microSD card, HDMI
Philips Pocket Projector PPX4010
|0.87×2.7×2.6 inches/2.93 ounces' weight
|100 lumen
|2 hours
|USB port, PC
Lenovo Pocket Projector
|1×4.1×3.9 inches/5.9 ounces
|854 by 480p
|50 lumens
|microSD card, IOS device, Windows computer, Wi-Fi
|Vivitek Qumi Q6
|1.2 by 6.4 by 4 inches (HWD)/1 pound
|800 lumens
|Wi-Fi, HDMI
UO Smart Beam Laser
The UO Smart Beam Laser is one of the smallest yet best cheap projectors you will find on the market. It weighs around 500 grams with 2.2 inches' dimensions all around. The portable projector features a 720p resolution along with fast laser autofocus. It gives you very clear and sharp images instantly. All the pictures are bright and rated at 60 lumens hence allowing you to watch videos and movies even in the dark areas. The image quality is simply up to the mark, and it finely focuses at even far distances with the maximum screen size of 100 inches.
Moreover, the projector has inbuilt speakers that are loud enough to watch movies in a huge crowd. The device comes with Bluetooth external speakers. It offers you the various option for setting up a video for playback. Also, you can connect your smartphone to the projector wirelessly using either DLNA or Miracast. In addition to that, it features mini HDMI port that can be used to plug in your laptop. The project has 4,200 mAh battery that lasts up to 2 hours and even more if you are connected with HDMI. Finally, if you are planning to watch a long movie then plug the device into an AC power outlet.
1 UO Smart Beam Laser features a 720p resolution with fast laser autofocus.
2 It is compatible with various platforms including HDMI, DLNA, etc.
3 It comes with 4,200 mAh battery.
1 At times, the projector tends to have a bluish tint.
2 It does not have audio output.
PicoPro is a beautifully designed portable projector which is small enough to comfortably fit in your pocket, among the best cheap projectors. The length of the projector is 6 inches, and it weighs 181 grams. The projector has a fascinating design and gives appearance of two bricks being stuck together. It is very easy to find a surface for the projector to rest as it comes with 360-degree rotation.
It features 720p resolution with 32 lumens light. The picture quality is fanatic. It has infinite auto focus feature hence you don't need to worry about fiddling with the focus. It gives a very clear image that does not go out of focus up to a screen size of 250 inches. PicoPro has built-in speakers, and quality of the sound is excellent. Moreover, there is a standard audio jack available thus letting you connect your set of speakers or headphones. It effectively supports the DLNA and Miracast. Also, it comes with a mini-HDMI port. Lastly, the battery of the projector lasts for approximately 2 hours. It can be connected both wirelessly and wired.
That's some handy gadget you're falling in love with!
1 PicoPro comes with 360-degree rotation.
2 It features a mini HDMI port.
3 It gives a very clear image with 720p resolution and infinite audio focus.
1 The sound of the speakers is not loud enough.
ZTE SPro 2
The ZTE SPro 2 projector is an Android-powered device with a 5-inch touchscreen among the best cheap projectors. The touchscreen can be used for web browsing, photos, message your friends and family, download apps from Google Play Store and much more. You can connect the projector to Wi-Fi and is also available for AT&T and Verizon Wireless.Moreover, you can take advantage of 4G LTE data connectivity and watch videos directly from YouTube and other media streaming websites. The portable projector gives you local storage as well, and it comes with microSD card slot to support up to 64 GB.
It can also be connected wirelessly through Miracast, HDMI and USB port for charging the device. Coming towards the picture quality, its rating is 200 lumens with 720p resolution. It gives you bright and sharp images with absolutely beautiful colors at 120 inches. You will not find any tints or hues as the color production is very accurate. It offers you different options for brightness, autofocus, etc. One of the unique features of ZTE SPro 2 is Keystoning in which the projector automatically connects to the wall, and the image will be of rectangular shape. Finally, the device has 6,300 mAh battery which keeps it running for approximately 3 hours.
1 ZTE SPro 2 features a 5-inch touchscreen with many options.
2 It gives you micro SD card slot to support up to 64 GB.
3 It offers a unique and significant Keystoning feature.
1 The implementation of the auto-focus feature is a bit slow.
Sony MP-CL1
Sony MP-CL1 is compact as a smartphone with a classic rectangular design. It is thin and lightweight thus becoming a truly portable option yet the best portable projector. It uses laser technology, and the brightness is 32 lumens. Giving you a dazzling image at any distance less than 40 inches away. The projector creates a 120-inch image with a 16:9 aspect ratio. It gives you Keystoning feature with both automatic and manual controls.
The image always remains clear due to laser-based projection. The device comes with a plastic stand that can be clipped onto the front or back which differs among other best cheap projectors. Sony MP-CL1 allows you to stream media through a plug in a USB flash drive, connect to Mini HDMI and MHL cable or Miracast. It comes with built-in speakers. Also, you can use the external pair of speakers through an auxiliary jack. Though the projector does not come with a lot of accessories, if you are looking for an extremely portable projector, then the device is for you.
1 Sony MP-CL1 has a very compact design.
2 It allows you to steam media through various platforms.
3 It features laser technology thus giving ravishing and clear image.
1 The projected image is a bit darker.
2 The Keystoning feature has no autofocus capabilities.
ASUS ZenBeam E1
The ASUS ZenBeam E1 features a LED based system with 150 lumens brightness. The portable projector is compact and lightweight with dimensions 83 x 29 x 110 mm and 307 grams' weight. The device projects image through via Miracast, HDMI or a USB flash drive. You can easily access the picture setting via the menu button. You will also find volume rocker and input selection button.
Moreover, there is a physical focus dial which gives you a very precise and accurate focus. ASUS ZenBeam E1 features Keystoning and inbuilt speakers. It comes with an aux port to let you plug in an external set of speakers. Coming towards the picture quality, the color reproduction is pretty impressive even darker scenes can be best viewed. The projector can be perfectly used for presentations and other related activities. Overall, it is an ultra-portable and affordable projector in the thick of best cheap projectors.
1 ASUS ZenBeam E1 features a LED based system.
2 It offers you various picture settings via menu button along with volume rocker and input selection button.
3 It features a physical focus dial for more accuracy and convenience.
1 The maximum resolution id just 480p.
JmGO View
JmGO View is one of the best portable projector, is a circular design and paired with a magnetic stand that holds it firmly. The device can be tilted to any angle thus allowing you to find the best position with ease. It has a great Keystoning feature which prevents the image from distorting even when the angles are not perfectly right. The most distinctive feature of the projector is that it runs Android 4.4.4 Kitkat. The software is very customized to give you clean and simple experience while navigating through the apps such as YouTube, Netflix, etc. It comes with a small remote to control everything.
Furthermore, you can upload the videos using a USB flash drive that can be plugged into the USB port or HDMI which distinguishes it among the best cheap projectors. Also, you can stream videos from your phone through Miracast, Netflix or other streaming services. The picture quality of the device is exquisite. It features a resolution up to 720p with 250 lumens. Besides this, it has a large pair of speakers with fantastic sound. Overall, the projector has an excellent functional design, picture quality, loud speakers and 3D capabilities.
1 JmGO View has 3D video capabilities.
2 The speakers of the projector have extraordinary quality.
3 It is running Android 4.4.4 Kitkat.
4 Very large throw distance.
1 It is an expensive projector.
2 1500 lumens of brightness.
3 1500 lumens of brightness.
The AAXA P300 is an excellent projector for both movies and presentations. It gives a bright image with 50-inch projection and 400 lumens. Has one of the shortest throw distances and you can get a picture big enough for viewing from as close as 4 feet and comes with a replaceable battery pack that offers up to 60 minutes. The projector has a standard HDMI input which makes it very easy to play all of your content.
Also, it can play files from USB drive and microSD card. Likewise, it has an integrated speaker, and you can listen whatever is displaying. There is also audio if you want to connect better speakers or headphones. AAXA P300 includes a remote that makes it very easy to adjust the volume, navigate files, swap inputs, etc. Lastly, there is a standard ¼"-20 tripod mount on the bottom of the P300 along with a mini tripod making it the best portable projector.
1 AAXA P300 comes with a remote for more convenience.
2 It can play files from both USB and microSD card.
3 It gives a 50-inch projection with 400 lumens.
1 The image is somewhat over-saturated and has a color tint.
Philips Pocket Projector PPX4010
The Philips Pocket Projector PPX4010 is one of the smallest portable projector with dimensions 2.1 x 3.8 x 0.7 inches and 9.6 ounces' weight. The projector only connects to USB port or a PC to an AC adapter as there is no other power source. It can connect to mobile devices through HDMI port or Displayport. Also, there are two connectors on it i.e. mini-HDMI port and micro-USB port.
It is an LED-based model with a three-position mechanical switch for adjusting brightness. The projector gives a 44-inch image in dark theater lighting which is quite a comfortable size for extended viewing. The quality of the image is also impressive, and the brightness is evenly distributed across the entire screen. The color balance is excellent as it gives exceptional and eye-catching colors in all the best cheap projectors. Overall, it is a strong contender if you need a project that perfectly goes along with your laptop.
1 Philips Pocket Projector PPX4010 is slight and lightweight.
2 It gives WVGA (854-by-480) resolution with 16:9 aspect ratio.
3 The LED source lasts the life of the projector.
1 There is no internal battery and speakers.
2 No battery.
3 Connecting to phones or tablets requires a separate connection for power.
Lenovo Pocket Projector
The Lenovo Pocket Projector measures 1.16 x 4.72 x 4.33 inches and weighs 6.4 ounces. The projector is two-toned and allows you to point the lens at any angle. It comes with an inbuilt rechargeable battery of 5,400mAh which lasts around 2.5 hours. It has 854 by 480 native resolution along with 50 lumens brightness. Coming towards the connectivity, you can either project from a microSD card, IOS device or Windows computer which is excellent among all the best cheap projectors.
For wireless connectivity, your mobile device or computer must be connected to Wi-Fi. The device throws a 40-inch image which is a good size for video whereas, with a lot of ambient light, the optimal size is approximately 18-inches. The video quality is good enough, and the color reproduction is also impressive. The pocket projector can be best used by both consumers and businesses making it another best portable projector.
1 Lenovo Pocket Projector features swiveling lens which provides great flexibility in projector placement.
2 It comes with an inbuilt rechargeable battery that has relatively long life.
3 It projects from both microSD card or wirelessly.
1 The projector lacks wired connectivity.
2 It has a very soft audio.
Vivitek Qumi Q6
The Vivitek Qumi Q6 is an LED-based portable projector. It includes built-in Wi-Fi along with 4GB of internal memory. The dimensions of the projector are 4.03 x 6.5 x 1.34 inches (HWD) and weigh 1.1 pound. It gives 1,280-by-800 resolution, and the brightness is rated at 800 lumens. The Q6 features Keystone and zoom that can be adjusted digitally by using the remote. The device includes both HDMI and an HDMI-to-mini-HDMI cable to connect to your mobile device.
Also, there is a port to fit in a USB thumb drive. The best portable projector comes with a remote control to navigate the projector's menu, and you can easily access various music, photos, videos and other files. Coming towards the image quality, it gives good enough quality that best suits to business and classroom presentations. The size of the image is about 36-inches. Lastly, Q6 has 3D projection capabilities, and it gives many bright images. Overall, it is a great projector with various convenience features that you must be looking for.
1 Vivitek Qumi Q6 is compact and lightweight.
2 It has 4GB of internal memory.
3 It comes with inbuilt Wi-Fi.
4 Sharp and bright pictures.
5 Good connectivity.
1 It shows scaling artifacts.
2 It has very feeble audio.
3 Poor black level response.
10 things to consider when buying a portable projector:
- Brand.
- Purpose of buying the portable projector.
- Battery life.
- Indoor vs Outdoor quality.
- Reliability.
- Cost.
- Resolution.
- Brightness.
- Aspect Ratio.
- Connectivity options.
All of these the very best cheap projectors are put into this buyer guide after a detailed research. They offer you an excellent quality picture, multiple connectivity platforms, various image options and much more. A portable projector is cost effective and gives you the same results that you expect from a big screen. These top 10 best cheap projectors are the most reviewed and highly rated ones. Grab one of them soon and enjoy your favorite movies with your friends and family. Also, for businesses they are the most convenient projectors to use to create a great impact on the audience. It is our valuable opinion for you to choose among these best cheap projectors.
Cast zoom!!


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Toddler Activities
Collection by Jamie Reimer - Activities for Toddlers and Preschoolers at Home • Last updated 18 hours ago
Quick and simple toddler activities to do at home! No prep crafts, art projects, sensory, fine and gross motor activities. Teach your toddler letters, numbers, shapes, colors without worksheets. Use supplies you already have - pipe cleaners, pom poms , play dough, popsicle sticks, toilet paper rolls, painter's tape and more. Activities for Christmas, Easter, Halloween and other holidays. Fun things to do with toddlers to keep them busy and having fun! #2yearolds
Super Simple Autumn Landscape Art Activity for Kids | HOAWG
Add a touch of Fall color to your home with an easy Autumn landscape art activity!
Halloween sensory bags for kids to make #halloween #halloweenactivitiesforkids #sensoryactivities #sensorybags #growingajeweledrose #activitiesforkids
10 Ways to Go on a Halloween Scavenger Hunt
On a search for Halloween scavenger hunts for kids, I found 10 spooky-fun hunts with pumpkins, spiders, monsters, ghosts and decorations.
Craft Stick Christmas Tree Ornaments
An easy ornament to make with the kids are these craft stick Christmas tree ornaments. Fun to decorate and pretty to see on the Christmas tree!
Button Sorting Activity for Simple Color Recognition | HOAWG
Easy, no-prep activity you can do at home to teach kids colors using supplies you already have. Works fine motor skills at the same time! #toddleractivities
Easy Scented Ice Sensory Play Activity for Kids
Cool off on a hot day with a scented sensory play activity! It's easy to DIY with supplies you have at home, too.
Pin on Activities for Toddlers and Preschoolers at Home
Get toddlers and preschoolers moving with this 5 Hungry Ants Chant! A super simple, no-prep and no-supply activity for kids to do at home! #grossmotoractivities
Reindeer Crafts and Activities for Toddlers
These reindeer crafts and activities for toddlers are so cute! They are such a fun Christmas activity and great for holiday gifts too. Reindeer Crafts and Activities for Toddlers These reindeer crafts are always popular
Create a Family of Pumpkin Mummies for a Halloween Craft for Kids
A family of pumpkin mummies is what every Halloween needs! Fun craft for both kids and adults to make for Halloween! Create one or many for a whole family.
Tons of Fun, Just Simple Lines of Colored Tape!
What to Do with Just Some Lines of Tape - 2 very simple tape activities can do quickly - pinned by @PediaStaff – Please Visit ht.ly/63sNt for all our pediatric therapy pins
Straw Drop Painting Apple Tree Craft
Create a straw drop painting apple tree craft to work on fine motor skills.
How To Decorate A Pumpkin With Dyed Pumpkin Seeds
How To Decorate A Pumpkin With Dyed Pumpkin Seeds via @handsonaswegrow
Apple Week: A Back-to-School Family Tradition
An apple book inspired week of reading and activities to get your kids ready for back-to-school this fall! Apple fun for the whole family!
Cute & Crafty Fingerprint Christmas Cards for Kids to Make | HOAWG
Send festive fun with adorable fingerprint Christmas cards - made by your kids! Learn how with this easy tutorial.
Shape Christmas Tree Cards
My kids had so much fun making these shape Christmas tree cards! We're going to use them as gift tags instead of cards though. I grabbed my stash of cardstock and let the kids pick
Beautiful Yarn Apple Craft for Kids to Make | Hands On As We Grow
Yarn crafts always make for fun crafts for the kids. Make this easy yarn apple craft for some simple kid-made Fall decor!

subset: commoncrawl


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While dieting and exercise can lead to results in moderately heavy individuals, it is much more difficult for those who are morbidly overweight or obese to lose weight by those means. In cases where normal dieting and exercising are beyond the capabilities of the individual, surgery for weight loss in Encino is both a viable and necessary means of losing excess weight to achieve a better state of health and livelihood.
For weight loss in Encino Dr. Feiz does a thorough evaluation to determine whether the patient is a good candidate for bariatric surgery, after which he determines which procedure is most beneficial to the patient. The weight loss surgeries Dr. Feiz performs include the Lap Band/Realize Band, lap-gastric bypass and the lap-sleeve gastrectomy, all of which achieve weight loss for the patient at a different pace. Although the Lap Band is the most popular option, as it is adjustable and results in minimal scarring, not everyone can undergo this procedure. In these cases, the patient will undergo the gastric bypass or sleeve gastrectomy.
Dr. Feiz ensures that his patients are fully informed as to the risks of surgery, as well as how the surgery is carried out and what to expect post-op. The extensive experience in performing weight loss surgeries coupled with the individualized care he gives each patient has made Dr. Feiz a premier surgeon for weight loss in Encino.


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BG is clearly focused on satisfying our clients. Our job is not simply to develop a project, but to help the client succeed. We approach projects to succeed, always recognizing that cost, quality, and delivery time are critical factors in creating and deploying systems that meet exactly functi
BG was established in 1992, under the name of Beshara Group Company. BG is fully Kuwait owned company with paid-up capital of $1 Million USD. For the past 20 years, our organization has grown and established a solid reputation in the business community and with our technology partners for developi
In order to stay ahead, modern sophisticated projects require careful planning and implementation. When these steps are executed well they pave the way for projects to proceed smoothly simply because expectations are clearly understood by all parties involved. The benefits: projects can go live fa
The key personnel at Beshara Group have vast and proven experience in the global software market in executing large offshore and on-site projects for companies of international esteem. They are also known for their technical and managerial capabilities in the areas of Product Development and
Position Description: The Network Security Analyst is responsible is responsible organizational User Policies. The Network Security Analyst strives to provide all approved users of the enterprise with uninterrupted access to network resources in all office locations, Internet, wireless, and remote connectivity to the organization network. The Network Security Analyst will be responsible for investigating, tracking and concluding security incidents that have occurred within the network. The Network Security Analyst acts as the liaison between outside organizations and approved users. Required Technical Expertise: Working knowledge in Network protocols and mechanism like MPLS, VPN, OSPF, SNMP and others. Working knowledge with WAN/LANs architecture and OSI model. Working knowledge in CISCO Routers and Switches network infrastructure with level 2 & level 3 implementations (preference for expertise related to KIN network infrastructure). Working knowledge with Internet protocols such as TCP/IP, HTTP, SMTP, DNS, FTP, BGP, NAT and others. Working Experience with CISCO Works and HP Openview. Working experience with Firewalls operation, policies, procedures and platforms (CISCO Pix, CheckPoint, Juniper, Netscreen, fortigate, sidewinder). Working Knowledge and experience in Proxy Servers, ISA servers (or equivalent), Mail servers. Required Technical Expertise: Minimum experience of 15 years in areas related to network operation, management, protocols, architecture and topologies with at least 5 years as a network security analyst. BS degree in computer science, computer engineering or equivalent degree. Detailed knowledge of security engineering (e.g. operating system, DBMS, application engineering, and workflow - methods, tools, software products, and environments and technology architectures, products and firewalls). Hands on knowledge of legacy system portfolio security management/solutions enhancement and application support. In depth know-ledge of business systems computing. Working know-ledge of hierarchical, network, relational, indexed file and object data structures/ products. Thorough understanding of network procedures and operations Demonstrated skills in human relations and communications with non-technical end-users Ability to communicate effectively and to deal with equipment vendors Knowledge at the expert level of X-25, SNA, Internet networks, connections, wiring and cabling, and network management. Years Experience Required: 15 yrs+ Travel Required: 80-100\% Contact Mail: email@example.com


text: Kimberly King Concerned about placing her child in a traditional bricks-and-mortar school, Kimberly enrolled her daughter with Nevada Connections Academy. She is very pleased with the program's use of technology, excellent curriculum, and supportive teachers. Kimberly shares her story below. "My experience this year has been nothing short of life-changing. I have been so impressed with this program! My child started out the school year unable to read or write. Now, she is writing almost better than I do, and the number of words she can read is staggering. This program allows the parent to be completely hands-on. You are able to see exactly in which subjects your student excels, and in which ones he or she needs more work. You can spend as little or as much time as you need on any assignment until your student masters it. You can go fast or slow, depending on the child, and therefore completely tailor your child's education to his or her individual needs." My experience this year has been nothing short of life-changing. I have been so impressed with this program!


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For work, I've been trying (rather unsuccessfully) to get the bluetooth on my DiNovo Keyboard working with devices other than a keyboard or mouse.
I found the BroadCom press release stating that they aquired the WIDCOMM company, stating that all the downloads have moved, but didn't point to where.
Back to Googling device drivers. 🙁


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Terms and Conditions
How to look after your shoes
Looking after your shoes and getting a long life out of them should be straight forward if you follow some simple rules.
Only use a competant cobbler to repair good shoes.
We can arrange repairs for you either with our cobbler, or a factory re-build on the last. Please call us for details.
If you believe that your shoes are faulty please return them to us for examination.
Please do not return them to us if the damage is obviously caused by wear and tear or neglect. (refer above to how to look after your shoes)
If we agree there is a fault, we will repair or replace.
Please note: There are a few less obvious causes of disintegration worth checking for.
Eye Footwear - www.eyefootwear.com - + 44 (0) 20 8911 0201


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Sponsored By
Samsung Recalls 2.8M Top-Loading Washers Whose Tops Can Detach Mid-UseSamsung is recalling an estimated 2.8 million top-loading washing machines over tops the company says can unexpectedly detach from the chassis during use.
Several Styles Of Mr. Coffee Coffeemakers Recalled For Burning Dozens Of PeopleSeveral styles of Mr. Coffee coffeemakers are being recalled after having badly burned dozens of people.
Product Safety Commission Issues Recall On Popular High Chair For BabiesThe Consumer Product Safety Commission has issued a recall on Evenflo's convertible high chair.
Feds: 'Walking On Water' Balls Could Kill You Officials are warning consumers to avoid the large inflatable plastic bubbles that children and even adults can get inside and use to walk on water.


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Come in a number of different forms depending on the person's abilities and skills; Community homes (up to 24 hour support), Semi-Independent Living, renting or owning your own home or apartment with support and Homeshare.
Community Homes
Provide community living options for individuals with an intellectual disability allowing them the opportunity to enhance their skills and be active and included in their community. Our staff encourages the individuals to participate in all aspects of daily living such as meal preparation, housework and budgeting. Our goal is to ensure the residence is regarded as the "home" of the people who live there. At the present we have two homes in Morrisburg, two homes in Williamsburg, and two homes in Winchester.
Offers support to adults with an intellectual disability in a shared home arrangement. Enrich your life by sharing your home with someone who has an intellectual disability on either a full-time basis or for weekend visits or short stays. If becoming a homeshare or respite provider interests you please contact us for more information. (Brenda Laviolette, 613-543-3737)
Semi-Independent Living
Accommodation support for adults with an intellectual disability who are more able to live independently but may still require guidance and support within their own home.
Provides parents and caregivers with an opportunity to renew themselves and people with an intellectual disability an opportunity to enjoy new experiences. Respite may come in several forms - in your home or out of your home.


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Diagnostic tools that are cheap to make, simple to use, and rugged enough for rural areas could save thousands of lives in poor parts of the world. To make such devices, Harvard University professor George Whitesides is coupling advanced microfluidics with one of humankind's oldest technologies: paper. The result is a versatile, disposable test that can check a tiny amount of urine or blood for evidence of infectious diseases or chronic conditions.
The finished devices are squares of paper roughly the size of postage stamps. The edge of a square is dipped into a urine sample or pressed against a drop of blood, and the liquid moves through channels into testing wells. Depending on the chemicals present, different reactions occur in the wells, turning the paper blue, red, yellow, or green. A reference key is used to interpret the results.


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Featured Stone - Tiger Iron
I came across Tiger Iron this winter at the Tucson Gem and Mineral Show.
Tiger Iron is a unique, semi-precious gemstone found in the Pilbara region of Western Australia. It has striking, undulating bands of Tiger Eye, Hematite, and Red Jasper.
The bands were formed during tectonic activity of the earth which caused tremendous pressure and heat. (In other words, the tiger eye, hematite, and red jasper were squished together when the earth's plates crashed against each other.)
This is a magnificent example of the Tiger Iron that I set along with citrine and garnet.
Here is another fantastic example with the three bands visible and oriented in a vertical pattern. This piece wanted to be a little mid-century modern.
There is a lot of information on the internet regarding the metaphysical properties of Tiger Iron. Just do a Google search for "Tiger Iron metaphysical properties" and you can continue reading for the rest of the day.


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Hi! My name is Sarah McLain I will be your life coach!
I'm so happy you have found me! Here is a little about me and how I landed in front of you!
I have always been drawn to "the change". How can I change one person's life for the better? What can I do to help others improve their life and accomplish their dreams?
I have found two paths that my education, experience, and personal journey, has equipped me to help others change their life.
Life Coaching and Parent Advocate Coaching...
Your goals will evolve as you achieve each one. I will teach you how to bridge that gap, create self-efficacy. I will walk with you and coach you along the way, so your usual stumbling blocks don't trip you up this time. We will find your personal capital and refocus your life to increase your quality of life.
Whether you need Life Coaching or Parent Advocacy Coaching you are in the right place. You see a goal or desire but don't know how to get there. You don't know what your next step or goal is. You want to create new healthy habits but can't quite reach it or make it stick.
Your child needs services, specialist, or outside of the box thinking, but don't know how to put the pieces together. I know the path because I have walked it!
"Quantity of life is out of your control, but quality of life is in your control"
Tune in weekly!
This "epiphany" hit me a few years ago…well honestly it was shouted at me by my husband during an argument. You know the early years of marriage when you fought over every simple topic as if it were life and death. But still I ...


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Ek Ghar Banaunga 12th November 2013 Written Episode Update
Ek Ghar Banaunga 12th November 2013 Written Episode, Ek Ghar Banaunga 12th November 2013 Written Update
The Episode starts with everyone sitting for the puja and Dadi doing the aarti. Kanno gives the aarti to everyone. Akash asks everyone to come outside as he will be preparing to celebrate the diwali with crackers. kanno does not give the aarti to Poonam's parents. Vandana asks Kanno and Kanno says I forgot as you are not our family members. Poonam sees her parents getting insulted. Vandana and Prabhunath takes the aarti.
Mangla asks Kanno and Poonam to go to the kitchen and brings sweets. Kanno asks Poonam to take few plates and she will bring the remaining plates. She says give this to your parents, I will bring the rest for everyone. Kanno smiles as she is upto something. Everyone are happliy celebrating diwali with the crackers. Akash asks Mangla and Shashikant to burn the crackers. Mangla says no, you carry on, it looks good to watch from here.
Akash asks Vandana and Prabhunath to come with him and burn crackers but they also refuse. Akash talks to Mama and jokes. Akash asks Prabhunath to sit while Shashikant looks at them. Poonam comes and offers the sweets to her parents first. Kanno smiles. Mangla and everyone get angry seeing this. Vandana asks Poonam to give the sweets to Akash's parents first. Poonam then goes to Mangla but Kanno stops them. Everyone look at Kanno.
Kanno says I will take care of everyone, you take care of your parents. She brings sweets for everyone. Vandana asks Poonam to give sweets to Akash first. Mangla asks Mama to come with her. Poonam brings sweets for Akash and he says my hands are dirty, I will wash and come. He goes after Mangla and Mama. Mangla asks Mama to go to Lucknow and find out about Poonam and her parents. She says maybe they are hiding something from us. Akash hears all this. He is shocked.
Mama says how can I do this. Mangla says Poonam is our bahu, its good for us, she is a nice girl but the way she came in this house, it shows her family values, I don't have any information about them, we don't know about her parents, we don't know what her dad does, how are they really, we should find out, so you go to Lucknow and find it secretly by asking to their neighbours. Mama says you are right, but we have to make a plan for it. Akash gets tensed hearing this.
Dadi talks to everyone saying importance of diwali festival. Poonam and Kanno also burns few crackers. Vandana feels hurt and Poonam goes to her and asks what happened. Vandana says I m fine, Poonam says maybe you are having strain while standing. Poonam goes to bring balm for her.
Akash is talking to Monica Didi and tells her about the house's auction. Monica Didi says yes you are right, think something. Akash says I don't know what to do. He turns and sees Poonam and is shocked.
Monica Didi says did Poonam come. He says yes, and ends the call. Poonam asks whats the matter, you ended the call seeing me. He says nothing, Monica Didi called and was talking about her loan problem. Poonam says she is sure the Lord won't let anything happen with Monica Didi. She asks Akash to talk to his parents about their shift to Lucknow. He says I will talk to them tomorrow. Poonam says everyone are out, and you are here in the room. He says I will come after you. she leaves saying come soon. Akash says its good she did not know anything, but how to stop Mama from going to Lucknow, have to think of some solution.
Vandana is finding the medicines. She says I think Akash has it. Prabhunath asks Vandana to call Poonam and talk to her. Vandana says I will go and bring. Shashikant is getting ready for going to office. Mangla asks him to forgive Akash. She says everyone does mistakes and its our work to forgive our kids, Akash is our son, talk to him peacefully so that he can choose some other way for them. Akash and Poonam come to them. Poonam says we came to talk about going to Lucknow. Mangla and Shashikant looks on.
jai and Kanno come to hear them whats going on. Shashikant says its decided that jai and Kanno are going. Vandana knocks Poonam's door and call their names. She goes inside the room and sees no one. She thinks where everyone went in the morning. She sees the pillow wall between Akash and Poonam and is shocked.
Shashikant says your mum will decide who will go to Lucknow. Mangla says she will tell the decision at night.
Update Credit to: Amena_Hasan


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Steps into unknown
It was a consummation devoutly to be wished, to steal a line. Terry Pratchett and Stephen Baxter, two of the most heavyweight writers of speculative fiction in the world today getting together to write a book, combining their amazing talents for a pyrotechnic literary event: The Long Earth.
The basis of the book is this: there are an uncountable number of parallel Earths that can be reached either via a small, easily made device, the plans for which are disseminated over the internet by its inventor, or through plain natural talent.
Kids start making the device, the stepper, and disappearing into other Earths. Parents are frantic, and then the kids reappear. Adults start to "step" and soon there are burgeoning colonies of people from our planet scattered through thousands of worlds beyond.
Some people can step without the device, such as Joshua Valiente, the viewpoint character. He has the added advantage of being born stepping and carrying his career on into his adulthood. There are a couple of problems with stepping, one of which doesn't bother Joshua at all. When you step you get sick for a spell. The other is that you can't carry metal with you; it just doesn't get transported by the potato-powered stepper.
Of course, the world takes advantage of the possibilities, while governments see them as problems. When the story starts, it's 15 years since step day, and worlds are being colonised, some quite close to Datum-Earth, our Earth, some further away, and everybody wants to know what's going on, so an expedition is mounted by the Black Corporation, led by the intrepid Lobsang, a Tibetan motorcycle repairman reincarnated as a computer. They travel by airship from world to world, and from that point on the story is largely the traditional adventure tale, encountering weird, wonderful and sometimes threatening things in the wilderness of worlds.
Make no mistake, this book is an entertaining read, filled with oddness and laughs and one or two tears, plus the usual acerbic Pratchett insights and Baxter plot intricacy.
The trouble is, it's a bit too full, and it is very obviously the beginning of a series, right up to the teaser at the end. So many plot elements are left unresolved, so many characters crying out for further development that the book becomes a jumble sale of orphans. The immense threat from the other worlds makes an obligatory appearance, driving all before it in waves of creatures that can step naturally. Then there's the the unforeseen disaster for which Lobsang had prepared comes and goes. The necessary love interest. The sub-plot of the colonists and their ambitions. And all the other sub-plots that are simply tossed in and seem to be forgotten about - until the next in the series.
The idea is big, an immense tapestry which can contain just about any story you wish to tell, and that's the problem. Pratchett and Baxter have tried to tell too many stories and introduce too many plot elements in one middling-sized volume. Rather than being slammed over the head with the immensity of it all, it might have been better to be given more measured doses of this particularly heady brew.
Nevertheless, I await the next book with some eagerness, if only to find out what happens with Lobsang.
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"Meditation is nothing but withdrawing all the barriers; thoughts, emotions, sentiments, everything that builds a wall between you and existence. The moment they drop, you suddenly find yourself in tune with the whole; not only in tune, you really find you are the whole." –Osho
"Remember you don't meditate to get anything, but to get rid of things. We do it, not with desire, but with letting go. If you want anything, you won't find it. You won't be able to find it. But when your heart is ready, peace will come looking for you." –Arjahn Chah
The seven chakras are an enigma to many people, but the more conscious we become of how energy moves through our body, the more we discover that which is healthy, superior, infinite, and unconditional within us. The more we meditate on this type of energy, the more we allow our personal frequency to resonate with the greater orchestra of the cosmos. And the more we allow our frequency to resonate, the more balance and health we will experience in our lives.
Opening the Earth Chakra:
"Life shrinks or expands in proportion to one's courage." –Anais Nin
This chakra, also known as the root chakra, deals with survival and is blocked by fear. In order to open this chakra we must be able to let go of fear so that it can go through the alchemical transformation into courage. The earth chakra doesn't just ground us physically it also grounds us temporally by keeping us in the present moment. Those with open earth chakras tend to be healthier and more balanced than others. They tend to be less fearful and more centered. Those with closed earth chakras are often imbalanced and disconnected, and they tend to be fearful and lack in focus.
To open the earth chakra, focus meditation on the base of your spine. Imagine a bright red energy moving down your spine and branching down into the earth like the roots of a tree. Visualize yourself receiving the full bounty of the earth's primordial energy. Relish in this most ancient of connections. Embrace your fear. Let go of your fear. Breathe the sacred breath of survival.
Opening the Water Chakra:
"Why do you stay in prison when the door is wide open?" –Rumi
This chakra, also known as the sacral chakra, deals with pleasure and is blocked by guilt. In order to open this chakra we must be able to release all blame and guilt. We must be able to forgive ourselves our past transgressions in order to delve fully into life's many unique pleasures. Those with open water chakras tend to be full of wonder and awe for their connection to the greater cosmos. They tend to be more adaptable, happy, and are able to go with the flow of life. Those with closed water chakras are often confused and disoriented about their place in the world, and they tend to suffer from autoimmune deficiencies.
The water chakra is fairly easy to transform as it responds to emotional and creative self-expression. The moon planet is a very powerful symbol with this chakra, as it controls the moving "tides" of our inner-waters. Meditate on the naval area. Imagine your psychophysiological "fluids" flowing out into the cosmos like rivers into a mighty ocean. Visualize yourself moving with the "tide" of your body's natural rhythm in balance with the greater cosmic waves of the universe. Let go of your guilt. Feel the sacred process of pleasure. Breathe.
Opening the Fire Chakra:
"There can be no transformation in the world outside unless there is transformation from within. It is our responsibility to bring about a radical transformation within ourselves." –Krishnamurti
This chakra, also known as the navel chakra, deals with willpower and is blocked by shame. We must be able to let go of past letdowns and disappointments. Or, better yet, transform them into steppingstones toward higher awareness. We must embrace our insecurities and our doubts. Dance them into something worthwhile. Dance with the fire. If it burns us to ashes, then we will rise like a phoenix. Life is too short to live it second-guessing our authenticity. Those with open fire chakras tend to lead their lives with dynamism, power, and authority. Those with closed fire chakras tend to feel unworthy and they have a low self-esteem.
To open the fire chakra, focus meditation on the solar plexus. Imagine a bright yellow light spinning there, like a brilliant sun. Imagine it bathing you in healing light, burning away the shame and replacing it with a will toward healthy power. Notice how you feel as the benevolent power of the universe blesses you with a self-esteem and a confidence to engage the world like only you can. Let go of your shame. Embrace your willpower. Breathe.
Opening the Air Chakra:
"As we let our own light shine, we unconsciously give other people the right to do the same. As we are liberated from our fear, our presence automatically liberates others" –Marianne Williamson
This chakra, also known as the heart chakra, deals with love and is blocked by grief. We must be able to release our sadness and loss in order to transform our ego into soul. We must let the pain from loss flow away like water off a ducks back. Learning how to love is learning how to let others love is learning how to let go of the egos attachment to love. This is the secret of attaining happiness despite grief. Those with open air chakras tend to be filled with unconditional love for self and others, what the Buddhists call Mahakaruna "the Great Compassion." Those with closed air chakras tend to experience poor circulation on the physical level, lack of empathy on the emotional level, and a lack of devotion on the spiritual level. They have trouble loving themselves, and they are paranoid and afraid to love others.
To open the air chakra, focus Meditation on your heart. Imagine a brilliant green light spinning there and emanating vibrant oxygen that connects you to all things. Feel this life-giving force invigorate and rejuvenate you. Imagine this connection nourishing your soul and healing your heart and skin. Touch is important with this chakra, so "feel" the cosmos pressing against your skin. "Feel" your skin absorbing the cosmos. Circulate with the Great Circulation. Let go of your grief. Allow love to wash over you and transform you into a being worthy of love and light. Breathe.
Opening the Sound Chakra:
"The mystical is not how the world is, but that it is." –Ludwig Wittgenstein
This chakra, also known as the throat chakra, deals with truth and is blocked by lies. Honesty is very important with this chakra. It is essential that we be impeccable with our word. We must be able to release ourselves from whatever we might be in denial about, and accept who we truly are. Those with open sound chakras tend to be able to say what they mean and mean what they say. Their speech is uplifting and wise and they communicate clearly their intent. Those with closed sound chakras tend to experience poor communication on the physical level, codependency on the emotional level, unclear thoughts on the mental level, and insecurity on the spiritual level.
To open the sound chakra, focus meditation on your throat. Visualize a blue sun rising up from your Solar Plexus and moving into your throat. Imagine it washing over your vocal chords and emboldening divine expression. Let the Divine Breath to activate your vocal organs. Allow your numinous voice to resonate in the sacred ether. Let go of the lies you've been telling yourself. Embrace the truth. Breathe.
Opening the Light Chakra:
"Our deepest fear is not that we are inadequate. Our deepest fear is that we are powerful beyond measure." –Marianne Williamson
This chakra, also known as the third eye chakra, deals with insight and is blocked by illusion. The illusion of separation is the greatest illusion. It is essential that we understand this, and move past the illusion, in order to actualize the Self in accordance with greater cosmic frequencies. The majority of people are unable to open this chakra. Those with open light chakras tend to see themselves and others as spiritually interconnected beings. They have great intuition, a strong sense of identity, and the ability to self-reflect. Those with closed light chakras tend to lack in imagination and have weak intuition, resulting in poor decision making and self-deception.
To open the light chakra, focus meditation on the forehead. Imagine a luminous ball of warm indigo energy emerging from your pineal gland and spinning slowly at the center of your forehead. Visualize it shooting powerful bands of light down and through your lower chakras, filling your entire being with divine light. Picture your third eye opening and reflecting aspects of the universe that you weren't aware of before. Let go of all your illusions. Allow your intuition to guide you. Breathe.
Opening the Thought Chakra
"Everything is energy and that's all there is to it. Match the frequency of the reality you want and you cannot help but get that reality. It can be no other way. This is not philosophy. This is physics." –Albert Einstein
This chakra, also known as the crown chakra, deals with enlightened transcendence and is blocked by earthly attachment. We must be able to let go of all attachments, especially love, in order to open this chakra. This is very difficult to do. Because of this, only a very small percentage of people are ever able to open this chakra. Those with open thought chakras tend to experience divine union and cosmic love, stretching out forever. Their unique frequency is in tune with the greater cosmic orchestra. Those with closed thought chakras tend to be nihilistic and disconnected spiritually, doubting everything they know to be true.
To open the thought chakra, focus meditation on the top of your head. The goal is complete surrender and dissolution; a letting go of the hold that the physical world has on you. Imagine an infinite crown of violet energy showering up into the cosmos like a mighty fountainhead connecting you to all things. Feel the powerful energy pool up from your roots, passing through the sacred waters of the sacral, basking in the fire of the solar plexus, breathing in the vital breath of the heart, absorbing the ethereal voice of the throat, pouring through the dissolution of the Third Eye, and spilling up and out the crown of your head into a thousand-petaled lotus. Feel the boundaries of your mind body and soul dissolve into all things. Let go of earthly attachment. Let go of love. You are now love itself. Breathe.
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August 2020
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Many stories make our history
Brevi was founded in 1954 by Giuliano Brevi, who had a passion for plastic and metal processing, in collaboration with his brothers, Attilio and Romano. The company stemmed from an idea: making childcare products, such as high chairs and beds, no longer with wood, but with plastic and metal. The founder's creativity led to the development of an entrepreneurial activity based on innovative style and products, which have been part of parents' everyday lives for generations


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Transcriptional regulation contributes to the maintenance of pluripotency, self-renewal and differentiation in embryonic cells and in stem cells. Therefore, control of gene expression at the level of transcription is crucial for embryonic development, as well as for organogenesis, functional adaptation, and regeneration in adult tissues and organs. In the past, most work has focused on how transcriptional regulation results from the complex interplay between chemical cues, adhesion signals, transcription factors and their co-regulators during development. However, chemical signaling alone is not sufficient to explain how three-dimensional (3D) tissues and organs are constructed and maintained through the spatiotemporal control of transcriptional activities. Accumulated evidence indicates that mechanical cues, which include physical forces (e.g. tension, compression or shear stress), alterations in extracellular matrix (ECM) mechanics and changes in cell shape, are transmitted to the nucleus directly or indirectly to orchestrate transcriptional activities that are crucial for embryogenesis and organogenesis. In this Commentary, we review how the mechanical control of gene transcription contributes to the maintenance of pluripotency, determination of cell fate, pattern formation and organogenesis, as well as how it is involved in the control of cell and tissue function throughout embryogenesis and adult life. A deeper understanding of these mechanosensitive transcriptional control mechanisms should lead to new approaches to tissue engineering and regenerative medicine.
Tissue and organ architecture are constructed as a result of the complex orchestration of various cell types that exhibit specific behaviors (e.g. growth, differentiation, migration and apoptosis) in specific locations at precise times during embryogenesis. Transcriptional programs confer and maintain cellular identity and functions that are necessary for the maturation of embryonic cells into terminally differentiated tissues or organs, as well as for stem cell fate switching throughout adult life. These behaviors are regulated by turning genes on and off in a highly spatiotemporally controlled manner, and this process is mediated at the level of gene transcription through the interplay between RNA polymerase II, various transcription factors and their co-regulators (Box 1). Whereas most studies on transcriptional regulation have focused on genetic or chemical control mechanisms of transcription, recent work suggests that mechanical forces (Box 2) are equally important regulators of transcriptional control in embryonic and adult tissues. In this Commentary, we review these new insights into cellular mechanotransduction, and discuss how mechanical cues influence transcriptional regulation to govern organogenesis and to ensure tissue maintenance throughout adult life.
Box 1. Regulation of transcription
Transcription: the synthesis of an RNA molecule from a complementary DNA sequence by RNA polymerase II that binds to the promoter region of a gene.
Transcription factor: regulatory protein that regulates transcription by binding with high affinity to its target promoter sequence on the DNA. Alone or in combination with other associated proteins, transcription factors promote or block recruitment of RNA polymerase II to the promoter regions of a gene.
Transcriptional regulation: controls the rate of transcription by regulating the binding of RNA polymerase II to the DNA strand.
Co-activator or co-repressor: associate with transcription factors to, respectively, up- or downregulate the rate of transcription.
Box 2. Mechanical forces involved in regulation of transcription
Hydrostatic pressure: mechanical force applied by fluids or gases (e.g. blood or air) that perfuse or infuse living organs (e.g. blood vessels or lung).
Shear stress: frictional force of fluid flow on the surface of cells. The shear stress generated by the heart pumping blood through the systemic circulation has a key role in the determination of the cell fate of cardiomyocytes, endothelial cells and hematopoietic cells.
Compressive force: pushing force that shortens the material in the direction of the applied force.
Tensional force: pulling force that lengthens materials in the direction of the applied force.
Cell traction force: is exerted on the adhesion to the ECM and other cells as a result of the shortening of the contractile cytoskeletal actomyosin filaments, which transmit tensional forces across cell surface adhesion receptors (e.g. integrins, cadherins).
Cell prestress: stabilizing isometric tension in the cell that is generated by the establishment of a mechanical force balance within the cytoskeleton through a tensegrity mechanism. Pulling forces generated within contractile microfilaments are resisted by external tethers of the cell (e.g. to the ECM or neighboring cells) and by internal load-bearing structures that resist compression (e.g. microtubules, filipodia). Prestress controls signal transduction and regulates cell fate.
Mechanical determinants of transcriptional control during early embryogenesis
During development, individual cells sense changes in mechanical forces and transduce them into intracellular signals that drive alterations in cell growth, differentiation, migration and apoptosis that are required for tissue and organ development (reviewed in Farge, 2011; Mammoto and Ingber, 2010; Wozniak and Chen, 2009). Early in mammalian embryogenesis, the totipotent inner cell mass (ICM) of the blastocyst gives rise to embryonic stem cells (ESCs) as a result of the expansion of the blastocoel and secretion of liquid into the cavity. The accumulation of liquid pushes the ICM against the surrounding zona pellucida, and the ICM establishes a stable transcriptional regulatory circuit, whereby specific sets of transcription factors, including OCT4 (also known as POU5F1), SOX2 and NANOG, promote pluripotency (Rossant and Tam, 2009) (Fig. 1). Importantly, dense cultures of compact, rounded mouse and human ESCs exhibit higher expression of these pluripotent transcription factors than flattened (sparse) ESCs cultured in vitro (Hemsley et al., 2011; Peerani et al., 2007). Moreover, cell stretching induced by cyclic mechanical strain leads to downregulation of OCT4 gene expression in mouse ESCs, and this is dependent on the level of cytoskeletal tension inside the cell (Chowdhury et al., 2010). These findings suggest that the transcriptional regulation that is necessary for pluripotency can be maintained and modified by the local micromechanical environment in the embryo.
Mechanical cues determine tissue pattern and size in the embryo
Studies of later developmental stages in the Drosophila wing have revealed that morphogen gradients determine tissue size and pattern, and that this process is mediated at the transcriptional level (Schwank and Basler, 2010). However, internal genetic programs and chemical cues do not appear to be sufficient to explain how these complex tissues form. Importantly, changes in the physical shape of the embryo can feed back to individual cells to mechanically control patterns of gene expression, and thereby govern tissue patterning during Drosophila morphogenesis (Farge, 2003). For instance, physiological deformations in embryonic Drosophila tissues caused by germband extension (GBE) triggers Src42A-dependent nuclear translocation of β-catenin from cell–cell junctions in the anterior pole of stomodeal cells, and activates the transcription of the basic helix-loop-helix transcription factor Twist, which is involved in pattern formation and is crucial for subsequent midgut differentiation (Desprat et al., 2008) (Fig. 2A).
Gastrulation in Drosophila is controlled by Twist in concert with the zinc-finger transcription factor Snail through Twist-dependent transcription of the gene encoding Folded gastrulation (Fog), and this process begins with mesoderm invagination (Seher et al., 2007) (Pouille et al., 2009) (Fig. 2B). First, Snail induces stochastic apical constrictions that are pulsed, and are subsequently stabilized by the secreted Fog protein (Martin et al., 2009). Mechanical tension that is generated in the apical membrane of the mesodermal cells by Snail-dependent constrictions inhibits Fog endocytosis, thereby enhancing the extracellular concentration and activating signaling pathways downstream of Fog (Pouille et al., 2009). These signals lead to local activation of the Rho and Rho-associated, coiled-coil containing protein kinase 1 (Rho–ROCK) pathway and myosin II (Myo-II) at the apical membrane, which subsequently drives mesoderm invagination (Dawes-Hoang et al., 2005). Twist is known to also activate another downstream signaling molecule, transmembrane protein T48, which reinforces apical constriction and subsequent invagination (Kolsch et al., 2007). Importantly, Myo-II, which is recruited locally in response to mechanical distortion, disappears from the membrane when mechanical tension is relieved during axis elongation in Drosophila (Fernandez-Gonzalez et al., 2009). These observations suggest that mechanical forces act in concert with chemical cues to orchestrate transcriptional and biochemical controls that are crucial for the formation of spatiotemporal patterns during early embryogenesis.
Mechanical cues also contribute to the control of cell proliferation, tissue growth and organ size during Drosophila development. For instance, computational modeling studies suggest that cells in the central parenchyma of the growing Drosophila wing become compressed, a cue that mechanically feeds back to suppress cell growth in the central area (Chen et al., 1997). Meanwhile, cell growth at the periphery of the wing will slow when the cells extend beyond the edges of the morphogen gradient. As a result, the model predicts that the tissue will grow uniformly (Hufnagel et al., 2007; Shraiman, 2005).
The Hippo pathway, a conserved signalling pathway that is crucial for the correct regulation of organ growth in Drosophila and vertebrates, appears to be involved in this feedback loop. The pathway is composed of the Hippo (Hpo) and Warts (Wts) kinases, together with their co-factors scaffold protein salvador (Sav) and MOB kinase activator-like 1 (Mats), and the transcriptional co-activator Yorkie (Yki; Yap1 in mammals) (Dick and Mymryk, 2011; Zhao et al., 2010). In both Drosophila and mice, active Hippo signaling results in phosphorylated Yki (and Yap1, respectively) being retained in the cytoplasm, which leads to transcriptional downregulation of target genes, such as the cell cycle regulator cyclin E (Fig. 2C) (Dong et al., 2007; Oh and Irvine, 2008; Oh and Irvine, 2009; Ren et al., 2010). This pathway, which enables cells to alter their proliferative rate in response to external mechanical cues, is sensitive to mechanical inputs from the extracellular matrix (ECM) and cell–cell contacts, and it requires an intact actin cytoskeleton (Assoian and Klein, 2008; Klein et al., 2007). Consistent with this observation, changes in the physical organization of the actin cytoskeleton can also alter cell growth by modulating Hippo signaling through Yap1. This further highlights a role for this cytoskeleton-dependent mechanical signaling pathway in transcription regulation, which leads to the inhibition of cell growth in response to environmental stimuli (Sansores-Garcia et al., 2011).
Mechanical control of organ-specific determination of the cell fate during development
Morphogen gradients in the embryo are converted into patterns of gene expression by concentration-specific responses of target genes (Wolpert, 1969). These gradients spatially limit the expression of target-differentiation genes and produce distinct organ-specific cell fates within precise physical boundaries of tissues (Small et al., 1992). Recent evidence suggests that external mechanical cues also contribute to the determination of tissue boundaries and organ-specific cell fates. This is important because maintaining the boundaries that are defined by these expression patterns is crucial for the maturation of these early patterns into stable tissue structures during embryogenesis (Dahmann et al., 2011). Studies in Drosophila have revealed that cytoskeletal tension – which is controlled by Rho, ROCK and Myo-II, and exerts tension on cell–cell adhesions – contributes to the formation of these discrete compartmental boundaries (Landsberg et al., 2009; Monier et al., 2010). Furthermore, during tooth formation in mouse, the dental epithelium produces morphogen gradients of opposing attractive and repulsive motility factors (FGF8 and semaphorin 3F, respectively) that generate defined areas of cell compaction in a process known as the 'formation of the condensed mesenchyme'. This, in turn, triggers the protein expression of sets of transcription factors that orchestrate organ-specific morphogenesis as a result of cell distortion and subsequent inhibition of Rho signaling (Mammoto et al., 2011) (Fig. 2D). Thus, developmental patterning and organ-specific determination of the cell fate seem to be governed through a complex mechanochemical mechanism in which chemical cues manifest their actions largely through changes in the physical microenvironment that feed back into chemical signals – which subsequently alter transcriptional control. This theory is supported by observations during mouse mammary gland development: reorganization of mouse mammary epithelial cells into three-dimensional (3D) polarized acinar structures, which are induced by the ECM protein laminin, exposes prolactin receptors to the local prolactin hormone. This, and following the nuclear translocation of the transcription factor STAT5, activates the receptors and leads to β-casein expression, which induces differentiation of cells into the mammary-specific cell lineage (Xu et al., 2009).
Mechanosensitive transcriptional control during organ development and homeostasis
Mechanical forces not only have a role during developmental processes, but are also crucial for maintaining the function of most adult organs and organ systems, including heart (Groenendijk et al., 2007; McCain and Parker, 2011), blood vessels (Culver and Dickinson, 2010; Shiu et al., 2005), lungs (Hooper and Wallace, 2006), hematopoietic system (Adamo et al., 2009; North et al., 2009), gastrointestinal tract (Gayer and Basson, 2009) and musculoskeletal system (Huang and Ogawa, 2010; Tidball, 2005). Below, we provide examples of this form of mechanoregulation in relevant organ systems.
GATA-binding protein 4 (GATA4) is a transcription factor that regulates heart development (Bruneau, 2002), and is activated by vasopressin-induced increases in cardiac afterload and through direct stretching of the ventricles in rats (Fig. 3) (Hautala et al., 2001; Hautala et al., 2002). GATA4 has also been implicated as a mechanical load-responsive mediator of transcription that regulates the expression of genes that contribute to cardiac remodeling and ventricular hypertrophy, such as B-type natriuretic peptide (BNP) (Marttila et al., 2001).
Formation of the heart valve is also flow-dependent (Bartman et al., 2004; Hove et al., 2003; Wirrig and Yutzey, 2011) and GATA4, which is also activated by the changes in blood flow in the heart (Huang et al., 2010), appears to partly mediate this response. For example, GATA4 interacts with SMAD4, another transcription factor that is part of the bone morphogenetic protein (BMP) and transforming growth factor β (TGF-β) TGF-β signaling cascade. In mouse, they co-regulate valve formation by controlling endocardial cushion development (Moskowitz et al., 2011). In zebrafish, Krüppel-like factor 2 (KLF2) – another flow-sensitive transcription factor that orchestrates the expression of angiogenic, antithrombotic and atheroprotective genes in endothelial cells (Lee et al., 2006) – has been shown to have crucial roles in valve morphogenesis (Vermot et al., 2009).
Hematopoietic system
Interestingly, in the mouse embryo, the initiation of heart pumping and blood flow also switches on the formation of blood cells, activating hematopoietic stem cells in the aorta–gonad–mesenephron (AGM) region, the origin of the dorsal aorta (Medvinsky and Dzierzak, 1996). This effect is mediated by the transcription factor RUNX1 that is induced by flow-sensitive production of nitric oxide (NO) in mice and zebrafish (Fig. 3) (Adamo et al., 2009; Lichtinger et al., 2010; North et al., 2009). Thus, mechanical forces generated by blood flow are central to the control of transcriptional activities that govern development of the circulatory system.
Blood vessels
Endothelial cells within blood vessels are constantly exposed to fluid shear stresses, pulsatile pressures and cyclic mechanical strain. The effects of fluid shear on the transcription of genes that encode proteins that are crucial for vascular homeostasis, such as platelet-derived growth factor B (PDGFB) (Resnick et al., 1993), nitric oxide synthase 3 (eNos, also known as NOS3) (Davis et al., 2004) and platelet endothelial cell adhesion molecule 1 (PECAM1) (Almendro et al., 1996), are regulated by shear-stress-responsive elements (SSREs) within their promoter regions. Fluid shear stress regulates binding of mechanosensitive transcription factors, such as nuclear factor kappa B (NF-κB) and early growth response 1 (EGR1), to SSREs in endothelial cells, where they maintain blood vessel homeostasis (Gimbrone et al., 2000). Endothelial cells also sense shear stress through a mechanosensory cell–cell adhesion complex containing PECAM-1, vascular endothelial (VE)-cadherin and vascular endothelial growth factor 2 (VEGFR2); flow-mediated mechanical distortion of the endothelial cells activates NF-κB through the integrin–p38 MAPK (also known as MAPK14) signaling cascade (Orr et al., 2005; Tzima et al., 2005). Activated NF-κB upregulates the expression of genes that encode proteins such as eNOS (Balligand et al., 2009; Davis et al., 2004; Ozawa et al., 2004), several cytokines (Allport et al., 2000; Martin et al., 1997) and adhesion molecules that are crucial for maintaining vascular homeostasis (Ahmad et al., 1998). In addition, fluid shear stress activates the transcription of the gene encoding VEGFR2 through binding of the transcription factor SP1 to its promoter, and this transcriptional regulation is crucial for endothelial cell survival (Urbich et al., 2003).
During angiogenesis, VEGFR2 protein synthesis and the formation of new microvessels are regulated by changes in ECM mechanics (e.g. stiffness or compliance), which alter the balance of activities between two transcription factors GATA2 and TFII-I (also known as GTF2I) in endothelial cells (Mammoto et al., 2009). In vascular smooth muscle cells, remodeling of the arteries in response to mechanical loads – such as changes in blood pressure – is also regulated at transcriptional level by the mechanosensitive transcription factor EGR1 (Morawietz et al., 1999). Mechanical strain induces transcription of the cysteine-rich angiogenic inducer 61 (CYR61), a crucial gene for vascular development and repair in smooth muscle cells (Chaqour and Goppelt-Struebe, 2006). In addition, cyclic stretching of rat aortic smooth muscle cells has been shown to increase the protein expression of endothelin B receptor, which is involved in blood-pressure-dependent arterial remodeling. At the transcriptional level this is mediated by activator protein 1 (AP1) and CCAAT/enhancer-binding protein (CEBP) following stimulation of the ROCK and the p38MAPK pathways (Fig. 3) (Cattaruzza et al., 2001).
Embryonic lung development is highly sensitive to mechanical cues (Costa et al., 2001; Mendelson, 2000; Minoo, 2000). Before birth, intraluminal pressures are generated by secretion of fluid by the pulmonary epithelium and the elastic recoil properties of the lung tissues (Harding et al., 1986; Vilos and Liggins, 1982). Physical stretching of lung epithelial cells activates NF-κB (Harding and Hooper, 1996), which enhances maturation of lung epithelial cells during embryogenesis in mouse (Londhe et al., 2008). In chicken lung, NF-κB activity in the mesenchyme also has a role during morphogenesis of lung branching (Muraoka et al., 2000). Similarly, the level of tensile prestress (isometric tension) generated by Rho-dependent changes in cytoskeletal contractility affects lung branching morphogenesis in mice (Moore et al., 2002; Moore et al., 2005). Mechanical stretching of the lung also drives myogenesis in airway smooth muscle, which is crucial for bronchial development. This process is mediated by the activation of the serum response factor (SRF) transcription factor (Badri et al., 2008; Yang et al., 2000). Overdistention of the fetal lung (as seen, for example, in congenital laryngeal atresia) results in the formation of larger lungs with an increased number of alveoli and a more mature architecture than expected for gestational age in humans (Wigglesworth et al., 1987). During the transition to breathing air at birth, the lung also undergoes dynamic physical changes that appear to influence formation and maturation of alveolar structures (Inanlou et al., 2005; Nelson et al., 2005; Wigglesworth et al., 1987). For example, in vitro studies have demonstrated that differentiation of rat embryonic lung cells into either type I or II alveolar cells, is modulated by mechanically distending cells in a way that mimics inflation and deflation of the alveolus during respiration (Gutierrez et al., 1999; Wang et al., 2006).
The gastrointestinal and musculoskeletal systems
Tissues within many other organs have been shown to exhibit mechanosensitive transcriptional regulation. For instance, mechanical pressure in the gut stimulates gene transcription and proliferation in rat gastrointestinal epithelial cells through MAPK-mediated activation of the transcription factor AP1 (Hirokawa et al., 2001). Exposure of these cells to pressure also modulates the synthesis of interleukin 6 (IL6) through the NF-κB pathway, which is crucial for gut homeostasis (Kishikawa et al., 2002). Mechanical loading, generated by gravity or physical movement, similarly stimulates the formation of bones, joints, tendons, ligaments, cartilage and muscle within the musculoskeletal system in humans and rats (Kahn et al., 2009; Lanyon, 1992; Raab-Cullen et al., 1994; Robling et al., 2006; Rubin and Lanyon, 1985). Many of these effects are mediated through the activation of specific transcription factors. For example, mechanical deformation of osteoblasts activates MAPK, which binds to and phosphorylates the transcription factor RUNX2, which subsequently controls expression of osteoblast-specific differentiation genes, including osteocalcin, type I collagen, bone sialoprotein, osteopontin and alkaline phosphatase in humans and rodents (Kanno et al., 2007; Ziros et al., 2008).
Similarly, during differentiation of skeletal muscle, the expression of specific sets of genes leads to the production of myofibril proteins and their assembly into contractile sarcomere units that are constantly remodeled in response to changes in mechanical load. Calcineurin, a molecular target of intracellular Ca2+–calmodulin signaling activates the transcription factors myocyte enhancer factor 2 (MEF2) and myogenic differentiation 1 (MYOD1), which mediate mechanical-load-induced myogenesis by inducing the expression of myogenin in mice (Friday et al., 2000; Friday et al., 2003; Parsons et al., 2004). Mechanosensitive endocytosis of BMP2 also has a crucial role in the transcriptional control of myogenic and osteoblastic differentiation in mouse mesenchymal stem cells (Rauch et al., 2002).
Deregulation of mechanosensitive transcriptional control and disease development
It is important to note that deregulation of normal mechanosensitive mechanisms of transcriptional control can lead to pathological changes (Table 1). In rodents, for example, excessive hemodynamic loading results in cardiac hypertrophy through exaggerated transcriptional activation of smooth muscle α-actin (ACTA2) (Mack and Owens, 1999; Zhao et al., 2007). The exposure of tissues to excessive mechanical forces increases the expression of pro-inflammatory proteins, such as interleukin-1β (IL1B), tumor necrosis factor α (TNFA), inducible oxide synthase (iNOS, also known as NOS2) and matrix metalloproteinases. Continued activation of these responses can lead to inflammatory diseases, such as arthritis (Agarwal et al., 2004; Ray et al., 2005; Yang et al., 2005), asthma (Kumar et al., 2003) and ventilator-induced lung injury (Ning and Wang, 2007).
At the same time, sustained application of mechanical force can sometimes repair diseased tissues. For instance, in a process referred to as distraction osteogenesis, gradual traction on bones is used to enhance osteogenesis for the treatment of skeletal deformities in dogs and humans (Ilizarov, 1989a; Ilizarov, 1989b; Aarnes et al., 2002). Similarly, constant stretching of the intestines leads to an increase in intestinal length in rats (Park et al., 2004) and stretching induces regeneration and lengthening of the esophagus in human infants with esophageal atresia (Foker et al., 1997). However, little is known about the transcriptional processes that mediate these mechanoresponses.
Mechanotransduction and transcriptional control
The multiple examples described above clearly demonstrate that mechanical forces can regulate the activity of transcription factors and the expression of genes that are crucial for developmental control and tissue maintenance. By contrast, the varied mechanisms through which mechanical forces applied at the cell surface or generated within the contractile cytoskeleton can produce these transcriptional alterations have only come to light recently.
Mechanosensitive transmembrane receptors
Mechanical forces can alter transcription by activating transmembrane receptors and harnessing intracellular signaling cascades that are used by soluble hormones and cytokines to alter the transcription factor activity. Work over the past two decades has revealed that mechanical signals are preferentially sensed by transmembrane surface adhesion receptors, such as integrins and cadherins, which can transfer physical forces across the plasma membrane (Fig. 3). Such mechanical signals are converted into cytoplasmic biochemical signals within cell surface focal adhesions and cell–cell adhesion complexes (reviewed in Mammoto and Ingber, 2010). These adhesion complexes can trigger transcriptional changes in the nucleus through modulating downstream signaling cascades (Ingber, 2006; Mammoto and Ingber, 2009; Mammoto et al., 2008; Orr et al., 2006). Mechanical signals can, thereby, elicit changes in the concentration of second messengers, such as Ca2+ flux, inositol trisphosphate (InsP3), diacylglycerol (DAG), cAMP and nitric oxide, or activate protein signaling molecules, such as MAPKs and Rho-family small GTPases, which are involved in controlling virtually all cellular processes, including migration, growth, differentiation and matrix remodeling (Alenghat et al., 2009; Balligand et al., 2009; Huang and Ingber, 2002; Mammoto and Ingber, 2009; Mammoto et al., 2008; Martinac, 2004; Orr et al., 2006; Papachristou et al., 2009; Sadoshima and Izumo, 1993).
One of the most rapid mechanical signaling pathways upstream of transcription involves the activation of mechanosensitive ion channels on the cell surface. In endothelial cells, cyclic mechanical strain applied through the ECM and ECM-bound integrin receptors induces Ca2+ influx through mechanosensitive transient receptor potential cation channel subfamily V member 4 (TRPV4) channels within 5 mseconds after the application of the mechanical force (Matthews et al., 2010). The resultant change in membrane potential stimulates phosphatidyl inositol-3-kinase (PI3K), which activates additional β1 integrin receptors and promotes cytoskeletal remodeling that is crucial for angiogenesis (Fig. 3) (Thodeti et al., 2009). In neurons, Ca2+ flux through mechanosensitive ion channels activates the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) pathway and stimulates the expression of genes that are essential for neuronal survival, plasticity and memory formation through activation of the transcription factor cAMP responsive element binding protein (CREB) (Dolmetsch et al., 2001; Wheeler et al., 2008).
Mechanical forces activate MAPK pathways including the ERK1/2, p38 MAPK (also known as MAPK14) and Jun N-terminal kinase (JNK, also known as MAPK8) pathways in endothelial cells, osteoblasts and fibroblasts by stimulating focal adhesion kinase (FAK) in focal adhesions (Boutahar et al., 2004; D'Addario et al., 2002; Huang and Ingber, 2002; Ishida et al., 1996). Mechanically activated ERK1/2 and/or JNK signals are transmitted into the nucleus where they activate the transcription factor AP1 and, thereby, upregulate expression of molecules that are crucial for tissue formation and remodeling, such as type I collagen and osteopontin in bone (Hong et al., 2010; Jeon et al., 2009; Kook et al., 2009). Mechanical strain and distortion of the cell shape also activate membrane-associated phospholipases and, thereby, increase the metabolism of inositol lipids and arachidonic acid in the cytoplasm, which results in the release of Ca2+ from intracellular stores, activation of protein kinase C (PKC) and the remodeling of cardiomyocytes through activation of mechanosensitive transcription factors, such as EGR1 and AP1 (Fig. 3) (Bishop and Lindahl, 1999; Komuro et al., 1991; Sadoshima and Izumo, 1993; Tseng et al., 1994). These findings suggest that mechanical cues are transmitted to the nucleus through an interplay between mechanosensitive transmembrane receptors and a variety of second messengers that modulate transcriptional activities that are crucial for cell differentiation and tissue remodeling.
The cytoskeleton as a regulator of transcription
Cells and tissues that are tensionally prestressed are held in a state of isometric tension as a result of micromechanical contractile forces, which are generated by ECM adhesions as well as adhesive contacts to neighboring cells that balance the cytoskeletal actomyosin filaments. These forces, in turn, stabilize cell shape and mechanics through a tensional integrity ('tensegrity') mechanism (Ingber, 1993). Mechanotransduction is sensitive to this micromechanical level of prestress in the cells, which is stored and released to control mechanotransduction in a way that resembles the use of a bow and bow string (Ingber, 2006).
Focal adhesion proteins that physically couple actin filaments to integrins and mediate transmembrane mechanical force transmission, including talin, paxillin, filamin A and vinculin, also act as mechanotransducers, in part by regulating cytoskeletal tension (Chan et al., 2009; Riveline et al., 2001). Part of this response is mediated by regulating the physical strength of the focal adhesion that resists cell traction forces to sustain cytoskeletal prestress (Fig. 3) (Ezzell et al., 1997). These focal adhesion proteins also facilitate translation of mechanical cues into chemical signals that modulate the Rho signaling pathway, which feeds back to control phosphorylation of myosin II and the generation of cytoskeletal tension (Mammoto et al., 2007; Zhao et al., 2007). Moreover, some focal adhesion proteins, such as paxillin and zyxin, alter their binding kinetics in a force-dependent manner (Lele et al., 2006). This enables them to shuttle between the cytoplasm and nucleus where they can act directly as co-activators of transcription to regulate gene expression (Wang and Gilmore, 2003).
In addition to the involvement of various signaling and adhesion proteins, the actin cytoskeleton itself seems to have a central role in coupling mechanical forces to the regulation of tissue growth at a transcriptional level (Wang and Riechmann, 2007). For example, actin cytoskeleton-dependent control of Rho GTPase activity through p190RhoGAP (also known as ARHGAP35) mediates cell-shape-dependent changes in cell-cycle progression by altering the balance between ROCK and mammalian Diaphanous-related formins (mDia) (Mammoto et al., 2007; Mammoto et al., 2004). When the actin cytoskeleton is disrupted and cells are round, filamin A binds to p190RhoGAP and its activity as a GTPase activating protein (GAP) is inhibited, leading to the activation of Rho (Mammoto et al., 2007). By contrast, in spreading cells, filamin A, an actin-binding protein that crosslinks F-actin, is cleaved by calpain and p190RhoGAP dissociates from filamin A. Subsequently, RhoGAP moves to the lipid-raft fraction where it inactivates Rho (Mammoto et al., 2007). This distortion-dependent signaling mechanism mediates cell-shape-dependent changes in cell cycle progression (Mammoto et al., 2004; Mammoto et al., 2007). Myocardin-like proteins 1 and 2 (MKL1 and MKL2, respectively), which are co-activators of SRF, also have a key role in controlling Rho-dependent gene expression and cell growth (Descot et al., 2008). RhoA regulates the nuclear translocation of MKL1 and/or MKL2 and mediates the formation of stress fibers and focal adhesions by activating the transcription of cytoskeletal and/or focal adhesion genes (Morita et al., 2007).
Human mesenchymal stem cells (MSCs) express organ-specific transcription factors and undergo tissue-specific cell fate switches (e.g. neuron vs myocyte vs osteocyte) when cultured on ECMs with mechanical stiffnesses that mirror the physical properties (i.e. the Young's moduli) of their respective tissues (e.g. brain vs muscle vs bone) (Engler et al., 2006). Changes in ECM compliance alter cytoskeletal tension, actin structure and cell shape (Ingber, 2003; Polte et al., 2004), and the effects of ECM compliance and cell shape on MSC fate switching is mediated by Rho and Myo-II, which generate cytoskeletal tension (Fig. 3) (Engler et al., 2004; Ren et al., 2009). These findings further suggest that the actin cytoskeleton and tensional prestress are central mechanosensitive control elements, which are involved in a complex feedback loop: they both mediate the effects of mechanical cues on transcription regulation and alter their functional state in response to changes in gene transcription.
The nucleus as a mechanical point of control of transcription
The cytoskeleton is coupled to the nuclear membrane, intranuclear scaffolds and chromatin, and molecular connections between integrins, cytoskeletal filaments as well as nuclear scaffolds provide a discrete path for the transmission of mechanical signals in response to changes in adhesion to the ECM or in the cytoskeletal prestress (Maniotis et al., 1997b) (Fig. 3). In fact, changes in nuclear mechanics and architecture that are modulated by the ECM substrate, focal adhesions and the cytoskeleton, have crucial roles in the transcriptional control of cell fate determination (Buxboim et al., 2010). Importantly, changes in cell fate between growth, differentiation and apoptosis can be controlled by altering cell shape (Chen et al., 1997; Dike et al., 1999), ECM elasticity (Engler et al., 2006), cytoskeletal contractility through Rho–ROCK signaling (McBeath et al., 2004) and tissue patterns (Ruiz and Chen, 2008). Given that nuclear mechanics are regulated by these same parameters (Khatau et al., 2010; Kihara et al., 2011; Sims et al., 1992), the nucleus itself might act as a mechanosensor that directly modulates regulation of transcription during cell fate determination in these cells. In support of this possibility, inhibition of Myo-II with blebbistatin or disruption of actin microfilaments with cytochalasin D, results in a dramatic decrease in the nuclear size of adherent cells, whereas inhibition of microtubule polymerization with nocodazole increases the nuclear size (Mazumder and Shivashankar, 2010). Thus, the area of the cell surface and the size of nuclei are directly coupled to integrin through cytoskeletal linkages; this physical connection results in the nucleus becoming prestressed, so that it balances contractile forces of the cytoskeleton with condensation forces of chromatin (Mazumder and Shivashankar, 2007; Mazumder et al., 2008; Mazumder and Shivashankar, 2010). Importantly, such a mechanism of nuclear mechanotransduction in response to forces that act on the cell surface is much faster than the propagation of signaling ions and molecules (Li et al., 2007). Nuclear prestress might also be crucial to determine the cell fate (Fig. 3), because stem cell differentiation leads to the dynamic reorganization of connections between the cytoskeleton and the nuclear membrane, thereby progressively leading to a stiffer nucleus as lineage-committed cells emerge (Mazumder and Shivashankar, 2010; Pajerowski et al., 2007).
Interestingly, the structure of the nucleus also appears to be crucial for transcriptional reprogramming of pluripotency. For example, transplantation of somatic nuclei into eggs or oocytes is sufficient to reactivate silenced pluripotent genes such as that encoding OCT4 (Pou5f1) (Kim et al., 2009; Stadtfeld et al., 2008). Moreover, this is a more-efficient way to reprogram cells into pluripotent stem cells than the forced induction of OCT4, SOX2, MYC and KLF4 protein expression in somatic cells (Kim et al., 2010; Pasque et al., 2010). Although the mechanism by which the physical structure of the nucleus induces gene reprogramming at the level of transcription is unclear, it is known that nuclear actin can regulate gene transcription through changes in cytoskeletal actin dynamics (Sotiropoulos et al., 1999) or by modulating the assembly of transcriptional regulatory complexes in the nucleus (Grummt, 2006). Nuclear actin polymerization also has an essential role in transcriptional reactivation of the gene encoding OCT4 in transplanted nuclei (Miyamoto et al., 2011), and decreased cytoskeletal tension destabilizes transcriptional regulation of pluripotency and, hence, compromises long-term survival of ESCs (Li et al., 2010). The different effects of pluripotency on transcriptional control in ESCs might, therefore, be regulated by mechanical forces that are exerted on the cell surface and transmitted to the nucleus across transmembrane adhesion receptors (e.g. integrins and cadherins) and the cytoskeletal filaments associated with these receptors, which result in tension-dependent changes in nuclear structure (Maniotis et al., 1997a; Maniotis et al., 1997b; Sims et al., 1992; Wang et al., 1993; Wang et al., 2009).
Mechanical forces can also regulate gene expression directly by altering the transport of transcription factors or other molecules into the nucleus. For example, nuclear transport of MKL1 is regulated by prestress in fibroblasts (McGee et al., 2011). Nuclear transport of NF-κB, which activates expression of the genes encoding PDGFA and PDGFB in response to fluid shear stress, is also specifically sensitive to mechanical perturbation in endothelial cells (Khachigian et al., 1995; Meiler et al., 2002). The levels of nuclear translocation of the two transcription factors TFII-I and GATA2, which control angiogenesis by regulating the expression of VEGFR2, have been shown to be sensitive to ECM mechanics in endothelial cells (Mammoto et al., 2009). In spreading cells, nuclear membrane distortion – as a result of cytoskeletal distortion – also stimulates cytoskeletal tension-dependent Ca2+ entry through nuclear ion channels (Fig. 3) (Prat and Cantiello, 1996) and induces gene transcription (Itano et al., 2003). Because nuclear envelope proteins, such as lamin A and emerin, bind to transcription factors and because these proteins are directly linked to the cytoskeleton through nesprin (Mejat and Méjat, 2010; Wang et al., 2009), any forces that are transferred through these molecules might also alter gene expression directly (Dreuillet et al., 2002; Haraguchi et al., 2004).
Taken together, these findings suggest that the micromechanical environment of the nucleus modulates the transcriptional activities that are crucial to control cell fate determination, and that are sensitive to the microenvironment of living embryonic and adult tissues. Furthering our understanding of these mechanisms will also be crucial for the development of new strategies to reprogram cells and to treat congenital diseases that are caused by perturbed nuclear structure and mechanics, such as Hutchinson–Gilford progeria syndrome, Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy and familial partial lipodystrophy (Worman et al., 2009).
In this Commentary, we have reviewed multiple findings that demonstrate the central role of mechanosensitive control mechanisms of transcription that determine stem cell fate, embryogenesis and that control organ homeostasis. It is now clear that both external stresses and intracellular cytoskeletal tension can be driving forces behind changes in transcriptional regulation. These mechanical signals influence transcription by altering intracellular signaling pathways or mediating changes in cytoskeletal and nuclear structure or mechanics. The extent of this response and the efficiency with which the mechanical signal is transferred through the cell and to the nucleus depend on the level of isometric tension or prestress in the cytoskeleton. Cell-generated tensile forces not only alter the chemical signals that are conveyed by cells, but also produce distortion of neighboring cells and ECM molecules that propagate mechano-chemical signaling over long distances. This process drives tissue patterning and organ formation on the embryonic and tissue scale. These findings also raise the possibility that a better understanding of these mechanotranscriptional control mechanisms will increase our chance of reversing developmental defects or treating diseases by restoring normal mechanical loading conditions or correcting abnormal transcriptional activities.
Despite a great effort to engineer 3D organs from ESCs, so far this approach has not been fully successful because of the lack of a comprehensive understanding about how tissues develop regarding a specific size, shape and material property during organogenesis. The necessity to integrate mechanosensitivity into existing models of transcriptional control to fully understand tissue and organ development is becoming clear. Advances in this area will require new methods in order to measure endogenous mechanical forces and local variations of the mechanical properties of cells, the ECM and entire tissues within forming organs, and a way to analyze how mechanical cues and chemical signals dynamically interact to regulate transcriptional activities during important morphogenetic and patterning events. Because cellular mechanotransduction is central to the control of developmental processes and tissue homeostasis, a deeper understanding of mechanosensitive transcriptional control mechanisms in embryonic and adult organs might also lead to new forms of therapeutic intervention for various diseases, as well as new strategies for tissue engineering and regenerative medicine.
We thank E. Jiang and A. Jiang for the figures. The authors declare no competing financial interests.
This work was supported by the National Institutes of Health [grant numbers CA45548 and DE019023], the Department of Defense [grant number BC074986], AHA, the Hearst Foundation and ABTA. Deposited in PMC for release after 12 months.
This article is part of a Minifocus on Mechanotransduction. For further reading, please see related articles: 'Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues' by Brendon M. Baker and Christopher S. Chen (J. Cell Sci. 125, 3015-3024). 'Finding the weakest link – exploring integrin-mediated mechanical molecular pathways' by Pere Roca-Cusachs et al. (J. Cell Sci. 125, 3025-3038). 'Signalling through mechanical inputs – a coordinated process' by Huimin Zhang and Michel Labouesse (J. Cell Sci. 125, 3039-3049). 'United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction' by Ulrich S. Schwarz and Margaret L. Gardel (J. Cell Sci. 125, 3051-3060). 'Molecular force transduction by ion channels – diversity and unifying principles' by Sergei Sukharev and Frederick Sachs (J. Cell Sci. 125, 3075-3083).
- © 2012. Published by The Company of Biologists Ltd


text:
Marcella Edwards
Dublin In Stasis
The Free and Easy
By Anne Haverty
Chatto & Windus 288pp £11.99 order from our bookshop
Anne Haverty burst onto the literary scene in 1997 with One Day as a Tiger, her brilliant dissection of rural life in Ireland. In The Free and Easy, she looks at the effects of the Celtic Tiger on Dublin. Tom is sent there from the States by his great-uncle Pender, to appease the dreams of the old country that have been disturbing the old man's sleep. He finds a city in thrall to American money and harking back to an ersatz Irishness based on suffering and penury. Dublin is in stasis – simultaneously embracing the cliché of the American Dream and clinging to an illusory, romanticised and 'authentic' past. Tom gets enmeshed with the Kinane family and Gibbon Fitzgibbon's murky political past. He shares a meal with the Kinanes, during which they cling to their mobile phones, presenting the semblance of a contented family while reaching towards some imaginary message from outside that will propel them to something better. Each night, Mrs Kinane charges her children's phones, brooding over them as her last maternal ministration. There is no here-and-now, only an atrophied past of famine and poets, and an idealised future of glistening theme parks and Irish artistic talent sanctioned by American buyers. Tom moves around the city and the outlying countryside, initiated into the privileged world of country-house parties and people jostling for social position, while toying with setting up a foundation to help the travelling community. This, he believes, is the embodiment of the ancient spirit of the Irish. Across the city flits Eileen Kinane, a beautiful, elusive and ethereal creature with a tendency to self-harm. She's the modern Cathleen ni Houlihan, but with pink hair. Tom is in love.