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Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455
Department of Biomedical Engineering, and Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN firstname.lastname@example.com
Corresponding author.
Though it is widely accepted that fiber alignment has a great influence on the mechanical anisotropy of tissues, a systematic study of the influence of fiber alignment on the macroscopic mechanical behavior by native tissues is precluded due to their predefined microstructure and heterogeneity. Such a study is possible using collagen-based bioartificial tissues that allow for alignment to be prescribed during their fabrication. To generate a systemic variation of strength of fiber alignment, we made cruciform tissue constructs in Teflon molds that had arms of different aspect ratios. We implemented our anisotropic biphasic theory of tissue-equivalent mechanics to simulate the compaction by finite element analysis. Prior to tensile testing, the construct geometry was standardized by cutting test samples with a 1:1 cruciform punch after releasing constructs from the molds. Planar biaxial testing was performed on these samples, after stretching them to their in-mold dimensions to recover in-mold alignment, to observe the macroscopic mechanical response with simultaneous fiber alignment imaging using a polarimetry system. We found that the strength of fiber alignment of the samples prior to release from the molds linearly increased with anisotropy of the mold. In testing after release, modulus ratio (modulus in fiber direction/modulus in normal direction) was greater as the initial strength of fiber alignment increased, that is, as the aspect ratio increased. We also found that the fiber alignment strength and modulus ratio increased in a hyperbolic fashion with stretching for a sample of given aspect ratio.
Image of test sample, following punching to AR=1:1 from a retracted cruciform construct, mounting for biaxial mechanical testing, and stretching back to in-mold dimensions. Custom adjustable compressive grips especially designed for small-dimension cruciform constructs were attached to the ends of each actuator. The four dots at the center of the specimen were made with Voerhoff's stain after mounting and stretching to track the local strain. The four dots visible at the corners, which were in the central region prior to punching the AR=1:1 test sample, were made prior to release from the mold and retraction to track local retraction. Another (third) set of dots no longer visible after punching the test sample from was marked near the Velcro at each arm prior release from the mold and used to measure global retraction.
Cruciform-shaped Teflon molds with bioartificial tissue constructs possess alignment that varies with arm dimensions. ((a1) and (b1)) AR=1:1, ((a2) and (b2)) 1:0.75, ((a3) and (b3)) 1:0.5, ((a4) and (b4)) 1:0.375, and ((a5) and (b5)) 1:0.25: (a) photographs; (b) alignment maps, where each segment indicates the local-average direction and strength of fiber alignment and the gray level is mapped to the local alignment strength (i.e., pixelwise retardation), with white being maximum and black minimum alignment. Stronger alignment in the direction of the wider arm is evident as the other arm becomes thinner. ABT-based FEM simulation of compaction and alignment of cruciform tissue constructs predicts observed dependence on cruciform mold arm dimensions. The fiber direction and strength of fiber alignment are represented by eigenvectors and magnitude of eigenvalues, respectively, of the fiber orientation tensor in ((c1)–(c5)).
(a) The strength of fiber alignment linearly increased with mold aspect ratio (i.e., with 1/Wn). The average value of the birefringence ⟨Δn⟩ within the central region prior to sample release is plotted. (b) ABT-based FEM simulation of compaction and alignment of cruciform-shaped tissue constructs predicts the observed dependence of strength of fiber alignment linearly increasing with mold aspect ratio (1/Wn). The average value of the principal eigenvalue within the central region is plotted.
Stress versus stretch ratio plots show stiffening and increasing mechanical anisotropy with stretching for AR>1
Modulus versus stretch ratio plots show stiffening in both axes for all AR, but with unexpected trends (see text)
Modulus ratio versus stretch ratio plots show increasing mechanical anisotropy and alignment with higher aspect ratio. The fiber alignment strength (average birefringence) also exhibits hyperbolic increase with stretch ratio in the cases where AR>1.
Dependence of sensitivity of mechanical anisotropy relative to microstructural anisotropy on stretch ratio, showing the sensitivity is greater for the more aligned sample (AR=1:0.375) and also decreases with stretch ratio. Values were derived from derivatives of cubic polynomial fits to the data in Fig. 6. Differences between AR=1:0.5 and 1:0.375 are statistically significant for λ=1.00–1.03.
Stretch ratios and fibril alignment strength possess a complex relationship in the cases where AR>1, particularly in the unstretching phase: (a) AR=1:1, (b) AR=1:0.5, and (c) AR=1:0.375
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The Take Care Songfacts reports that the song samples Gil Scott-Heron and Jamie XX's "I'll Take Care of You" from their 2011 album, We're New Here. The record was a reworking of Scott-Heron's final studio album I'm New Here. 'Take Care' is a re-working of the Gil Scott-Heron/Jamie XX collaboration 'I'll Take Care Of U' – this sultry version by Canadian rapper Drake peaked at No.9 on the UK singles chart in late 2011. He had previously teamed up with Rihanna for her 2011 No.1 hit 'What's My Name'. Read more on Last.fm.
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subset: commoncrawl


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I was able to go on a hike with Tess and Laura a couple weeks ago. I haven't been hiking nearly enough this summer, so it felt great to be in the canyon. We went up to Mill Creek with a plan to hike up to Dog Lake, but all the parking lots were full. So we decided to take a different path and hike Alexander Basin instead. Now, the three of us are familiar with the length and steepness of the Dog Lake trail, but we weren't too acquainted with Alexander Basin before attempting to conquer it. The trail turned out to be pretty difficult, even for me and I didn't have a baby strapped to my back. Yeah, that's right, Tess and Laura both had their babies with them on the hike! I'm so impressed with the two of them. I mean, the backpack that Tess had little Zoey in was nearly as big as she is! I wish I had a picture of her with the backpack on so you could see for yourself. Even though the hike was challenging, it was a gorgeous, clear day, but not too hot...the perfect day for a hike.
Monday, July 19, 2010
Thursday, July 15, 2010
James Tissot
I was able to go to a lecture at the BYU Museum of Art tonight. The lecture was on the life of the artist, James Tissot, and his series of paintings on the life of Christ. He completed the series toward the end of his life. I enjoyed the lecture and was able to browse through the exhibit afterward. BYU's MOA will have the exhibit up for at least the next month, I think. You should check it out. Tissot painted with opaque watercolor. The amount of detail he was able to create with watercolor is pretty amazing. One of my favorites from the exhibit is called Jesus Wept, a depiction of Jesus after the death of Lazarus. This picture I posted is really small so go here if you want to see it and others in more detail.
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PROFIT system consultants prepared more than 300 franchise systems working in Central and Eastern Europe
A business model is a method by which an enterprise is set-up to sell goods or services to an end customer. It describes the method by which the business will monetise its concept or unique selling point. The business model which succeeded in your domestic country not necessarily has to work in the country you are going to enter. This is why your business model should be tailored to your destination market - its economic reality, investment potential of your future franchisees, purchasing-power of your end customer, business customs and many other factors.
Business model includes:
Well defined business model is a proper starting point for preparation of franchising package or its adaptation to destination market. PROFIT system consultants provide also support in preparation or adaptation such documents as:
Please contact one of our offices for more information.
The benefits for both sides
are nessesary for a successful franchise


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ELT Coding
How to decode the official Cospas-Sarsat 15 HEX Code identification ?
This link will help you retrieving the detailed fields of the identification.
Click here for more information
Is coding included in the price of my ELT ?
Yes, ELTA encodes all ELT prior to shipment against the receipt of appropriate coding form.
How do I recode my ELT ?
ELT can be recoded:
- By ELTA or by one of ELTA's approved service centers
- By operator by using ELTA encoder tool or test bench, after following a specific training in order to incorporate this task in the PART145/FAR145 (…. ) capability list.
Nota : For ELT A06V2, both ELT P/N 95N6088 and bracket/prog box P/N 95N6089 must be returned to ELTA/service center as the coding is stored in the bracket/prog box.
Who is responsible for the final ELT registration ?
The operator must register each ELT to its local authority.
You will find hereafter the Cospas Sarsat to get your local authority contact
Click here for more information
How to encode my ELT ?
Authorised coding methods (protocols) are managed by your local authority. Please contact them.
Definition of coding methods can be found on Cospas-Sarsat website.
Encode ELT : http://cospas-sarsat.org/fr/balises - http://cospas-sarsat.org/en/
When the local authority does not require a specific protocol, we recommend the aircraft registration protocol or 24 bit-address.
In which country should I register my ELT ?
The country code of the ELT should always reflect the country in which the final operator is based.
For instance, the ELT on an aircraft operated by an airline in Italy, leased from a US company, that has the aircraft registered in Ireland, should have the country code of Italy.


text: The Rural Law Center provides training services in a wide range of areas. Training sessions, mostly in the form of one-day seminars and workshops, are designed to specifically address legal issues critical to low-income individuals in New York's rural counties, as well as to rural service providers. Participant groups have included senior citizen groups, youth groups, high school and college classes, social workers, probation officers, school counselors and administrators, health care providers, Special Education advocates and Family Court mediators. Syllabus and curriculum materials are arranged to suit the needs of each group. These sessions can be arranged at various locations throughout rural New York. Inquiries should be directed to the Center's main office in Plattsburgh, New York.


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Courtesy of Wishpot
For some couples, registering at one store might not be enough. That's why registry site Wishpot is the perfect option for the bride and groom who want to register for electronics, china and wine—all in one place. Creating your wish list is easy. You just set up your free registry, selecting items from almost every store imaginable (Amazon.com, Target and Etsy are just a few of options available). Even better, Wishpot offers price comparisons and sale alerts so that your guests can find the items you selected for the least expensive price. —Kathryn Papanek


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Oakley Airwave 1.5 Snow Goggle
This fall, Oakley is taking wearable technology to the next level with the release of the Airwave 1.5 snow goggle. Airwave 1.5 combines Oakley's superior lens quality with the high-tech features of integrated Heads-Up Display (HUD). Currently, Oakley athletes are utilizing the product for training purposes as they prepare for the 2014 Olympic Games in Sochi. The googles also allow you to view incoming calls, text messages, music playlists and connect with social media channels via your phone as well as locate and track friends on the mountain who have an Airwave goggle or app. Head over to oakley.com to get them now.


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These are just the cutest little mother of pearl buttons, still on their original card, and measuring a teeny 0.7cm across. So perfect for those of you who work small, for dolls'/bears' clothing, fabric brooches, fabric tags etc. There are 36 buttons on the card, one of which is broken -
PLEASE START THE BIDDING ( in US$ ) IN THE COMMENTS AT 8.00
Payments at the finish of the auctions can be made in US$, British£ or Euros.
UK postage £1.26( $1.95 ), Europe $5.75, US/CAN $7.35, AUS/NZ $7.85
Of course, if you end up winning more than 1 item, I'll combine postage, you could save oodles on shipping ;-).
Who will benefit: -
Paws2Rescue - https://www.facebook.com/Paws2Rescue/
Romanian Rescue Appeal - https://www.facebook.com/romanianrescueappeal/
Help Bulgaria Street Cats and Dogs -
Rudozem Street Dog Rescue -https://www.facebook.com/rudozemstreetdogrescue
Auction closes 15th December at 7pm UK time.


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This Sunday at the Survivor Series pay-per-view Seth Rollins will captain Team Authority as they go up against Team Cena in a traditional Survivor Series tag team elimination match, but there could be bigger things on the horizon for Mr. Money in the Bank in the coming months.
Seth Rollins will lead out Kane, Mark Henry, United States Champion Rusev and the new Intercontinental Champion Luke Harper as they take on the Cena-led team consisting of Dolph Ziggler, The Big Show, Ryback and Erick Rowan with more than The Authority's careers on the line.
Big things are expected of this match as a number of superstars will have the chance to shine at a big stage. Rusev could continue to build himself up as a main event star, Dolph Ziggler has the opportunity to show what he can do on the main event scene once more whilst eyes will also be on Erick Rowan and Luke Harper as to what they can now achieve since they were set free from The Wyatt Family.
But the focus will be on Seth Rollins, and how he can go about leading his team to glory and looking strong at the same time.
If the reports surrounding an even bigger push for Seth Rollins are true, then the pressure will be on for the former Shield member at Survivor Series.
This year, the TLC: Tables Ladders and Chairs event will take place in Cleveland, Ohio at the Quicken Loans Arena and the current plan for the event could see Seth Rollins occupy a spot in the main event match next month.
There's a strong feeling amongst the WWE Universe that The Viper, Randy Orton could make an appearance at the Survivor Series pay-per-view this Sunday and could cost Team Authority the win which could – and should – trigger a feud between Orton and Rollins after weeks of tension culminated in Orton eating a Curb Stomp on the steel steps.
It doesn't necessarily mean that Orton could cost Team Authority the win, if he does appear he might only help eliminate Seth Rollins for example. This will still result in the two men colliding in the main event at TLC as Brock Lesnar isn't scheduled to compete until the Royal Rumble in January where he is set to defend his WWE World Heavyweight Championship against John Cena.
If the plan does go ahead for Seth Rollins to compete in the main event at TLC in a TLC match then Randy Orton is set to be his opponent.
But Randy Orton might not be the only name involved, if the WWE don't go ahead with the one-on-one match then expect John Cena to also be inserted into this main event match as he too still needs to get his hands on Seth Rollins.
There is also the chance that the Money in the Bank briefcase may also be on the line, where a victory for Seth Rollins would make him an even bigger threat to the WWE World Heavyweight Champion, whoever that may be at the time he decides to finally cash in.


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One morning, after the office holiday party, I woke up with a massive hangover next to my boyfriend who looked at me with complete disgust. My antics, or "adventures" as I liked to call them, just weren't cute anymore. I knew I had to do something; I wasn't going to remain alone for the rest of my life because I couldn't drink. I knew a woman who was sober and happy about it so I reached out and asked for help. That was seven years ago.
At first I was so scared. I didn't know what to do with myself and I had absolutely no idea of who I was or what I was capable of. I had hated myself for so long that I was sure everyone else felt the same way. Little by little I began to open my eyes and realize people weren't nearly as obsessed with me as I thought; in fact, they were coping or struggling just like me. I found this very comforting . . . I am not alone. I am not insane. I am not a bad person. I am an alcoholic and so I do whatever I need to do to stay sober. I laugh, cry, play, dance and walk through all that life has to offer without regret. I have friendships based on trust, love and service. I belong.
Maria, 43


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In 2013, Candidate.Guru started with a simple mission, to use AI and big data to solve the fit between manager and employee fit.
Fast forward to 2017 when we acquired Elevated Careers by eHarmony, we now have a product and story that far outweighs anything we had hoped for!
Today, the rebranded company "Elevated" provides an end to end, all in one HR tech stack that is unrivaled in the industry.
Below are a few of the people that made all this possible.
Steve Carter
CEO and Co-Founder
Steve has spent his career growing and exiting various software companies in the enterprise tech space, he brings experience from both the sales, product marketing and technical aspects of technology.
Immediately prior to Candidate.Guru, Steve lived in New York City and lead the US sales team for Panaya, an Israeli startup that sold for $200M, before that, he moved to the US from New Zealand with Zeacom, a customer experience company that sold for $40M to publicly traded company Enghouse (TSX: ESL), which he then served as VP of Sales following the acquisition. Steve started his career on the tech side as a Systems Administrator and Server Engineer.
Sport and technology are Steve's passion outside of work, being competitive by nature Steve
Rob Bennett
VP Sales
Rob has spent the last 14 years helping companies leverage technology and human capital solutions to better hire,
Laura Carter
Sales and Marketing
Laura works in marketing and sales development at Candidate.Guru. Immediately prior to joining the team, she was an executive assistant to two VPs at American Jewish World Service, a human rights grantmaking nonprofit in NYC. There, she spent most of her 20s as a professional actress after earning her Bachelor of Science in mathematics and psychology from Fordham University.
Originally from Cape Cod, Laura spends most of her weekends at the beach. She is an avid reader and also takes care of local in-need cats or plays her piano in her spare time.
Dr Steve Carter, PhD
Data Science and Org Psych
As a member of the founding team at eHarmony, Dr. Carter has extensive experience in the development and optimization of consumer-facing services and features in e-business, and how to leverage data and data science to drive innovation and optimization.
Dr Carter continues his passion for science and technology working as a Data Scientist at Facebook.
Dr Andrew Larsen, PhD
Data Science and Org Psych
Dr Larsen did his Ph.D. work in behavioral medicine studying motivation, habits, cognitive decision making, and environmental influences of behavior, where he specialized in multivariate-longitudinal analysis and program evaluation.
He extended his analytical background to topics such as user retention, forecasting lifetime value, marketing attribution, and modeling compatibility to make 'match' recommendations.
John Stanfill
Board Member
John is Chief Executive Officer at Rainking and serves on the Candidate.Guru Board.
John brings over 20 years of operational excellence in providing strategic leadership to sales, marketing, product management and customer support teams. Prior to joining RainKing, John worked for CoStar Group (NASDAQ: CSGP), the leading provider of commercial real estate information, analytics and online marketplaces in the United States, United Kingdom, and France.
As an Executive Officer of CoStar, John held numerous senior positions over his 19 year tenure. John's contributions were instrumental in CoStar's growth from $2 million in revenue when he joined in 1995, to nearly $600 million and a market capitalization of over $5 billion when he left in 2014. John has lived in the Washington D.C. metro area for over 17 years.
Chris Daniels
Board Member and Founder
Chris is the Founder & CEO of Candidate.Guru. Prior to that, Chris spent 4 years as a Partner with Acertitude, a New York-based leadership consulting and executive search firm. Chris brings more than 20 years' experience in enterprise software and big data & analytics markets.
Prior to joining Acertitude, Chris was based in London as the VP, Financial Services Business Unit for NICE Systems (NASDAQ: NICE), a $1B enterprise software company headquartered in Tel Aviv, Israel. Chris had global P&L responsibility for the company's products and services sold into the financial services market.
Previously, Chris served as CEO at Nicom Technologies, Inc., a leading telephony VAR that he exited to a $200M+ systems integrator. He also held several Vice President positions with Avaya managing indirect channels and global accounts with revenue responsibility in excess of $250M. Chris serves on the Boards of several early-stage technology companies including OP3Nvoice (a Techstars company) based in Austin, TX as well as Candidate.Guru, a Florida-based talent acquisition technology start-up apart of Florida Atlantic University's (FAU) Tech Runway incubator program.
Soccer is Chris' life outside of work. It became a family passion when they lived in London. He and his wife Julia and their three kids like to watch it, play it and strategize about it. It's a minor obsession (5-6 days a week), not to speak of good exercise.
Kathy Chiu
Board Member
Kathy is the COO of the FanFund, Candidate.Guru's lead investor; Wireless venture capitalist at Denver-based iSherpa Capital;
Consultant to clients from startups to Fortune 500; Research analyst with Boston economics consulting firm Cornerstone Research; business development, strategy, product management at Level (3) Communications, Lefthand Networks, Compaq Computers; Technical roles at Tektronix, MIT Media Lab, and Superconducting Supercollider Lab,
Kathy holds a BSEE and MSEE from MIT; MBA from Stanford Graduate School of Business.
Kathy speaks fluent Chinese and Taiwanese.
Greg Greene
Mr. Gregory F. Greene, also known as Greg, served as the Chief Administrative Officer of Ryder System, Inc. until June 2016 and served as its Executive Vice President since December 2006 until his retirement in June 2016. Mr. Greene was responsible for Human Resources, Information Technology and Facilities. He served as the Chief Human Resources Officer of Ryder System Inc.
Mr. Greene also served as Senior Vice President of Strategic Planning and Development of Ryder System Inc. where he played a key role in Ryder's transformation process, leading teams that focused on improving profitability of Ryder System Inc., enhancing its business model, and aligning organizational structures. Mr. Greene also served as Senior Vice President of Global Talent Management, where he worked closely with members of the Ryder management team to support and enhance Ryder's global organizational effectiveness and profitability. In addition to his formal role, Mr. Greene successfully led several broad-based internal team projects that involved cross-functional coordination, strategic analysis, process improvement and efficiencies that impact Ryder System Inc.
Mr. Greene joined Ryder in 1993 as manager of Executive and International Compensation. He later served as Director of Human Resources for Ryder's international division and held various positions of increasing responsibility in Human Resources, including the role of Senior Vice President of Field Human Resources. In the past, Mr. Greene served as Director of Human Resources for Sunglass Hut International, Inc. His professional experience also includes several years in executive and management positions with NationsBank and other financial institutions.
Mr. Greene is the Vice Chair of the Board of Trustees at Barry University, a Board member for Costa Farms and a faculty member for Deloitte. He is also an adjunct professor in the MBA program at Florida International University. Mr. Greene earned a master of business administration degree from Barry University, and a bachelor of arts degree in Economics from the University of Pittsburgh


text: I have searched the Mid-Atlantic thread, the forum in general, Googled quite a bit, and even asked the folks at the Tesla showroom in DC, but I can't get the answer to this simple question: is the 4-year/50,000 mile extended warranty (I guess Tesla calls it the Extended Service Plan) available for purchase in VA? I am giving serious thought to buying the car, and I get the sense that it might be wise, given the "newness" of the car and the many unknown costs of the parts, to buy the extended warranty. However, I have the impression that the warranty isn't available in a number of states (WA for example) and that VA might be one of them because Tesla still hasn't built the service center/dealership or that the warranty is a form of insurance which Tesla must have a license to sell, which it doesn't have yet. Could any of the VA owners chime in on this question. Thanks.


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AUBURN UNIVERSITY – An eight-member team of Alabama Cooperative Extension System educators is conducting "Eat Healthy, Be Active" workshops throughout the state to address the poor eating habits and physical inactivity that sets Alabama apart as a state with one of the nation's highest obesity rates.
Onikia Brown, an Alabama Extension nutrition and health specialist and assistant professor in Auburn University's Department of Nutrition and Food Science who is heading the statewide effort, said the goal is to conduct these workshops in all 67 counties by the end of 2013.
Brown said another goal of the program is to help people break the nutritionally destructive patterns of eating that have contributed to spiking obesity rates.
"That's not to say that you should never have a donut, a cookie or a piece of cake," she said. "Nutritionally destructive behavior occurs when you're eating a donut with every meal or consuming an entire bag of chips at one sitting instead of consuming only a handful."
Despite some progress in recent years, Alabamians are still plagued with one of the nation's highest obesity rates. Obesity is closely linked with chronic, even life-threatening conditions, such as type 2 diabetes, hypertension and heart disease.
"We're improving," said Helen Herndon-Jones, one of the regional Extension agents involved in the training. "We're now fourth, though we used to be ranked second and, even at one point, first, in the nation in obesity rates.
Much remains to be done, she said, citing a recent survey showing that Dallas and Greene counties are among the five counties in the nation with the highest obesity rates.
Herndon-Jones and other Extension educators stress that there is no quick fix for obesity, only a series of incremental steps to healthier eating and more active lifestyle habits that must be reinforced over time through changed behavior. As they see it, this emphasis on incremental steps is one of the program's greatest strengths.
"I really think this program brings some fresh ideas to the table," said Valerie Conner, a regional Extension nutrition and health agent conducting the programs throughout parts of central and south Alabama. "We offer practical suggestions about cutting down on all the things that contribute to obesity, such as fats, sugar and sodium. Instead of just talking, we actually demonstrate things. For example, considering that a 12-ounce can of cola contains 10 teaspoons of sugar, we show how drinking a can of cola a day amounts to consuming 30 pounds of sugar in a year's time."
Developed by the U.S. Department of Health and Human Services and the Office of Disease Prevention and Health Promotion, "Eat Healthy, Be Active" is offered as a series of six one-hour workshops that are based on the Dietary Guidelines for Americans, released in 2010, and the 2008 Physical Activity Guidelines for Americans.
"We try to take them through the small steps – things they can do, not just for a few weeks or a few months, but for the rest of their lives," Herndon-Jones said.
The workshops focus on six topics that help participants identify and correct potentially destructive behaviors. Each session is designed around a lesson plan, learning objectives, talking points, hands-on activities, videos and handouts.
The first session identifies foods that are not only healthy but tasty. The second session focuses on how to prepare and choose quick meals and snacks that are also healthy, while the third deals with how to eat healthy on a budget. The fourth session offers tips for losing weight and keeping it off, while the fifth session acquaints participants with ways to adopt healthy eating as an integral part of one's lifestyle. The final session explores the value of physical activity as integral to healthy living.
For more information about Eat Healthy, Stay Active training in your area, contact your county Extension office.
(Contributed by Jim Langcuster.)
Contact: Jim Langcuster, (334) 844-5686 (email@example.com), or Charles Martin, Office of Communications and Marketing, (334) 844-9986 (email@example.com)


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Warwick, NY
Angelo Di Gregorio of Warwick, passed away on July 30, 2008 at St. Anthony's Hospital. He was 92 years old.
Born on December 24, 1915 in Worcester, MA, he was the son of the late Joseph and Rose (Sciascia) Di Gregorio. He was married to the late Grace (Grazina) Di Gregorio.
A World War II Army veteran, Mr. Di Gregorio was a retired Steel Worker with White Plains Iron Works, White Plains, NY and was a member of the Iron Workers Union #455, NYC. He was a member of St. Stephens R.C. Church, Warwick.
He is survived by his daughter, RoseMarie Di Gregorio of Warwick; a son, Joseph Di Gregorio, of Warwick; a sister, Grace Migliozzi of Massachusetts, and a brother, Leo Di Gregorio, of the state of Florida.
"He will fondly missed by Silkie Ben and Maggie Mae."
Visitation will be held today, Friday, August 1, from 2-4 and 7-9 p.m. at Lazear-Smith & Vander Plaat Memorial Home, 17 Oakland Ave., Warwick, NY.
A Funeral Mass will celebrated at 10 a.m., on Saturday, August 2, at St. Stephens R.C. Church. Interment will follow in Warwick Cemetery.
In lieu of flowers, memorial donations may be sent to American Heart Assn., PO Box 3049, Syracuse, NY 13220.
Arrangements by Lazear-Smith & Vander Plaat Memorial Home; 845-986-4331. For information, directions or to send condolences, please visit www.lsvpmemorialhome.com.
Angelo Di Gregorio 92
Warwick, NY


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30 Years Of 'The Legend Of Zelda'
February 21st marked 30 years since the original game was released in Japan. In 1986, the game was released on the Family Computer Disk System, a console that read floppy disks. Since then, the series has come a long way. The video breaks down why we continue to follow this series, even though its timeline is convoluted and confusing.
Over the last 30 years the series has sold over 65 million copies of all 18 total games. Clearly, something is working. Along with the iconic soundtrack and commitment to characters, it introduced us to free-roaming game play which requires players to explore the Zelda universe. Also, even though the games were released in non-chronological order, each individual game has its own intricate story. The Legend of Zelda allows both dedicated fans and newcomers to enjoy each game.
Watch more videos from The Verge here.


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Event box
In this workshop you can make holiday gifts and more using the Carvey CNC Router with wood and plastic materials. Including setting up an image in Illustrator.
- Learn how to perform all the steps involved to cut a design on the Carvey - the Carrier Makery's CNC Router.
- Date:
- Monday, November 12, 2018 Show more dates
- Time:
- 2:00pm - 3:00pm
- Location:
- Carrier Makery
- Campus:
- Carrier Library
- Audience:
- Faculty Students
- Categories:
- Workshop


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Duolingo Creates English Learning App for Hindi Speakers
Duolingo, the popular online language learning app, has launched a Hindi version to help those in India learn English.
The app will help native Hindi speakers learn English, while those who already speak English can choose from Duolingo's 16 other languages, which are all offered for free.
Duolingo's co-founder and CEO Luis von Ahn said:
In developing markets like India, learning English is crucial to people's professional development and can double or triple their income potential. Our goal is to give everyone in India the best possible language education money can buy, but for free.
The team for the Hindi app, made up of just four people, is the company's first group to focus specifically on one nation.
Von Ahn, who has a personal stake in language education, said:
I come from a small country called Guatemala… and, over there, you will see a lot of inequality because the people who are educated in English have more opportunities and can improve the quality of their lives and they rise, but the people who don't have that advantage get fewer and fewer opportunities.
The changes for the Hindi version of the app include reducing the amount of memory it takes to install, removing the need to type in Hindi, improvement of the initial proficiency-level test, and customized content specifically for Hindi speakers. Because of the incompatibility of Hindi and western-style keyboards, the app instead utilizes bubbles that can be clicked for translations rather than typing in content.
The app will give those who complete their English tests a certificate for only $20, which is already being accepted by many American universities and companies as formal language training. A study by the City University of New York found that 34 hours using the Duolingo app is equivalent to a semester of traditional language classes.
The Hindi app is also designed to be particularly easy for those new to smartphone operating systems, reports Nandagopal Rajan of the Indian Express. For example, the team noticed that people in India were using Duolingo to learn French or Spanish rather than English. They discovered that since many users had their smartphones set to English as the default language, they were not even being shown English as a learning option. The Hindi app will take this, and other technical issues that may baffle new users, into account.
Other languages commonly spoken in India will be added soon.
Duolingo is the most downloaded education app for Android, iOS, and Windows phone, and has received awards from both Google and Apple. According to the Times of India, it has 110 million users worldwide. The app was designed to keep users motivated with unlockable levels, points, and high score tracking.
Before working on Duolingo, von Ahn invented CAPTCHA/reCAPTCHA, which he sold to Google while in his twenties. In an interview with Gopal Sathe of Gadgets 360, he joked:
I'm really sorry about that, and I created Duolingo as an act of penance.
He is also a MacArthur fellow and a professor at Carnegie Mellon University, which is where he met Duolingo co-founder Severin Hacker.


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Darcy Brownell, Executive Director of SVP Boston, was recently interviewed by the Boston Foundation for their "City of Ideas" blog.
Interview Excerpt
There is an assumption out there that donors aren't as interested in supporting infrastructure, the nuts and bolts of organizations, versus programs. Are your funder and donor partners interested in this?
This work is so fundamental to the SVP model. One of our partners often says that he really values that SVP asked for him to give something more than just his money. SVP does have a dual mission to not only build the capacity of nonprofits but to also build and inspire a community of philanthropists. Many join to become strategic philanthropists themselves. They're asking questions beyond what an organization's overhead is etc.
Read the full interview here >>


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Eclipse P400 Midi Tower Case - White Window
- Phanteks continues its user friendly designed PC case range with the new Eclipse Series P400. Without much effort
- the P400 allows users to create a clean and beautiful system.
20+ In stock
Stock Code: CA-042-PT
Manufacturer: Phanteks
+44 (0)1782 44 44 55
Eclipse P400 Midi Tower Case - White Window
Phanteks continues its user friendly designed PC case range with the new Eclipse Series P400. Without much effort, the P400 allows users to create a clean and beautiful system. Ambient RGB illumination adds character while the solid metal exterior gives the case a simple elegant design. The P400 is suitable for beginners and experienced systems builders with all the extra features.
The Phanteks Eclipse P400 can support 360mm radiators, 395mm VGA cards, 160mm CPU coolers and up to 270mm PSU's for impressive compatibility with enthusiast level hardware. The Phanteks Eclipse range are also fully compatible with the new Asus Aura RGB motherboard range, and through use of the Phanteks RGB LED adapter cable (sold separately) it can be synchronised with the Aura software to control both interior and exterior RGB functionality.
The Phanteks Eclipse P400 range represents outstanding value for money, combining a host of attractive features with a extremely well built and aesthetically pleasing structure, at a pricepoint that commands attention.
- Full Metal Body
- Clean interior - Featuring a PSU shroud
- Fully equipped with dust filters
- Ready for AIO Watercooling - Supports up to 360mm radiators.
- Equipped with 2 x 120mm fans
- 25 mm cable management space + additional cable compartment in bottom, along with Phanteks Velcro cable ties
- Front I/O (Hidden) - 2 x USB3.0, Headphone, Mic, LED Control, Reset
- RGB Power Light + Ambient Down Light, choose from 10 different colours, compatible with Phanteks RGB LED Strips (sold separately)
- Dimension: 210 mm x 465 mm x 470 mm (W x H x D) 8.3 in x 18.3 in x 18.5 in
- Form Factor: Midtower
- Material(s): Steel chassis, steel exterior, ABS
- Colour: White
- Motherboard support: ATX, Micro ATX, Mini ITX, E-ATX *(up to 272mm wide, cannot use rubber grommets)
- Front I/O: 2x USB 3.0, Mic, Headphone, Reset, LED control
- Side window: Yes
- Expansion slots: 7
- Internal 3.5": 6x (2x included)
- Internal (dedicated): 2.5" 2x (2x included)
- Cooling: Front - 120mm Fan x 3 (1 included), 140mm Fan x 2, Top - 120mm Fan x 2, 140mm Fan x 2, Rear - 120mm Fan x 1 (included)
- Liquid Cooling: Front - Up to 360mm (with removal of midplate cover) or 280mm (without removal), Rear - 120mm
- GPU Clearance: 395mm, 280mm (with optional HDD brackets installed)
- CPU Cooler: 160mm
- Cable Management: 25mm
- PSU (including cable): 270mm
- Model: PH-EC416P_WT
- Net Weight: 7 kg (15.4 lbs)
- Gross Weight: 8 kg (17.6 lbs)
- Package Dimension: 300 mm x 555 mm x 520 mm (WxHxD) 11.8 in x 21.9 in x 20.5 in
- Warranty: 5 Years
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Bought this case to build my daughter a small(ish) PC for Christmas. Its well made, plenty of room, decent space for cable routing in the rear, reasonable space for the PSU and at a pretty good price. I also installed some corsair RGB fans + controller and the front Top and Bottom case LED changes colour to match (yes its now pink!). My second Phantek case and both have been excellent.
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Come for a Visit
We know that visiting a new church can be a pretty intimidating experience because you don't
even know what to expect! So we want to give you a glimpse of what an average Sunday looks like at Forest Hills.
Before the Service…
Service Time
Find the Church
Get Settled
Sunday Service
10:00 – 11:00 a.m.
(A Gathering of Worship and Prayer)
Every 3rd Sunday
6:30 p.m.
Forest Hills is located at 1790 11th Street S.E. in Forest Lake. It's on the north side of Scandia Trail (Highway 97) about a mile east of Highway 61. It's right across the street from the BP gas station. Fuel your vehicle there, but your soul here!
Stop by the Hebrews Coffee Shop to enjoy a specialty roast or other beverage.
Help yourself to a worship bulletin and take a seat anywhere in the sanctuary.
During the Service…
This is a time set aside to gather with others to interact and communicate with God. Our worship team leads with a mix of modern songs and older hymns. Our aim is to come before God in an authentic and honest way. We want to enjoy his presence!
Everyone worships in his or her own unique way. You are welcome to do whatever makes you feel most comfortable.
Giving is part of the way we worship God. Each week there are opportunities to offer praise and thanksgiving, prayers and a heart open to God. There will also be a time to give financially to support the exciting work God is doing through Forest Hills into the wider community. Often a special project or outreach is highlighted and anyone wishing to support that project is welcome to give to it. Financial gifts can be received in the "plate" or electronically through EFT as well as using your mobile device with the QR code provided. It is exciting to be a part of what God is doing! Click here for more info.
Forest Hills strives to foster a living faith, one that people live out every day. Therefore, each week the pastor gives a message that not only digs into the Bible, but also applies directly to everyday life. Past messages are available here. These messages will help you develop a growing, vibrant relationship with Jesus Christ and apply Biblical teaching to your own life.
Babies and Toddlers
Holy Communion is celebrated the first Sunday of the month. This is a simple expression of love and devotion to Jesus as a way of remembering how His death and resurrection brings forgiveness and new life to all. Usually people are invited to come forward to receive a small piece of bread and a small cup of grape juice (there is a gluten free option), although sometimes other methods are used. Everyone is invited to participate, as Forest Hills celebrates "open communion." Children are also invited to receive, if their parents agree.
Forest Hills loves kids! Parents are free to keep their children with them during worship or, if they prefer, make use of our professionally-staffed nursery located next to the worship center.
Jesus said, "Be sure to bring all the children to me!" Our goal is to provide a worship experience that engages all age groups. Kids are included and involved in our services. We want them to be a part of the life of our church! Demonstrations, videos and skits help both kids and adults better absorb the message.
There are activity bags available and a table in the back of the worship center if families should choose to use them.
After the Service…
Prayer Request
Make a Difference
If you have a special prayer request or have a concern that needs specific prayer, please remain in the worship center after worship is over. Members of the prayer team will be available in the front of the worship space to meet with you.
Forest Hills demonstrates a spiritual walk that includes all of life. What we do the rest of the week is as important to God as what we do in corporate worship. You will find a list of ways to grow spiritually through small groups, activities, fellowship, opportunities of service and sharing listed in the program each week.
. Just ask anyone from the worship team, members of the hospitality team or those at the welcome center for more information. Get involved and make a difference!
Stop by the Welcome Center
Stop by the Welcome Center in the lobby for more information about the ways Forest Hills is making a difference in the wider community. If you are interested in ways of getting connected in specific kinds of ministry or ways your whole family can get involved, you'll find a friendly host to help you out. It's located in the lobby just to the right of the front doors as you enter the church.


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Dominant mutations in leucine‐rich repeat kinase 2 (LRRK2) are the most frequent molecular lesions so far found in Parkinson's disease (PD), an age‐dependent neurodegenerative disorder affecting dopaminergic (DA) neuron. The molecular mechanisms by which mutations in LRRK2 cause DA degeneration in PD are not understood. Here, we show that both human LRRK2 and the Drosophila orthologue of LRRK2 phosphorylate eukaryotic initiation factor 4E (eIF4E)‐binding protein (4E‐BP), a negative regulator of eIF4E‐mediated protein translation and a key mediator of various stress responses. Although modulation of the eIF4E/4E‐BP pathway by LRRK2 stimulates eIF4E‐mediated protein translation both in vivo and in vitro, it attenuates resistance to oxidative stress and survival of DA neuron in Drosophila. Our results suggest that chronic inactivation of 4E‐BP by LRRK2 with pathogenic mutations deregulates protein translation, eventually resulting in age‐dependent loss of DA neurons.
Parkinson's disease (PD) is a neurodegenerative disease that affects the maintenance of dopaminergic (DA) neurons. PD prevalence is estimated at ∼1% among people over the age of 65 years and is increased to 5% for people aged 85 years and older. Most PD cases are sporadic, with oxidative stress being one prominent pathological feature (Jenner, 2003). A small percentage of PD cases are inherited in a Mendelian manner, and several disease‐causing genes have been identified (Moore et al, 2005). Although most of the familial cases are of early onset, mutations in leucine‐rich repeat kinase 2 (LRRK2) cause an autosomal‐dominant form of familial PD late in life (Paisan‐Ruiz et al, 2004; Zimprich et al, 2004). LRRK2 encodes a large protein with multiple domains, including GTPase and kinase domains. LRRK2‐associated familial PD is largely indistinguishable from the more common sporadic PD in clinical and pathological aspects. Among the known familial PD genes, LRRK2 is most frequently mutated in sporadic cases, suggesting a general involvement of LRRK2 in PD pathogenesis (Taylor et al, 2006). So far, amino‐acid substitutions associated with familial PD have been identified within the multiple domains (Mata et al, 2006). Some pathogenic mutations in the kinase domain, such as G2019S and I2020T, were shown to cause moderately enhanced kinase activity in vitro (West et al, 2005; Gloeckner et al, 2006). It is not clear whether mutations in other domains (e.g., R1441G and Y1699C) also affect kinase activity. The pathogenic function of LRRK2 mutations and the biochemical pathways involved are unknown. Key to addressing these important questions is the identification of the physiological substrate(s) of LRRK2.
Translational control is critical for early development of most metazoans and for cell survival under various stress (Holcik and Sonenberg, 2005). It allows an organism to quickly respond to physiological or environmental cues by controlling the expression of proteins from existing mRNAs. Although translation can be regulated at multiple steps, control of translation initiation represents a primary regulatory mechanism. The eukaryotic initiation factor 4E (eIF4E) subunit mediates the binding of eIF4F to the 5′ m7GpppX cap structure of mRNAs (Sonenberg et al, 1979; Gingras et al, 1999b). The activity of eIF4E is inhibited by eIF4E‐binding protein (4E‐BP), which sequesters eIF4E from the eIF4F complex (Gingras et al, 1999b; Richter and Sonenberg, 2005). In vivo, 4E‐BP has an important function for survival under starvation stress, oxidative stress and unfolded protein stress, suggesting that control of translation initiation is closely linked to stress and lifespan (Teleman et al, 2005; Tettweiler et al, 2005; Yamaguchi et al, 2008). 4E‐BP is regulated by phosphorylation. One pathway known to influence 4E‐BP phosphorylation is the target of rapamycin (TOR) pathway, which integrates nutrient availability, growth factors and cellular energy status to control cell growth. Phosphorylation of 4E‐BP causes its release from the eIF4E and relieves its inhibitory effect on translation (Gingras et al, 2001; Inoki et al, 2005). At least six phosphorylation sites have been identified in human 4E‐BP1 (h4E‐BP1), including T37, T46, S65, T70, S83 and S112 (Fadden et al, 1997; Heesom et al, 1998). A sequential phosphorylation of 4E‐BP1 in the order of T37/T46>T70>S65 has been proposed (Gingras et al, 1999a, 2001). Although the regulatory mechanisms involved in 4E‐BP phosphorylation are not fully understood, it appears that a combination of perhaps all phosphorylation events is required to dissociate 4E‐BP from eIF4E (Gingras et al, 2001).
Here, we show that LRRK2 exerts an effect as a regulator of protein translation by phosphorylating 4E‐BP at the T37/T46 sites in vitro and in vivo. These phosphorylation events appear to be functionally important for the in vivo pathogenic effects of the mutant Drosophila orthologue of LRRK2 (dLRRK) on stress sensitivity and DA neuron survival. Our results suggest a novel molecular mechanism linking deregulated protein translation to stress sensitivity and neurodegeneration in PD.
dLRRK regulates DA neuron function and maintenance
To understand the biological function and pathogenic function of human LRRK2 (hLRRK2), we have used Drosophila as a model system. Drosophila, which possesses a dopaminergic system regulating locomotor behaviour and has a short lifespan, is particularly suitable for modelling the late‐onset PD caused by LRRK2 mutations. A single orthologue of LRRK2 (referred to as dLRRK hereafter) was identified in the Drosophila genome. We cloned full‐length dLRRK cDNA by RT–PCR. It encodes a 2445 amino‐acid protein containing the various domains found in hLRRK2. Critical residues disrupted in familial PD are conserved between hLRRK2 and dLRRK (Figure 1A).
To study the biological function of dLRRK, we analysed its gain‐of‐function (GOF) and loss‐of‐function (LOF) effects. For GOF analysis, we generated transgenic (Tg) flies expressing wild‐type (WT) dLRRK or mutant dLRRK carrying point mutations found in human PD patients (Figure 1B and Supplementary Figure 1). The DA neuron‐specific tyrosine hydroxylase (TH)‐ and dopa decarboxylase (Ddc)‐Gal4 drivers, pan‐neuronal elav‐Gal4 driver or the ubiquitous daughterless (Da)‐Gal4 driver were used to direct transgene expression. For LOF analysis, we obtained one P‐element insertion line, in which the expression of full‐length dLRRK protein is disrupted, as indicated by the lack of detectable full‐length dLRRK protein expression (Figure 1B). In addition, there was no detectable expression of a truncated dLRRK (data not shown). By RT–PCR analysis, we determined that the expression levels of the two genes immediately flanking dLRRK were not affected in this dLRRK (−/−) mutant (Supplementary Figure 2). Mutant animals are viable, but have decreased fertility in females. In addition, malformed abdomen is often observed in females (Figure 1C), especially when nutritional status is compromised at the larval stage. Because mutants with this phenotype show higher sensitivity to various stress and have shortened lifespan, we excluded them in subsequent analyses.
To test whether dLRRK regulates the function and maintenance of DA neurons, we performed immunohistochemical and neurochemical analyses in Drosophila. Immunohistochemical analysis using an anti‐dLRRK antibody showed that endogenous dLRRK protein expression is fairly ubiquitous in the fly brain (Supplementary Figure 1B and C). Double labelling with TH showed that it is expressed in DA neurons (Supplementary Figure 1M and N). In Tg animals, we estimated that exogenous WT and mutant dLRRK were expressed at 1.5‐ to 2.6‐fold of endogenous level in TH+ neurons (Supplementary Figure 1M). At the cellular level, endogenous dLRRK was localized in a punctate pattern in the cytoplasmic part of the cell bodies and neurites (Supplementary Figure 1L). Transgenic WT and mutant dLRRK proteins derived from the transgenes were also localized to vesicular structures that co‐stain with endosomal markers and partially overlap with synaptic vesicle markers (Supplementary Figure 1H–K and O–V).
In Tg flies expressing PD‐related mutant dLRRK, brain dopamine content was significantly reduced compared with dLRRK WT Tg or control flies (Figure 1D, left). Conversely, dopamine content was elevated in dLRRK (−/−) flies, suggesting that dLRRK negatively regulates steady‐state dopamine levels (Figure 1D, right). We tested whether this difference in DA content might reflect differential maintenance of DA neurons. In young flies (10‐day‐old), no difference in DA neuron number was observed when compared with a normal control (Supplementary Figure 3). In aged flies (60‐day‐old), however, animals expressing pathogenic dLRRK showed a significant reduction of DA neurons in the protocerebral posterior lateral (PPL) 1 and protocerebral posterior medial (PPM) 1 and 2 clusters (Figure 1E). Expression of a kinase‐dead form (3KD) of dLRRK or WT dLRRK had no significant effect on DA neuron number (Figure 1E). In both young and aged dLRRK (−/−) flies, DA neurons appeared healthy and well maintained (Figure 1E and Supplementary Figure 3). The increase of brain dopamine level in dLRRK (−/−) flies is thus likely due to changes of dopamine transmission, storage or metabolism, but not to a change of TH+ neuron number.
Transgenic animals were morphologically normal when dLRRK was ubiquitously expressed. No gross brain degeneration other than DA neuron loss was observed when dLRRK was pan‐neuronally expressed, and no neurodegeneration was observed when dLRRK was expressed in specific neuronal types (Supplementary Figure 4 and data not shown), indicating that the toxicity of mutant dLRRK is relatively specific to DA neurons.
Altered dLRRK expression affects organismal sensitivity to oxidative stress
We further analysed animals with altered dLRRK activities to gain insight into the effect of dLRRK on DA neuron maintenance. Oxidative stress is suspected as one of the major causes of DA neuron degeneration in PD. We tested whether dLRRK Tg flies manifest altered response to oxidative stress. Compared with the controls, flies ubiquitously expressing dLRRK Y1383C and I1915T mutants showed significantly higher sensitivity to exogenous ROS inducers paraquat and H2O2 (Figure 2A and B). In contrast, dLRRK (−/−) or dLRRK RNAi animals were significantly more resistant (Figure 2C and D). Animals transheterozygous for dLRRK mutant and a chromosomal deficiency that covers dLRRK (Df/−) were also more resistant to H2O2 (Figure 2C and D).
To investigate whether dLRRK is involved in cellular response to endogenous oxidative stress, we examined untreated flies for the extent of oxidative damage as measured by 4‐hydroxy‐2‐nonenal (4‐HNE) immunostaining of lipid peroxidation. An age‐dependent increase of 4‐HNE level in DA neurons was evident in control flies (Figure 2E and F). In age‐matched dLRRK(−/−) flies, 4‐HNE level was significantly reduced (Figure 2E and F). In contrast, dLRRK Tg animals showed significantly increased 4‐HNE levels (Figure 2E and F), with mutant dLRRK showing stronger effect than WT dLRRK. Changes of 4‐HNE levels in dLRRK(−/−) and Tg animals were confirmed by dot blot analysis of 4‐HNE adducts (Supplementary Figure 5A). We also used 2,7‐dichlorofluorescein diacetate staining, which is an indicator of hydroxyl‐free radical levels, to analyse dLRRK(−/−) and Tg flies. Hydroxyl‐free radical levels were significantly reduced in dLRRK (−/−) and dLRRK(Df/−) flies, whereas an increase was observed in dLRRK Tg flies (Supplementary Figure 5B). These results suggest a physiological function of dLRRK in handling oxidative stress and a pathological function of heightened oxidative stress in mediating the toxicity of mutant LRRK2.
dLRRK genetically interacts with genes in the TSC/Rheb/TOR/4E‐BP pathway
As our previous studies implicated altered PTEN/PI3K/Akt signalling in fly PD models (Yang et al, 2005), we tested possible genetic interaction of dLRRK with this pathway. dLRRK exhibited strong interaction with the TSC/Rheb/TOR/4E‐BP pathway, a downstream branch of the PTEN/PI3K/Akt signalling network that regulates cell growth and cell size through protein synthesis. For instance, inhibition of TOR signalling through the co‐overexpression of TSC1 and TSC2 inhibited cell growth in the fly eye (Gao and Pan, 2001; Potter et al, 2001). This was enhanced by the loss of dLRRK (Supplementary Figure 6C), although loss of dLRRK in an otherwise WT background had no effect (Supplementary Figure 6A and F). Conversely, stimulation of TOR signalling by Rheb overexpression enhanced cell growth (Saucedo et al, 2003), which was partially suppressed by the loss of dLRRK (Supplementary Figure 6E and G). Overexpression of a constitutively active form of d4E‐BP (4E‐BP(LL)), which has stronger affinity for eIF4E (Miron et al, 2001), caused a mild reduction of eye size (Supplementary Figure 6H). This effect was significantly enhanced by the loss of dLRRK (Supplementary Figure 6I). As the numbers of ommatidia per fly eye and rhabdomeres per ommatidium were not changed (Supplementary Figure 6J and K), the reduction of eye size was mostly due to a reduction of cell size, a measure of cell growth. The genetic interaction between dLRRK and 4E‐BP was also evident in other tissues. Overexpression of 4E‐BP(LL) in wing imaginal discs with the MS1096‐Gal4 driver resulted in a moderate reduction of wing size (Miron et al, 2001), which was enhanced by the loss of dLRRK (Supplementary Figure 6L and N). The effect of removal of dLRRK on TSC1, TSC2 and Rheb overexpression was recapitulated by dLRRK knockdown and was rescued by the introduction of dLRRK WT but not 3KD transgenes (Supplementary Figure 7). These results suggest that dLRRK positively regulates cell growth through interaction with the TSC/Rheb/TOR/4E‐BP pathway of protein translational control.
LRRK2 phosphorylates 4E‐BP
We then sought to investigate the molecular mechanism underlying the effect of dLRRK on protein translation. To study its biochemical function, we purified dLRRK from transfected 293T cells by immunoprecipitation (IP). dLRRK purified this way possessed kinase activity, as shown by autophosphorylation (Figure 3A, upper panel in lane 2 compared with lane 1). As a control, we similarly purified a mutant dLRRK containing three point mutations (3KD), including the K1781 mutation predicted to disrupt ATP‐binding (Greggio et al, 2006). The 3KD mutant exhibited no kinase activity, suggesting that the activity detected above was derived from dLRRK rather than some associated kinases in the IP complex (Figure 3A, lane 3). We also purified dLRRK containing PD‐associated point mutations. The kinase activity of dLRRK containing the I1915T mutation was notably higher than WT dLRRK (Figure 3B, lane 4 compared with lane 2).
Having obtained active dLRRK kinase, we next searched for its substrate(s). On the basis of the genetic interaction data, we tested candidate proteins in the TSC/Rheb/TOR/4E‐BP signalling pathway. Robust phosphorylation of d4E‐BP by dLRRK was detected (Figure 3A, lane 2). The activities of WT and I1915T mutant dLRRK towards d4E‐BP correlated with their autophosphorylation activity (Figure 3B, lanes 2–4). eIF4E, the binding partner of 4E‐BP and itself a phospho protein, was not phosphorylated by dLRRK (Supplementary Figure 8), supporting the specificity of dLRRK action towards d4E‐BP. The situation holds true for the human proteins, with purified hLRRK2 robustly phosphorylating h4E‐BP1 and the I2020T mutant possessing a higher activity (Figure 3C, lane 3 compared with lane 2).
To precisely map the phosphorylation site(s) in h4E‐BP1, we made a series of Ser/Thr to Ala substitutions in h4E‐BP1 and tested their effects on phosphorylation by hLRRK2 in vitro. Mutating T37/T46 and S65 reduced the amount of P32 incorporation, whereas mutating T70 and S83 had minimal effect (Figure 3D, lanes 7 and 9 compared with lanes 10 and 12). Combining T37/T46A and S65A mutations further reduced P32 incorporation (Figure 3D, lane 3). Addition of a T70A mutation into the T37/T46/S65A triple mutant background had no further effect (Figure 3D, lane 4 compared with lane 3). Western blot analysis of in vitro‐phosphorylated h4E‐BP1 with phospho‐specific antibodies showed that the T37/T46 and S65 sites were directly phosphorylated by hLRRK2 (Supplementary Figure 9). Similarly, T37/T46A mutations in Drosophila 4E‐BP reduced its phosphorylation by dLRRK (Figure 3E, lane 3 compared with lane 2). These in vitro results suggest that T37/T46 and S65 in 4E‐BP represent major LRRK2 target sites.
To verify the in vitro phosphorylation result, we examined the effect of overexpression or knockdown of hLRRK2 on h4E‐BP1 phosphorylation. A clear increase of h4E‐BP1 phosphorylation at T37/T46 was observed in cells transfected with WT or mutant hLRRK2 (I2020T) (Figure 3F, lanes 2 and 3 compared with lane 1). In contrast, p‐T37/T46 level was reduced in cells transfected with hLRRK2 siRNA, which effectively knocked down hLRRK2 expression (Figure 3G), whereas a control siRNA had no effect. As mTOR is known to affect 4E‐BP phosphorylation, we tested whether hLRRK2 might exert an effect through mTOR. No change in mTOR phosphorylation or protein level was observed when hLRRK2 activity was altered (Supplementary Figure 10). Thus, the T37/T46 sites in h4E‐BP1 appeared to be physiological hLRRK2 target sites. Despite the fact that T70 was not directly modified by hLRRK2 in vitro, its phosphorylation was affected by alterations of hLRRK2 in the cultured cells (Figure 3F and G). This is consistent with the notion that p‐T37/T46 may prime subsequent T70 phosphorylation (Gingras et al, 2001) by other kinases. Alternatively, T70 could be a direct target of dLRRK in vivo. On the other hand, although S65 was modified by hLRRK2 in vitro, its phosphorylation was not affected by hLRRK2 in cultured cells (Figures 3F and G). The S65 site may be more tightly regulated by other kinases or phosphatases in vivo.
We sought for further in vivo evidence that LRRK2 is a 4E‐BP kinase. Western blot and immunostaining of dLRRK Tg and mutant flies showed that phosphorylation of d4E‐BP at T37/T46 sites was increased in dLRRK Tg but decreased in dLRRK(−/−) flies, supporting the fact that T37/T46 in d4E‐BP are in vivo dLRRK target sites (Figure 3H–J). Note that, in dLRRK(−/−) mutant flies, phosphorylation of d4E‐BP at T37/T46 sites was reduced but not abolished, suggesting that there exist other kinase(s) that exert an effect on these sites. Both WT and a pathogenic LRRK2 effectively stimulated the phosphorylation of T37/T46 sites of 4E‐BP1 to similar levels upon insulin treatment (Figure 3F). Under starvation (serum‐free) condition, however, some pathogenic mutants exhibit higher kinase activity than WT LRRK2 (Figure 3K). These data suggested that LRRK2 interacts with the insulin/IGF signalling pathway to regulate 4E‐BP phosphorylation, but the kinase activity of some pathogenic mutants is not dependent on insulin/IGF stimulation.
The genetic interaction between LRRK2 and the TSC/Rheb/TOR/4E‐BP pathway of growth control and the phosphorylation of 4E‐BP by LRRK2 suggest that LRRK2 is a positive regulator of protein translation. Consistent with this notion, direct addition of purified hLRRK2 WT and I2020T proteins to an in vitro translation system effectively stimulated the translation of a luciferase reporter mRNA, whereas hLRRK2 3KD had no effect (Figure 3L).
Activities of 4E‐BP and eIF4E are important for cellular stress response and DA neuron maintenance
Previous studies revealed a function for d4E‐BP in conferring resistance against starvation and oxidative stress (Teleman et al, 2005; Tettweiler et al, 2005). We asked whether phosphorylation of 4E‐BP at T37/T46 residues, which is promoted by dLRRK kinase activity, affects resistance to oxidative stress in vivo. For this purpose, we generated Tg flies expressing d4E‐BP T37/T46A (TA) mutant protein. Whereas expression of d4E‐BP WT restored oxidative stress resistance in d4E‐BP(−/−), expression of similar levels of d4E‐BP TA resulted in higher resistance against oxidative stress (Figure 4A and B, and Supplementary Figure 11). This suggests that complete blockage of 4E‐BP T37/T46 phosphorylation and the consequent tighter binding and stronger inhibition of eIF4E lead to higher stress resistance. To test this idea further, we asked whether manipulation of eIF4E is sufficient to alter oxidative stress response. Overexpression of deIF4E significantly sensitized animals to oxidative stress treatments, similar to the effect induced by mutant dLRRK overexpression (Figure 4C). Furthermore, deIF4E Tg animals showed a significant increase of 4‐HNE in the absence of stress (Figure 4D), suggesting that excessive eIF4E activity altered endogenous stress response and resulted in more oxidative damages.
Consistent with the above findings, removal of one copy of deIF4E in dLRRK I1915T Tg flies increased resistance against oxidative stress (Figure 4E). We further tested whether the co‐expression of d4E‐BP TA mutant, by inhibiting the release of d4E‐BP from deIF4E, rendered dLRRK I1915T flies more resistant to oxidative stress. This was indeed the case (Supplementary Figure 12). We next used 7‐methyl GTP (m7GTP) sepharose‐binding assay to biochemically assess the level of 4E‐BP‐free eIF4E, an indicator of translation efficiency, in the various genetic backgrounds. In vivo, eIF4E protein level is fairly constant and both the 4E‐BP‐bound and 4E‐BP‐free forms of eIF4E bind to m7GTP sepharose beads. By measuring the amount of 4E‐BP‐bound eIF4E, we can get an estimate of 4E‐BP‐free, active eIF4E. As shown in Figure 4F, in d4E‐BP WT Tg animals co‐expressing GFP, a significant portion of d4E‐BP WT was released from deIF4E under normal conditions; however, under oxidative stress condition, almost all d4E‐BP WT was bound to deIF4E (Figure 4F, lanes 1 and 2). The amount of d4E‐BP WT released from deIF4E was increased in the presence of dLRRK I1915T under both normal and oxidative stress conditions (Figure 4F, lanes 3 and 4). In contrast, d4E‐BP TA was tightly bound to eIF4E in the presence or absence of dLRRK I1915T, and under normal or stress conditions (Figure 4F, lanes 5–8). These results suggested that dLRRK releases the inhibition of eIF4E by 4E‐BP, enabling free eIF4E to engage in translation.
We next tested whether d4E‐BP and deIF4E influence dLRRK‐mediated DA neurodegeneration in the flies. Whereas overexpression of d4E‐BP had no effect on DA neuron number in control Tg flies, it partially suppressed the DA neuron loss phenotype seen in dLRRK Tg flies (Figure 5A). Introduction of d4E‐BP TA fully protected against DA neuron loss caused by dLRRK I1915T (Figure 5B). Furthermore, introduction of d4E‐BP WT rescued DA neuron loss seen in d4E‐BP(−/−) flies (Figure 5B). Supporting a function for deregulation of the eIF4E/4E‐BP pathway in inducing DA neuron loss, overexpression of deIF4E alone caused a reduction of DA neurons; however, in dLRRK(−/−) background, this effect of deIF4E was suppressed (Figure 5C). Given that DA neuron loss was observed in aged dLRRK Tg flies, we searched for evidence of motor dysfunction caused by DA degeneration. As shown in Figure 5D, dLRRK I1915T expression caused locomotor dysfunction with age, which was improved by the co‐expression of d4E‐BP TA (Figure 5D). Taken together, these results indicate that the interaction between dLRRK and the eIF4E/4E‐BP pathway is intimately involved in the maintenance of DA neurons.
In this study, we used Drosophila as a model system to understand the normal physiological function of LRRK2 and how its dysfunction leads to DA neurodegeneration. We provide genetic and biochemical evidence that dLRRK modulates the maintenance of DA neuron by regulating protein synthesis. We demonstrate that LRRK2 primes phosphorylation of 4E‐BP and that this event has an important function in mediating the pathogenic effects of mutant dLRRK. These results for the first time link deregulation of the eIF4E/4E‐BP pathway of protein translation with DA degeneration in PD.
eIF4E is a key component of the eIF4F complex that initiates cap‐dependent protein synthesis. It has long been recognized that a key mechanism regulating eIF4E function is through phosphorylation‐induced release of 4E‐BP from eIF4E. A number of candidate kinases, including mTOR, have been implicated on the basis of in vitro or cell culture studies, but the physiological kinases remain to be identified. We show here that LRRK2 is one of the physiological kinases for 4E‐BP. LRRK2 exerts an effect on 4E‐BP primarily at the T37/T46 sites. Phosphorylation at T37/T46 by LRRK2 likely facilitates subsequent phosphorylation at T70 and S65 in vivo by other kinase or LRRK2 itself. 4E‐BP phosphorylation by LRRK2, therefore, could serve as an initiating event in an ordered, multisite phosphorylation process to generate hyperphosphorylated 4E‐BP (Figure 6), similar to the phosphorylation of the Alzheimer's disease‐associated tau (Nishimura et al, 2004). Our results show that LRRK2 is not the only kinase that phosphorylates 4E‐BP T37/T46 sites (Figure 3H). Similarly, 4E‐BP is unlikely the only substrate of LRRK2. A recent study showed that human LRRK2 phosphorylates moesin (Jaleel et al, 2007), the physiological relevance of which remains to be determined.
The role of 4E‐BP in regulating eIF4E function has been well established in vitro. Recent studies in Drosophila, however, have revealed the complexity of the in vivo function of 4E‐BP. Loss of the only d4E‐BP gene does not affect cell size or animal viability (Bernal and Kimbrell, 2000), suggesting that it is dispensable for cell growth or survival under normal conditions. However, d4E‐BP mutant flies are defective in responses to various stress stimuli (Bernal and Kimbrell, 2000; Teleman et al, 2005; Tettweiler et al, 2005). d4E‐BP has also been proposed to exert an effect as a metabolic brake for fat metabolism under stress conditions (Teleman et al, 2005). Whether this role of 4E‐BP is relevant to dLRRK function in stress resistance and DA neuron maintenance remains to be tested. eIF4E, the target of 4E‐BP, functions primarily in regulating general protein translation in vitro. It has been suggested that overactivation of eIF4E is linked to the aging process and lifespan regulation in vivo (Ruggero et al, 2004; Syntichaki et al, 2007). We observed that overexpression of eIF4E as well as dLRRK leads to an aging‐related phenotype in DA neurons, which strongly suggested that chronic attenuation of 4E‐BP activity promotes oxidative stress and consequent aging in DA neurons. This is consistent with the finding of similar patterns of gene expression under oxidative stress and aging conditions (Landis et al, 2004), and the fact that PD caused by LRRK2 mutations is of late onset, with aging being a major risk factor.
We analysed effects of removing dLRRK activity using a transposon insertion allele (dLRRK−), a chromosomal deletion allele (dLRRK Df) and gene knockdown (dLRRK RNAi). dLRRK(−/−), dLRRK (Df/−) and dLRRK RNAi flies are all resistant to oxidative stress treatments and show reduced endogenous ROS damages. In the paraquat treatment assay, dLRRK (Df/−) appeared more resistant than dLRRK(−/−) (Figure 2D). It is possible that dLRRK(−/−), which contains a transposon insertion in the COR domain of dLRRK, is not a null allele, although we have not been able to detect a truncated protein product using an antibody against the N‐terminus of the protein. Alternatively, the chromosomal deletion in dLRRK (Df) may include other gene(s) relevant to stress sensitivity. One candidate is the gene for PI3K Dp110 subunit. A recent study reported that dLRRK(−/−) animals are slightly sensitive to hydrogen peroxide but are comparable to control animals in response to paraquat (Wang et al, 2008). It is possible that the different genetic backgrounds and the nutrient conditions may account for the divergent results. In our studies, we backcrossed the mutant chromosome to w− WT background for six generations in an effort to eliminate potential background mutations. A consistent finding from our study and two other studies of dLRRK(−/−) animals is that dLRRK is dispensable for the maintenance of DA neurons (Lee et al, 2007; Wang et al, 2008), although in one study it was reported that dLRRK(−/−) animals show reduced TH immunoreactivity and shrunken morphology of DA neurons (Lee et al, 2007). In contrast, overexpression of hLRRK2 containing a pathogenic G2019S mutation (Liu et al, 2008), or overexpression of mutant dLRRK as reported here, caused DA neuron degeneration, supporting the fact that the pathogenic mutations cause disease by a GOF mechanism.
The pathogenesis caused by mutations in LRRK2 could be partially explained by their higher kinase activity. Indeed, some pathogenic mutants of both hLRRK2 and dLRRK show elevated kinase activity towards 4E‐BP. However, other mutants (e.g., hLRRK2 Y1699C and dLRRK Y1383C) did not show elevated kinase activity in vivo. Therefore, these pathogenic hLRRK2 mutations might confer cellular toxicity through mechanisms other than protein translation. For example, some hLRRK2 mutants are prone to aggregation in cultured cells (Smith et al, 2005; Greggio et al, 2006). Consistently, dLRRK Y1383C mutant appeared as more prominent vesicular aggregates in fly DA neurons (data not shown). Nevertheless, the facts that overexpression of eIF4E is sufficient to confer hypersensitivity to oxidative stress and DA neuron loss and that co‐expression of 4E‐BP suppresses the dopaminergic toxicity caused by more than one pathogenic dLRRK mutants provide compelling evidence that the eIF4E–4E‐BP axis has an important function in mediating the pathogenic effects of overactivated LRRK2. The more downstream events that lead to DA neurotoxicity remain to be elucidated. So far, we have found no clear evidence of altered autophagy, caspase activation or DNA fragmentation (data not shown).
There are several possibilities of how elevated protein translation could contribute to PD pathogenesis. First, given that protein synthesis is a highly energy‐demanding process, stimulation of protein translation by LRRK2 could perturb cellular energy and redox homoeostasis. This could be especially detrimental in aged cells or stressed post‐mitotic cells such as DA neurons. Second, increased protein synthesis could lead to the accumulation of misfolded or aberrant proteins, overwhelming the already compromised ubiquitin proteasome and molecular chaperone systems in aged or stressed cells. Third, altered LRRK2 kinase activity may affect synapse structure and function, which is known to involve local protein synthesis. Deregulation of this process could lead to synaptic dysfunction and eventual neurodegeneration.
Materials and methods
Drosophila genetics
See Supplementary data for details.
RT–PCR, plasmids and siRNAs
See Supplementary data for details.
Cell culture, immunopurification, western blot analysis and m7GTP pull‐down assay
Transfection of 293T cell, immunopurification of FLAG‐protein from the transfected cell lysate and western blot analysis were performed as described previously (Imai et al, 2000, 2001). For preparation of fly samples for western blot analysis, fly heads were directly homogenized in 20 μl of SDS sample buffer per head using a motor‐driven pestle. After centrifugation at 16 000 g for 10 min, the supernatant was used in SDS–PAGE. For immunoprecipitation or m7GTP pull‐down assay, fly heads were homogenized in 10 μl of lysis buffer per head (50 mM Tris, pH 7.4, 150 mM NaCl, 5 mM EDTA, 10% glycerol, 1% Triton X‐100, 0.5 mM DTT, 60 mM β‐glycerolphosphate, 1 mM sodium vanadate, 20 mM NaF and complete inhibitor cocktail (Roche)). After centrifugation at 16 000 g for 30 min, the supernatant was subjected to the assays. For m7GTP pull‐down assay, the supernatant of each lysate from 15 fly heads was incubated with 15 μl of m7GTP‐Sepharose (GE Healthcare) for 2 h. The precipitates were washed four times with lysis buffer. The precipitates (m7GTP‐bound) and the flow through (unbound) were analysed by western blot. Densitometry was analysed using Image J software from the US National Institute of Health (http//rsb.info.nih.gov/ij/).
See Supplementary data for details of antibodies resources.
In vitro phosphorylation assay
FLAG–dLRRK or FLAG–hLRRK2 immunopurified from transfected 293T cells and mock fractions processed by the same procedures were used as kinase sources. Five micrograms of His–d4E‐BP or His–h4E‐BP1 were incubated with FLAG–dLRRK or FLAG–hLRRK2 in a kinase reaction buffer (20 mM HEPES, pH 7.4, 15 mM MgCl2, 5 mM EGTA, 0.1% Triton X‐100, 0.5 mM DTT, 1 mM β‐glycerolphosphate and 2.5 μCi [γ‐32P]‐ATP) for 30 min at 30 °C. The reaction mixture was suspended in SDS sample buffer and then subjected to SDS–PAGE and autoradiography.
Dopamine measurement
Monoamine measurement was performed as described previously (Yang et al, 2005), with investigators blind to the genotypes during the measurement.
Whole‐mount immunostaining
Counting of TH‐positive neurons was performed by whole‐mount immunostaining of brain samples as described previously (Yang et al, 2006). Immunohistochemical analysis for 4‐HNE was carried out in whole‐mount brain samples of animals originated from TH‐Gal4>UAS‐GFP crossed to the indicated genotypes. Anti‐4HNE signals were normalized with GFP signals derived from the UAS‐GFP transgene expressed in the same TH‐positive neurons. Image J software was used for signal quantification. For dot blot analysis of 4‐HNE, total lysates made from fly heads were spotted onto a PVDF membrane and subsequently incubated with anti‐4HNE (1:15) overnight. As a control, we used western blot analysis of β‐tubulin from the same extracts. Properties of the 4‐HHE antibody are described on the manufacturer's Web site: http://www.jaica.com/biotech/e/. Immunohistochemical analyses were performed using a Carl Zeiss laser scanning microscope system.
Oxidative stress assay
The survival rate of 10‐day‐old male adult flies (n=15–20 per vial) kept in a vial containing a tissue paper socked with 0.5% H2O2 or 2 mM paraquat prepared in Schneider's insect medium was measured as described (Yang et al, 2005). To control for isogeny, dLRRK(−/−), 4E‐BP(−/−), UAS‐4E‐BP and the Da‐Gal4 driver were backcrossed to w− background for six generations. For studies in transgenic overexpression, the UAS‐dLRRK transgenes, UAS‐dLRRK RNAi and UAS‐d4E‐BP TA transgenic lines were generated in w− background and thus have a matched genetic background. For the analysis in Figures 4 and 5, Thor1 (4E‐BP null) and its revertant served as 4E‐BP(−/−) and 4E‐BP(+/+), respectively. UAS‐d4E‐BP WT and UAS‐d4E‐BP TA transgenics, which shows similar protein expression of d4E‐BP, were backcrossed to 4E‐BP(−/−) background for five generations.
Climbing assay
The climbing assay was performed similarly to a previously described protocol (Feany and Bender, 2000). Thirty flies were placed in a plastic vial (18.6 cm in height × 3.5 cm2 in area) and gently tapped to bring them down to the bottom of the vial. Flies were given 18 s to climb, and the number of flies above 6 cm from the bottom was counted. Twenty trials were performed for each time point for the same set of flies.
Statistical analysis
Two‐way repeated‐measures ANOVA was performed in multiple groups unless otherwise indicated. If positive (P<0.05), the means between the control and the specific groups were analysed using the Dunnett's test.
Supplementary data
Supplementary data are available at The EMBO Journal Online (http://www.embojournal.org).
Supplementary Information
Supplementary data [emboj2008163-sup-0001.pdf]
Supplementary Figure Legends [emboj2008163-sup-0002.doc]
Supplementary Figures [emboj2008163-sup-0003.pdf]
We are grateful to Drs B Edgar, DA Kimbrell, P Lasko, D Pan, N Sonenberg, Z Zhang, T Xu and the Drosophila Stock centers for flies; Drs NJ Dyson, P Lasko, N Sonenberg and J Sierra, and RH Wharton for antibodies; Drs P Bitterman and V Polunovsky for plasmids; and Dr S Guo for reading the manuscripts. Special thanks go to J Quach, Y Zhang and W Lee for technical supports and members of the Lu lab for discussions. Supported by the NIH (R21 NS056878‐01, R01 AR054926‐01), the McKnight, Beckman and Sloan Foundations (BL), the Naito Foundation, JSPS Postdoctoral Fellowships for Research Abroad and Program for Young Researchers from Special Coordination Funds for Promoting Science and Technology commissioned by MEXT in Japan (YI).
- Copyright © 2008 European Molecular Biology Organization


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5 Comments Leave a Comment
February 26, 2017 4:08 pm
Product tester
July 20, 2016 3:16 pm
didnt work. sent me o a questionnaire that asked one question and when i clicked next it said that i already filed it out (when i haven't). then some popup form came up for something calld Isay.. there was nothing about a smart app download.
July 20, 2016 10:17 am
It says "Take the 3-minute qualifying questionnaire to find out! Please provide the following information to get started" Based on my details it says I don't even qualify for the prequalification questionaire??
December 20, 2015 7:58 pm
Hi Leah, They only open enrollment for short periods so we'd suggest signing up as soon as possible.
December 20, 2015 4:23 am
Is there a deadline for this?


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The brainchild of Aaron Price of the NJ Tech Meetup, Amit Baria of the new-tech school Fuel.am, and Bret Morgan of the Jersey Shore Tech Meetup, NJ Spark Summit hosted prominent speakers discussing strategies for building successful startups.
The conference covered many topics, including a discussion on the future of data security by Dr. Ed Amoroso of AT&T, entrepreneurial advice from attorney David Sorin, and information on entrepreneurial opportunities in the city of Hoboken by Mayor Dawn Zimmer.
Sessions addressed effective crowd funding, offered fundraising strategies from major seed investors and venture capital groups, and discussed upcoming trends for marketing, promotion, public relations and media. Panel members included legal and funding specialists, as well as technologists from Indiegogo, TechCrunch, StartupValley, Techstars NYC and VentureBeat.
Personally, I enjoyed hearing Brett Martin's experiences working through his failed startup Sonar Media, as well as discussions on how to effectively crowdfund, by Stantt co-founder Matt Hornbuckle, and on the gamification of products by Gabe Zichermann.
Building Engagement Though LiveCube
A truly galvanizing element of Spark Summit was the LiveCube app, co-created by event host Aaron Price, speaker Gabe Zichermann and Justin Schier. Used as the social media aggregator for the event, the big benefit of LiveCube was that it allowed attendees to post and then return later to monitor and engage with content created that day.
Gamifying engagement and offering prizes from sponsors and speakers strongly encouraged NJ Spark Summit attendees to use LiveCube and delivered a memorable meta-experience on top of the conference talk. An added bonus for attendees is LiveCube's persistence after the event, letting them engage with speakers they did not have time to speak to during the conference.
Plugging Into Phone.com
As a sponsor, Phone.com provided a much-needed service at Spark Summit—a device charging station! Manned by Aaron Rosenthal and myself of Phone.com's upcoming API, the stylized idea box held USB, Apple and AC charging units to let attendees recharge the devices they were using at the event.
Phone.com CEO Ari Rabban also spoke briefly about the boost that Phone.com provides to startups with our professional, low-cost business phone service. Phone.com also offered a free year of service for attendees of the conference!
Overall, I think NJ Spark Summit was well executed and gave startups, investors and developers the chance to engage with the New Jersey business community. As a young business, we at Phone.com love it when startups reach out and promote each others' services, thereby encouraging those partners to return the favor down the road. Paying it forward was never so much fun!


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MIPS Learning Center
The MIPS learning center was created to ensure you have all the information necessary to succeed with MIPS reporting in 2017. Whether you are just doing research, have questions about eligibility, or specific MIPS registry measures, you will find answers to all your MIPS questions below.
Step 1 : What is MIPS?
On January 1, 2017, CMS launched the Merit-based Incentive Payment System (MIPS). This new program merges measure reporting from previous CMS quality initiatives, while also strengthening financial incentives for participation. MIPS combines and streamlines familiar activities into one program:
- MIPS Quality - Previously Physician Quality Reporting System (PQRS)
- Advancing Care Information (ACI) - Previously the EHR Incentive Program (Meaningful Use)
- Improvement Activities - Previously quality improvement activities performed without reporting
- Cost - Previously Value-Based Payment Modifier
(starts in 2018)
Under MIPS reporting, a provider's MIPS Composite Performance Score (CPS) is rated on a scale from 0 to 100, and significantly influences Medicare payment adjustments for each payment year. MIPS scores are calculated based on each providers level of participation in the different categories and ultimately determine the CMS penalty or level of incentive earned for a reporting year.
Click to read: What is MIPS? FAQ
Why Start Now?
The 2019 payment adjustment schedule will be based on the 2017 performance metrics. In other words, provider performance in 2017 will be measured by the new MIPS scoring model and will have a direct impact on your 2019 reimbursements or penalties.
In addition to the payment adjustment, each eligible clinician's MIPS CPS and individual performance category scores will be made publicly available on the Physician Compare website, including a comparison of the ranges of scores for eligible clinicians across the country. The sooner you can solidify a strong reporting strategy, the better prepared you'll be for MIPS reporting success.
What will be posted when your provider performance score becomes public?
Over the next few years, CMS will make information about group practices, physicians, and other healthcare professionals enrolled in Medicare available to the public. This information will include MIPS performance data of each provider compared to his/her peers nationally.
Who does this impact?
Every eligible clinician with claims to Medicare. MIPS scores will result in either bonus or penalty payment adjustments. There is no score that will not affect reimbursement.
Check Step 2 to find out if you are eligible for MIPS reporting
Who does this NOT impact?
Neither hospital Medicare nor Medicaid Meaningful Use incentives will be impacted by MIPS.
Additionally, providers electing to participate in an advanced alternative payment model (APM), providers who enroll in Medicare for the first time, and providers who do not service a minimum number of medicare patients.
See Step 2 for additional information
What is the Bonus and Penalty Adjustment Schedule?
The MIPS score's maximum impact on reimbursement increases from plus or minus 4% for the 2019 payment year to plus or minus 9% for the 2022 and subsequent payment years.
For full payment adjustment details see Step 4.
Step 2: Are you eligible?
During the 2017 performance year, the pool of eligible clinicians (formerly referred to as eligible providers) is shrinking significantly. However, any clinician that bills Medicare Part B is encouraged to report in 2017 and 2018. Check if you are eligible to report in 2017 below.
In 2019 the pool of eligible clinicians expands to include additional professions.
Check your eligibility
Click to see exemptions for MIPS Eligible Clinicians
Participation in an Advanced Alternative Payment Model (APM)
Eligible clinicians part of an Advanced APM, are exempt from MIPS reporting. Current examples of APMs are Accountable Care Organizations (ACO), Patient Centered Medical Homes, and bundled payment models.
MACRA Quality Payment Program Low-Volume Threshold
Eligible clinicians or groups will be exempt from MIPS reporting if they bill ≤ $30,000 or provide care for ≤ 100 Medicare Part B patients.
Newly Enrolled in Medicare
If a clinician enrolls in Medicare in the middle of a performance year, they do not have to participate in MIPS reporting that year. For example, if a clinician was to enroll in Medicare on February 6, 2017, would be exempt for the 2017 performance year (January 1, 2017- December 31, 2017).
Stay up to date with the latest news regarding MACRA and MIPS
Step 3 : MIPS Performance Categories
With launch of MIPS came the introduction of new performance categories. Each of the categories below is an updated version of a previous quality program that has been consolidated under MIPS.
MIPS Quality:
The MIPS Quality Performance Category is closely related to its predecessor, the Physician Quality Reporting System (PQRS). Much Like PQRS, the Quality Performance Category can be reported individually or as a group, and requires submission of quality measure information to CMS. It is the most valuable performance category in 2017, worth 60% of the MIPS composite score.
Read more about MIPS Quality
Key Changes from PQRS:
- With MIPS reporting quality matters! High performing groups or clinicians can earn up to 22% in incentives
- Unlike PQRS, measure groups are no longer available, and 50% of ALL payers must be reported on
- Reporting through a registry like MIPSPRO requires only 6 measures or 1 specialty measure set to be reported
One must be an outcome based or high priority measure
- MIPS does not have NQS domain requirements
Quality Measures:
- Must select 6 measures, including 1 outcome or high-priority measure.
- Can select from individual measures or specialty measure set
- Population measures are automatically selected
Advancing Care Information:
The Advancing Care Information Performance Category is Meaningful Use updated to be more flexible, customizable, and focused on patient engagement and interoperability.
Read more about Advancing Care Information
Advancing Care Information (ACI) Key Objectives:
- Protect patient health information
- Electronic prescribing
- Patient electronic access
- Coordination of care through patient engagement
- Health information exchange
- Public health and clinical data reporting
ACI, is responsible for 25% of the MIPS Composite Score and requires:
- That eligible clinicians report at least the 5 required measures
- Scoring is based on patient engagement and information exchange
- Flexible scoring is introduced for all measures in order to promote care coordination for better patient outcomes
ACI performance is calculated using 2 distinct scores:
- Base Score: To receive base score points, clinicians must provide either numerator/denominator or yes/no for each required measure. The base score accounts for 50% of the ACI category performance.
- Performance Score: Beyond the required 5 measures, physicians can select measures that best fit their practice. They will then be ranked on performance of these measures. The performance score accounts for 90% of the ACI category performance
Improvement Activities:
The Improvement Activities Performance Category is a new concept introduced by MIPS reporting and rewards eligible clinicians for participating in activities related to their patient population. Clinicians and groups can choose to participate in activities most relevant to both their practice and patient population. The Improvement Activities Performance Category is worth 15% of the MIPS Composite Performance Score in 2017.
Read more about Improvement Activities
Summary of the Improvement Activities Category
- A minimum of one Improvement Activity out of the 92 available must be selected
- Activities are weighted as either High (20 points) or Medium (10 points)
- Eligible clinicians can use a combination of high and medium weight activities
- The maximum Improvement Activities score is 40 points, or 20 for small/rural practices
- The Improvement Activities category score is calculated by dividing the total activity points earned by the total available points for your practice
Improvement Activities Category Exemptions
- Non-Patient facing eligible clinicians and groups, practices of 15 or fewer professionals, practices located in rural areas and geographic health professional shortage areas can report two medium weight activities or one high weight activity to achieve the full 40 points
- Certified patient-centered medical homes, comparable specialty practices, or medical homes receive full credit in this category automatically
- APMs automatically receive 20 points for this category.
Step 4: Payment Adjustment and Pacing Options
Payment Adjustment
Much like the Value-Based Payment Modifier Program (VM) of the past, MIPS determines each eligible clinicians' payment adjustment based on how they rank versus their peers. The score that is used to determine the performance threshold for MIPS is called the MIPS Composite Score. This scores is calculated on a scale from 0 to 100 and is comprised of the 3 performance categories referenced in
step 3.
Read more about the financial impact of MIPS
The performance in each MIPS category can have serious impact on revenue. For the performance year 2017 non-participating eligible clinicians will see an automatic -4% adjustment on their Medicare reimbursements. The cost of not participating in MIPS increases each year and reaches a maximum of -/+ 9% for performance year 2020.
Additionally, the top performing professionals are eligible for bonus reimbursements of 22% in the 2017 performance year and up to 37% for performance year 2020.
Pacing Options
To ease the burden of transitioning to MACRA/MIPS, CMS has introduced 3 pacing options for at least the performance year 2017. Each pacing option has different reporting specifications; however, all three options offer the safety of knowing the MIPS negative payment adjustment can be avoided.
Read more about available pacing options
Submit a full year:
Eligible clinicians who completely report all three performance categories will be eligible for a positive payment adjustment
Submit a partial year:
Eligible clinicians who submit "more than minimal" data for the three MIPS performance categories for at least 90 days will be eligible for a slight positive payment adjustment. Longer reporting periods are likely to result in higher incentives, as will reporting the full requirements for each performance category.
Submit a something:
Minimal reporting for MIPS is considered to be, at least a 90 day reporting period and:
- One Measure from the Quality Performance Category
- One Activity from the Improvement Activities Category
- Five measures from the Advancing Care Information Category
Step 5 : Get Started with MIPSPRO
Under MIPS, performance matters! It's no longer enough to just report quality data. In 2017, CMS penalties and incentives will reach 4% and although Medicare quality reporting is complicated, MIPSPRO makes the reporting process easy, while; our quality reporting team guides you through the MIPS reporting process, and to success!
MIPSPRO delivers key features to ensure your success
- Real-time Dashboards
- MIPS Quality, PI (Formerly ACI) & IA for all specialties and all measures
- MIPSPRO adapts to your practice
- Choose your pace of reporting
- Integrated data
- Data Validation & Support
With prices starting as low as $229 per provider/year, starting today is the key to MIPS reporting success in 2017.