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When shopping for a truly matte-finish foundation, you may have noticed that the options are slim to none at the drugstore. Imagine our surprise with Rimmel's Stay Matte Liquid Mousse Foundation: This is an excellent fragrance-free addition from the drugstore lineup. For most, the name is to be taken seriously, as this can absolutely "stay" matte for most of the workday.
Packaged in a tube, this formula is best for oily to combination skin (even acne-prone skin) and provides medium to full coverage. Among the eight shades, there are options for very fair to medium skin tones—those with deeper or very tan complexions won't find an option here. All eight shades are neutral, with nary a peach, yellow, or overly pink-toned option among them.
While the finish is natural looking, it's mousse-like texture builds coverage rapidly—a little of this formula goes a long way. In fact, because of its somewhat unique texture and coverage, we recommend experimenting by buffing it on with a foundation brush or sponge, because your fingers can easily deposit more product than you need.
Given its matte finish, the Stay Matte Liquid Mousse Foundation dries quickly, so it may take an application or two before you get the hang of it—all qualities that you'll find consistent with very matte formulas like this.
A feather light, oil free formula with an airy mousse texture that won't feel heavy or greasy. Delivers all day shine control and blends flawlessly for a natural looking matte finish. Minimizes the appearance of pores. The weight is over – finally, shine has met its matte. 8 available shades
Cyclopentasiloxane, Dicaprylyl Ether, Water, Isododecane, Talc, Trihydroxystearin, Disteardimonium Hectorite, Dimethicone/Vinyl Dimethicone Crosspolymer, Silica Dimethyl Silylate, Ethylhexyl Methoxycinnamate, Polyglyceryl 3 Beeswax, Sorbitan Sesquioleate, Trimethylsiloxysilicate, Kaolin, Tribehenin, Aluminum Starch Octenylsuccinate, Propylene Carbonate, PEG 10 Dimethicone, Caprylyl Glycol, Polypropylene, Phenoxyethanol, Methyl Methacrylate Crosspolymer, Sodium Chloride, Dimethiconol, Laureth 4, BHT, Tocopherol, May Contain (+/-):, Titanium Dioxide (CI 77891), Iron Oxides (CI 77491, CI 77492, CI 77499)
Rimmel At-A-Glance
Strengths: Inexpensively priced; a great pressed bronzing powder; several impressive mascaras; a collection of praiseworthy of lip color products including gloss and lipstick; a couple of good foundations.
Weaknesses: Not the most user-friendly packaging; lackluster skincare-esque products; some gimmicky makeup items that turn out to be duds.
Rimmel is a London-based company, under the ownership of Coty Inc. since 1996 (Coty also owns other cosmetic lines such as philosophy and Sally Hansen). A self-proclaimed "edgy" cosmetics line that's all about experimentation and "setting trends, not following them", Rimmel livens things up with a mix of trendy and classic shade options and new product launches at a rapid pace.
While not all of Rimmel's products are an absolute hit, there are some individual standout items (see top-rated reviews) that can compete with the best of what's out there—at rock bottom prices no less. A few of their lip color products deserve special mention for their elegant texture and fashion-forward colors.
Where Rimmel falls into hit-or-miss territory is with its excessive collection of mascaras (it seems as though they launch a new one every month) which makes it confusing to try to figure out which one is the best. Some are impressive and absolutely worth buying, while others are gimmicky duds. Lucky for you, we've put them rigorous testing so you can make an informed decision! Oh, what our lashes go through so you avoid frustration and wasting money!
Rimmel also dabbles in a smidgen of skincare-esque products that claim to go above and beyond the norm. For various reasons mentioned within the individual reviews, these products tend to fall short of being worthwhile purchases, even at their bargain-friendly price point.
Overall, while Rimmel has some misses, they earn our praise for several good to excellent makeup items at nearly unbeatable prices. Sort by three-star and four-star rating under this brand to find the best of what Rimmel has to offer!
Note: Many Rimmel products featured on their Web site are not available in the United States; they are exclusive to United Kingdom drugstores. The products reviewed below are those that are consistently found at U.S. stores nationwide, specifically Target, Walgreens and Wal-Mart.
For more information about Rimmel, visit www.rimmellondon.com.
The new Beautypedia Team proudly and unequivocally maintains the commitment to help you find the best products possible for your skin. We do this by relentlessly pursuing and relying on published scientific research so you will have unbiased information on what works and what doesn't-and the sneaky ways you could be making your skin worse, not better!
The Beautypedia Team reviews all products using the same research, criteria, and objectivity, whether the product being reviewed is from Paula's Choice or another brand.
Tried this one once and never wore it again.
I have very pale acne-prone skin and I hate this thing.
No coverage. Way too dark (even in the lightest).
There's way better things out there.
Horrible foundation. I bought 2 tubes based on the beautypedia review and I wholeheartedly regret it. My face looks blotchy and the foundation gets into my pores. It looks like something a mime would wear. Just awful!
I love the coverage this gives, It feels lightweight and it is inexpensive. The downside for me is the colors, I'm in the lightest shade and even though I'm cool toned this foundation is a little to pinky/peachy for me. I checked out the other shades and they seem to get more orange the darker the foundation colors get.
It takes too much effort to make this work. If I don't apply straight after putting on primer, it's a cakey, streaky, blotchy mess. Never wear it with a BB cream, or it'll look way too orange and give this weird noticeable foundation build up look. Even with my best efforts, it is pretty obvious I'm wearing foundation. I've never seen the lightest shade (081) in any store and the next shade up can look wrong very easily. Not much variety in colours. Face always needs to be powdered by midday.
When i apply this foundation it goes on very nicely but with in 5 to 10 mins of applying powder on top the foundation seems to cake up but i do lovd this foundation i would recommend it
I disagree with the review. I have very oily skin and this foundation doesn't last on me, it breaks down at about lunch time. If I try to apply powder on top, it makes my face very cockeye and it looks like snake skin. Awful results. I like it is in tube and cheap but I would rather save my money. Try it before you buy it.
I absolutely love this foundation, its perfect for me & very affordable... Gives me all day coverage & feels light on my skin. Definitely recommend to anyone looking for a great product for a great price.
would recommend this foundation to anyone with acne prone/oily skin due to its medium to full coverage. this is a truly matte product perfect for hot and humid climates. i find this product blends beautiful using a damp beauty blender and even a damp brush and using stippling motions to get the most coverage. if u find it a bit too dry u can moisturizer beforehand and this will give u a dewy finish. inexpensive product around $4 at my local walmart and the product lasts so long.
If you have combination skin just try this for a full but not cakey coverage. It lasts all day and so inexpensive.
Sometimes I agree with the reviews here at Beautypedia, sometimes not. This review is spot on.
This foundation could easily be priced in the high-end foundation range (although I love that it is accessible to almost everyone's budget!). I bought this foundation in a pinch when I left mine at home on a weekend outing. I can't believe how great this stuff is. I like it much better than the other foundations in my kit (Urban Decay Naked Skin, Lancome Teint Idole).Try this foundation, it's amazing!
I love this foundation!! The coverage is perfect and stays all day. Great product and price too!!
On this review I went out and bought 4 of the shades to use in my professional makeup kit. I used the true Ivory shade on myself, and white it is the look and coverage I live on others, somehow it has a texture and looks cakey/peely on my cheeks. It could just be my skin is dehydrated? But I use PC cleanser, BHA 2% and a best rated Mary Kay moisturiser/serum and always PC sunscreen. I'm going to try with extra moisturiser then go back to MK mattewear foundation which looks less dry.
I am a sucker for trying new beauty products, particularly foundations as I like full coverage and there aren't a lot of products out there who give the coverage they promise. This product does. I tried it from a sample in a magazine and loved it. I am on my second tube now. It doesn't last too long but at $8.99 (Cdn price) who cares. I love the texture, the coverage and the Ivory is a perfect shade for me. I have combination/normal skin. I would think any skin type could use this product.
I'm so torn about this one!
The Pros: I love the packaging, as it's much less bulky than my beloved Colorstay Whipped. The satiny finish and buildable coverage are wonderful. Shade 103 is a nice match for me...which is hard to find.
The Cons: this does NOT last on me. It slides right off after a few hours and leaves me feeling pretty gross. Even with different primers and powders, no luck.
I absolutely love this product, and at less than $5, it's a no brainer. I live in a very hot, humid climate and it wears well all day even through profuse sweat.
This light-weight medium coverage mousse is truly lovely. I tried the lightest color and I was pleasantly surprised. At $4.99 I am absolutely blown away by the lovely dewy finish I have after 8 hours, with no touch-ups! If you have combo skin, this will glide easily over your dry areas while leaving your T-zone matte. Touch-up with powder after 6 or so hours and your matte finish should last all day. This is a great alternative to a powder foundation that may leave you too dry in spots.
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Top 100
Richard Rushfield made it into BuzzFeed's Top 100 on March 28, 2013! Their posts will now appear in the Just Launched section of the site.
Think you have what it takes to move up in the rankings? Here's a nifty little tool that will help you get there.

subset: commoncrawl


text:
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Each strand is approximately 16 inches long and contain variations among each strand.
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A small and simple utility for downloading RSS feeds to your iPod.
Required OS: not specified
, rss
, sync
Want to chat to us or other iusers? We have a irc channel #iusethis on irc.perl.org. You can find an irc client
please give us feedback |
Advertising | FAQ.Share
Created by Arne & Marcus.
| Powered by FreeBSD, Postgres & Catalyst.


text:
Dre and The Collective:
When Dre decided to start a band in her hometown of Tampa Bay, she knew it made sense to draw on the celebrated roots of successful and talented bands that cut their musical teeth there, such as Tom Petty and Ray Charles.
Borrowing from many of the best bands and studio musicians in the region, she took those roots and blended them with her Swedish musical heritage, to create something new called Dre and The Collective. It started out as a huge 11 piece band called The Tampa Collective, but through writing and experimentation has ultimately settled into a smaller band that grows depending on where they are and who's available to play…a collective that flows between the blues, Gospel, folk, rock and Americana…sweetened with the strong melodies Sweden is known for.
Comparisons have already been made to such bands as Nicki Bluhm and the Gramblers, Grace Potter and The Nocturnals and First Aid Kit. According to Dre, "To create something new, you need to draw from past sounds and mix them with your point of view, your unique voice and experiences…then go paint your own picture"…and that's exactly what Dre and The Collective are doing.
Dre and the "Delfest" Collective at Delfest 2015, where Dre and her always present drummer Joey Interrante collaborated with Ronnie McCoury, Rob McCoury, Cody Kilby, Jason Carter, Alan Bartram, Sierra Hull and Justin Moses–dream team!


text:
Marcel Maldonado, schmucky car thief, escapes from cops, then gets busted sitting in driveway
Video, pics below.
Marcel Maldonado seems like the kind of criminal who doesn't know the meaning of laying low.
A wanted man in Washington state, he managed to make it to Colorado, only to tweak the cops here. But after getting away again, where did he hide? In the car police were chasing. Which was parked in a driveway.
Earlier this month, according to Washington's KNDU-TV, Maldonado, 21, allegedly held up a convenience store in the community of Grandview. But while he fled with an undisclosed amount of cash, he didn't get far, crashing his car just ten minutes later.
The end for Marcel. No way! Yakima County Sheriff's Department reps say he promptly carjacked a Ford Ranger from a nearby homeowner, using a gun as persuasion. Shortly thereafter, he ditched that vehicle in favor of a 2011 Volkswagen Jetta, which he allegedly carjacked from a young couple at a rest stop.
Cops spotted him in the Jetta and gave pursuit, only to break off the chase when it reportedly became too dangerous.
Days later, on November 24, notes CBS4, Maldonado resurfaced, this time in Colorado's Kit Carson County. When officers tried to pull him over in yet another vehicle, he rabbited, blitzing through a total of five counties at speeds up to 131 miles per hour.
The search is said to have gone on for hours. But eventually, police spotted the car near Byers, in the driveway of a house. And Maldonado? He was sitting inside. Also accompanying him -- a gun that may have been used in those Washington carjackings.
Now, in addition to charges in Washington state, Maldonado faces a raft of counts here in Colorado. Among them: driving under the influence of alcohol and drugs, which, if true, puts the frosting on the schmucky cake.
Look below to see Maldonado's latest mug shot, followed by the CBS4 report.
Marcel Maldonado.
More from our Schmuck of the Week archive: "Henry Sawaged, owner of the world's largest booze store, now the city's biggest schmuck."
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Feb 2, 1993
|Filing date
|Aug 21, 1992
|Priority date
|Jan 16, 1991
|Fee status
|Publication number
|Kenneth B. Riordan
|Original Assignee
|Motorola, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (7), Non-Patent Citations (2), Referenced by (72), Classifications (11), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation of application Ser. No. 07/642,253, filed Jan. 16, 1991 and now abandoned.
The invention generally relates to Time Division Multiple-Access (TDMA) radiotelephone systems and more specifically to TDMA radiotelephone systems requiring automatic gain control to maintain a linear amplitude response in the radiotelephone receiver.
Time Division Multiple-Access (TDMA) radiotelephone systems which require channel equalization typically impose the need for a linear receiver employing automatic gain control (AGC), conforming to stringent dynamic requirements. Frequently, an additional requirement of the AGC system is to first acquire and then hold the appropriate AGC state for the majority of the timeslot. This permits the receiver to maintain a linear amplitude response which is necessary for optimal channel equalization.
The dynamic requirements for the AGC system can be broken into two cases: the traffic channel (TCH) or the "voice channel", and the random access channel (RACH). In a TCH condition, a given timeslot within the TDMA frame is occupied by the same mobile user for consecutive frames. Neglecting the effects of long-term signal variations, the received power level for a TCH has a tolerably small amount of variation from one TDMA frame to the next. Consecutive timeslots within the frame, however, represent different mobile users, and as such, can be received at widely different levels. For a TCH timeslot, the receiver's AGC system can take advantage of previous knowledge of the appropriate AGC state. It therefore needs to re-configure to that AGC state during a guard period between timeslots.
Unlike the TCH, the RACH can be considered a one-time event. As a result, the base-station receiver does not have the benefit of advanced knowledge of the mobile's received signal level. It must therefore acquire and hold the appropriate AGC state during the actual random access burst. In addition, it must perform this function quickly so as to permit proper reception of the transmitted data and proper channel equalization.
RACH operation is further complicated by the uncertainty of the start of the random access burst with respect to the start of the random access timeslot. In the Pan-European Digital Cellular system, or better known as GSM, the RACH utilizes a shortened TDMA burst called the random access burst. This shortened burst is required to compensate for the time delay between mobile transmission and base reception which when combined with the requirement for the receiver gain to be held constant throughout the majority of the burst, results in the requirement for the AGC system to first detect the mobile's presence on channel and then institute an acquire and hold process. The time period that the receiver uses to institute the acquire and hold process needs to be minimized so that the impact on the radio sensitivity or receiver bit error rate is negligible.
Thus, a need exists for a receiver incorporating an AGC system which detects and applies the appropriate AGC value to a RACH channel in a TDMA system.
A receiver module in a time-division multiple access (TDMA) communication system controls the amplitude of a received burst signal, wherein the received burst signal is input into the receiver module during the time of one TDMA timeslot. The receiver module stores amplitude control values related to continuous signal amplitudes, detects when during the TDMA timeslot time the received burst signal arrives, responsive to the detection, monitors the amplitude of the received burst signal for at least one predetermined time period of the TDMA timeslot. The receiver module, responsive to the monitoring, selects an amplitude control value corresponding to the amplitude of the received burst signal, and responsive to the monitoring, controls the amplitude of the received burst signal after at least the one predetermined time period.
FIG. 1 generally depicts a base-station receiving the burst signal or more specifically a random access burst signal.
FIG. 2 depicts the random access burst timeslot in accordance with the invention.
FIG. 3 generally illustrates the hardware performing AGC of the random access burst in accordance with the invention.
FIG. 4 generally depicts in flow diagram form the steps the receiver module or RCU performs to AGC the random access burst in accordance with the invention.
FIG. 1 generally depicts a base-station 115 which may employ the present invention. The random access burst which would be transmitted by a subscriber unit in a single timeslot is received by an antenna 100 which is coupled to a bulkhead connector 103 mounted at the top of the base-station 115. A receiver front-end 105 accepts the random access burst and distributes the burst to a receiver 110. The receiver has as input a random burst which is used to initiate communication and a series of traffic bursts used to maintain or sustain communication, along with various other types of bursts. Each type of burst occurs in a timeslot specifically reserved for that particular burst or transmission. The receiver 110 will detect or demodulate each burst into an in-phase and quadrature phase (I & Q) components which are input into an equalizer 120. The receiver, as is the equalizer, is coupled to a controller 125 which contains all control hardware necessary to perform the RACH AGC process. The controller has a data-out port for sending data to additional devices and a data-in port for receiving data from additional devices. A controller interface which essentially allows the controller 125 to communicate to a user is also available, and in the preferred embodiment is typically connected to a PC. The controller interface, through the controller 125, is the interface used for entering calibration factors of the base-station 115. The controller 125 is coupled to a read only memory (ROM) 135 and a random access memory (RAM) 130. The receiver 110, equalizer 120, controller 125, RAM 130, and ROM 135 generally comprise a receiver module or radio channel unit (RCU) 140. The receiver front-end 105 is used to distribute the incoming signal to at least one RCU 140, depending on the configuration of the base-station 115.
FIG. 2 illustrates the random access burst as defined in Groupe Special Mobile (GSM) Recommendation 5.01, version 3.1.0, Feb. 15, 1988. The burst is comprised of 8 tail bits which occur for 29.5 μs of the timeslot followed by a 41 bit synchronization sequence used to synchronize the burst to the corresponding channel. The 41 bit synchronization sequence is followed by 36 encrypted bits which contain information regarding the subscriber, such as the subscriber ID number, subscriber registration number, etc. The encrypted bits are followed by three tail bits which are then followed by 68.25 guard bits. The guard bits are reserved to compensate for time delays the burst 200 encounters in getting to the base-station 115. The total timeslot length is 577 μs.
FIG. 3 generally depicts components of the RCU 140 which perform AGC of the random access burst 200 in accordance with the invention. Before the RCU 140 is installed into a base-station 115, the RCU 140 receiver linearity characteristics must be determined. During this characterization or calibration, a known RF input is applied to the RCU 140. The known RF signal is amplified by a RF amplifier 300 and may either pass through an attenuator 305 or bypass the attenuator 305. The signal then enters a mixer 310 which also has as input a local oscillator (LO) 312 to mix the signal down to a first intermediate frequency (IF). The signal amplitude after mixing is input into a signal strength indicator 325 which produces a raw DC voltage proportional to the logarithm of the received signal level. The raw SSI voltage is then input into an analog-to-digital converter (A/D) 335 which converts the raw SSI voltage to a digital word which at this point has not been linearized. The non-linearized raw SSI word is monitored by the control processor 340 which in the preferred embodiment is a Motorola 68030 microprocessor. Multiple samples of the raw SSI word are taken and an average value is calculated. This value is then sent as an address to a SSI RAM 345 and the linearized SSI word for that particular RF input power level is written as data to that address. This process is repeated for the complete RF power input range, which in the preferred embodiment is -110 dBm to -10 dBm. The control processor 340 also stores all SSI information in a SSI ROM 342 so that the SSI RAM 345 may be reloaded whenever the RCU is re-initialized.
The AGC look-up table must also be calibrated. During AGC calibration, a known RF power level is applied to the RCU 140. The I and Q signals exiting the receiver 110 are monitored to determine if they are at the correct level for A/D input located at the equalizer 120. If I and Q are not at the correct level, the attenuation represented by attenuator AGC7 305 and a series of attenuators AGC0 -AGC6 315 is varied until the correct levels are reached. To comply with specified RF performance requirements, AGC7 305 is forced active or is input for attenuation states greater than 55 dB, and forced inactive, or bypassed, otherwise. The state of the eight attenuators is recorded and used as the AGC word for that particular RF input level. The control processor 340 then sends the linearized SSI word as an address to the AGC RAM 350 and sends the AGC word as the data for this address. The most significant bit represents AGC7 305. The lower seven bits represent the IF attenuators AGC6 through AGC0 315. The same procedure is repeated for all RF input levels. As it does for SSI, the control processor 340 stores all AGC information in the AGC ROM 343 for RCU 140 reinitialization.
AGC during a traffic channel (TCH) relies on the past history of the TCH signal strength. During the guard period preceding the TCH timeslot, a processor (not shown) on the equalizer 120 writes a modified SSI word to the address lines of the AGC RAM 350. The modified SSI word is the result of an averaging algorithm which produces the estimated average value of the mobile's signal strength. All eight bits of the correct AGC state are then latched to associated attenuators, inserting the attenuators as required. The entire procedure requires less than 10 μs and is completed before the start of the timeslot. This procedure is repeated every timeslot.
Initiation of AGC acquisition during the RACH requires a determination of the mobile's presence on the appropriate channel. Due to the required immediacy of detection, only the mobile's received signal strength qualifies for this purpose. Therefore, the SSI voltage, as it compares to a specific threshold voltage, is used as the basis for presence detection. The mobile detect threshold voltage is selected via software. Access to the presence detect threshold hardware is accomplished via a three bit bus, which permits one of eight values to be selected from a predetermined range. The range is intended to allow compensation for two variables: 1) Different cell-site characteristics may result in a need for different presence detect Carrier to Noise Ratios (C/N). As an example, a small urban cell may require a higher detect threshold to avoid co-channel interference, while large rural cells may require lower detect threshold in order to detect distant, low level mobiles. 2) Different receiver front-end 105 configurations produce different receiver noise floors. Therefore, in order to detect mobile presence at a specific value of C/N, the detect threshold must be variable.
AGC during a random access channel (RACH) is accomplished as follows. Beginning in the guard period preceding the random access burst 200 timeslot, the output from the SSI RAM 345 is routed directly to the address line of the AGC RAM 350. The output of the AGC RAM controls eight attenuators, AGC7 305 and a block of attenuators AGC0 -AGC6 315. The output of the AGC RAM is updated every A/D converter 335 sample (approximately once per microsecond). Sometime during this process, the mobile presence detect 330 will indicate that the random access burst 200 has arrived in the timeslot. The presence detect 330 notifies the control processor 340 of the burst presence and at this point, the AGC system begins to converge on the appropriate AGC state. This iterative process is repeated until approximately 28 microseconds has passed since the mobile was determined to be present, at which point AGC7 is inserted. After an additional 20 microseconds, AGC0 through AGC6 315 are inserted. The 48 microsecond total acquisition time is chosen to ensure sufficient SSI response time in the case when the mobile is detectable 28 microseconds before the start of the random access burst. This scenario can occur as a result of the mobile power ramping during the guard period preceding the random access burst 200 timeslot. In all cases, the AGC system will acquire the correct AGC state before the end of the first 8 tail bits of the random access burst 200.
FIG. 4 depicts the steps the RCU 140 performs to AGC the random access burst 200. The RCU 140 stores at 400 amplitude control values related to continuous signal amplitudes and detects at 405 when during a TDMA timeslot the received burst signal arrives. The RCU 140 then monitors at 410 the received burst signal for at least one predetermined time period of the TDMA timeslot and selects at 415 an amplitude control value corresponding to the amplitude of the received burst signal. The RCU 140 then controls at 420 the amplitude of the received burst signal after at least the predetermined time period. With this method, the burst signal of the RACH is detected and AGC applied during the duration of a RACH timeslot.
|Cited Patent
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|Jan 21, 1986
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|Alcatel Thomson Faisceaux Hertizens
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|Aug 1, 1985
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|Siemens Aktiengesellschaft
|Method and apparatus for transmitting signals between a master station and a number of terminals
|Nov 21, 1990
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|Nec Corporation
|Automatic gain control
|Dettro et al., "AGC Isolation of Information in TDMA Systems" PCT Application, International Publication Number WO90/06641 Filed Nov. 13, 1989.
|Dettro et al., AGC Isolation of Information in TDMA Systems PCT Application, International Publication Number WO90/06641 Filed Nov. 13, 1989.
|Citing Patent
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|Feb 1, 1993
|Mar 22, 1994
|Cirrus Logic, Inc.
|Gain control circuit for synchronous waveform sampling
|Jan 14, 1992
|Jul 19, 1994
|Nokia Mobile Phones Ltd.
|Gain control in a TDMA radio-telephone system
|Jan 31, 1994
|Sep 13, 1994
|Clarion Co., Ltd.
|Spread spectrum communication device
|Jul 24, 1992
|Sep 5, 1995
|Cyplex Corporation
|Frequency hopping time-diversity communications systems and transceivers for local area networks
|Apr 18, 1994
|Sep 5, 1995
|Matsushita Electric Industrial Co., Ltd.
|Intermittent operation receiver
|Mar 23, 1994
|Feb 20, 1996
|At&T Corp.
|Fast AGC for TDMA radio systems
|Jun 1, 1995
|Apr 9, 1996
|Japan Radio Co., Ltd.
|Receiver with an AGC circuit capable of expanding a dynamic range
|Jun 7, 1995
|Jun 4, 1996
|Nokia Mobile Phones Ltd.
|Fast AGC setting using RSS (I) measurement procedure
|Dec 27, 1994
|Aug 20, 1996
|Nec Corporation
|Compact AGC circuit with stable characteristics
|Sep 22, 1994
|Nov 26, 1996
|Motorola, Inc.
|Receiver path selection based on burst-type in a time division multiple access receiver
|Aug 19, 1996
|Jul 15, 1997
|Rockwell Semiconductor Systems, Inc.
|Multiple antenna home base for digital cordless telephones
|Dec 15, 1995
|Aug 26, 1997
|Rockwell Semiconductor Systems, Inc.
|Multiple antenna home base for digital cordless telephones
|Dec 15, 1995
|Dec 9, 1997
|Rockwell Semiconductor Systems, Inc.
|Multiple antenna home base for digital cordless telephones
|Sep 30, 1996
|Feb 24, 1998
|Qualcomm Incorporated
|Method and apparatus for increasing receiver immunity to interference
|Aug 31, 1995
|Mar 24, 1998
|Qualcomm Incorporated
|Method and apparatus for increasing receiver immunity to interference
|Oct 26, 1995
|Jun 16, 1998
|Matsushita Electric Industrial Co., Ltd.
|Radio receiving system with adaptive antennas having reduced variation of amplification
|Mar 4, 1996
|Sep 15, 1998
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|Jul 28, 2009
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|Method and apparatus for automatic gain control on a time slot by time slot basis
|Sep 30, 2002
|May 22, 2003
|Ronald Taylor
|Maintenance/trouble signals for a RF wireless locking system
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|May 29, 2003
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|Sep 30, 2002
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|Ronald Taylor
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|Sep 30, 2002
|May 29, 2003
|Wiemeyer James F.
|Energy saving motor-driven locking subsystem
|Sep 30, 2002
|Jul 31, 2003
|Ronald Taylor
|RF channel linking method and system
|Jul 16, 2004
|Apr 14, 2005
|Scott Hahn
|Communications system and method with A/D converter
|Aug 26, 2003
|Nov 10, 2005
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|Feb 11, 2002
|Nov 3, 2010
|Method for controlling receive signal levels at a network node in TDMA point to multi-point radio communications systems
|Aug 4, 1997
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|Samsung Electronics Co., Ltd., Suwon
|Vorrichtung und Verfahren zum Minimieren �u�erer Interferenzsignale in einem Mobiltelefon mit Mehrfachzugriff durch Kodetrennung
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|Method of adjustment for receiver of signals transmitted in bursts and corresponding receivers
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|Aug 3, 1995
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|Mar 4, 1997
|Sep 12, 1997
|Edward J Anthony
|Digital diversity receiver system
|Dec 22, 1998
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|Huttunen Mikko
|Reception method and receiver
|Aug 31, 1999
|Dec 21, 2000
|Atmel Corp
|Digital automatic gain control
|Jan 5, 2001
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|Motorola Inc
|Radiotelephone receiver and method with improved dynamic range and dc offset correction
|Feb 11, 2002
|Aug 22, 2002
|Ericsson Telefon Ab L M
|Method for controlling receive signal levels at a network node in tdma point to multi-point radio communications systems
|U.S. Classification
|370/347, 455/138, 455/136, 455/234.1, 375/345, 455/250.1, 455/251.1, 455/249.1
|International Classification
|Cooperative Classification
|European Classification
|Apr 26, 1996
|Fee payment
Year of fee payment: 4
|Jul 31, 2000
|Fee payment
Year of fee payment: 8
|Jun 29, 2004
|Fee payment
Year of fee payment: 12


text: Thomas Murray | IBDB: The official source for Broadway Information IBDB: The official source for Broadway Information Official Broadway League sites: - sites - broadway.org broadwayleague.com broadwayfanclub.com kidsnightonbroadway.com stagespecs.org tonyawards.com Quick Search For: In This Category: All Show People/Org. Theatre Season Thomas Murray Performer ( b. circa 1873 IRELAND - d. Mar 07, 1959 Dublin, IRELAND ) Male Productions ProductionsDate of ProductionsOur Mrs. McChesney[Play, Original] Performer: Thomas Murray Oct 19, 1915 - Feb 1916 Find out where Thomas Murray and are credited together © 2001-2015, The Broadway League, All Rights Reserved. (Copyright and Disclaimer)


text:
Expression of epidermal growth factor, transforming growth factor-β1 and adiponectin in nipple aspirate fluid and plasma of pre and post-menopausal women
© Miller et al.; licensee BioMed Central Ltd. 2013
Received: 13 February 2013
Accepted: 6 April 2013
Published: 15 April 2013
Nipple aspirate fluid (NAF) contains large amounts of protein thought to reflect the microenvironment of the breast, and is of interest in breast cancer prevention research. The correlation between specific NAF proteins to plasma concentrations have not been well studied in healthy women. We collected matched NAF and plasma from 43 healthy pre and postmenopausal women participating in an early phase clinical study to compare the levels of putative cancer protein biomarkers. We compared baseline NAF and plasma levels of epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), and adiponectin and evaluated menopausal status and body mass index (BMI) as potential modifying factors.
NAF and plasma levels of EGF, TGF-β1 and adiponectin were not correlated. EGF and TGF-β1 levels in NAF of premenopausal women were significantly higher than postmenopausal women (P's < 0.01). These differences by menopausal status were not observed in plasma. Both NAF and plasma adiponectin levels were non-significantly higher in postmenopausal women. NAF biomarker levels were not associated with BMI whereas plasma EGF, TGF-β1 and adiponectin levels in postmenopausal women were all inversely correlated with BMI (P's < 0.05).
Protein biomarkers differ significantly between NAF and plasma and are affected differently by both BMI and menopausal status. This study demonstrates important differences in biological information gained by characterizing biomarkers in NAF compared to plasma and suggests each sample source may independently inform on breast cancer risk.
Body mass index
Epithelial growth factor
Nipple aspirate fluid
- TGF-β1:
Transforming growth factor beta 1
- Her-2/neu :
Human Epidermal Growth Factor Receptor 2
Enzyme-linked immunosorbent assay.
Nipple aspirate fluid (NAF) is a rich source of protein postulated to more closely reflect the local breast microenvironment than plasma. Petrakis et al. [1] showed that simply producing NAF doubled a woman's risk of breast cancer, which lead to a handful of studies using NAF as a source of breast tissue risk biomarkers [2–4]. The components of NAF are regularly metabolized and re-absorbed by the epithelial lining of the ductal/alveolar system [5]. It is hypothesized that drug, protein and hormone levels in NAF more closely reflects breast tissue environment and exposures than plasma [6, 7]. In women with breast cancer, Kuerer et al. found no association between serum and NAF levels of soluble Her-2/neu although the Her-2/neu levels between the affected and unaffected breasts were highly correlated [8]. Whether protein levels in NAF of healthy women are correlated with plasma is largely unknown.
In an effort to better understand the relatedness between plasma and NAF composition in healthy women, we conducted a correlative analysis of candidate breast cancer risk markers in matched NAF and plasma samples from healthy pre- and postmenopausal women participating in a Phase I clinical trial. Here we report on our findings for biomarkers previously related to breast cancer, epidermal growth factor (EGF) [9], transforming growth factor-beta 1 (TGF-β1) [10], and adiponectin [11].
Study participants
We recruited healthy women age 18–65 to a Phase I trial to evaluate the safety and feasibility of topical application of limonene as massage oil to the breast and to determine limonene levels in NAF. Details of the trial have been described elsewhere [12]. Participants were excluded if they were pregnant or breastfeeding, had invasive cancers within the past 5 years, participated in another clinical intervention trial within the past 3 months, had uncontrolled metabolic disorders, serious acute or chronic diseases, or were unable to produce NAF. The study was approved by the University of Arizona Human Subjects Committee and written consent was obtained from all participants.
Sample collection
Baseline (pre-intervention) NAF was collected via breast massage and a Medela breast pump into capillary tubes and immediately diluted in phosphate buffered saline (1:10). Baseline blood sample was collected into Vacutainer tubes containing sodium heparin and centrifuged for plasma separation. Plasma and diluted NAF were stored at -80°C prior to analysis.
Plasma and NAF biomarker analysis
NAF and plasma EGF, TGF-β1, and adiponectin were measured using ELISA based immunoassays (R&D Systems, Minneapolis, MN, USA). Plasma samples were diluted prior to the analysis according to the manufacturer instructions for EGF and TGF-β1, and were diluted 1:200 for the adiponectin assay. NAF samples were further diluted 1:100 – 400 for EGF, 1:20 – 40 for TGF-β1 and 1:3 – 1:20 for adiponectin. Assays were linear over the concentration range of 3.9 - 250 pg/mL, 31.2 – 2,000 pg/mL, and 3.9 - 250 ng/mL for EGF, TGF-β1, and adiponectin, respectively. Each sample was analyzed in duplicate for each assay (CVs <10% for all assays).
Statistical analysis
Linear regression was performed to control for body mass index (BMI) while comparing differences between pre- and postmenopausal in protein biomarker levels in NAF as well as in plasma. Spearman correlation coefficients were derived to determine correlations between NAF and plasma biomarkers as well as BMI and NAF or plasma protein biomarkers. A P-value of < 0.05 was considered statistically significant.
Participant characteristics
Participant demographics
Premenopausal women (N = 16)
Postmenopausal women (N = 27)
45 (41.4 ± 10.9)a
56.0 (56.2 ± 5.0)a
Body Mass Index (kg/m2)
25.3 (27.3 ± 6.0)a
25.1 (25.7 ± 4.6)a
Race/Ethnicity: n (%)
15 (93.7)
24 (88.9)
Pacific Islander
1 (6.3)
0 (0.0)
Native American
1 (6.3)
1 (3.7)
0 (0.0)
2 (7.4)
Plasma and NAF biomarker levels by menopausal status
Plasma and NAF biomarker correlations and relationship to BMI
Association between biomarker levels in NAF and plasma
Spearman correlation
Premenopausal (n = 9)
Postmenopausal (n = 24)
Premenopausal (n = 11)
Postmenopausal (n = 24)
Premenopausal (n = 6)
Postmenopausal (n = 22)
Association between biomarker levels and BMI
Spearman correlation
Premenopausal (n = 9)
Postmenopausal (n = 25)
Premenopausal (n = 16)
Postmenopausal (n = 27)
Premenopausal (n = 11)
Postmenopausal (n = 26)
Premenopausal (n = 16)
Postmenopausal (n = 27)
Premenopausal (n = 6)
Postmenopausal (n = 23)
Premenopausal (n = 16)
Postmenopausal (n = 27)
In a cohort of 43 healthy women, we measured the secreted protein biomarkers EGF, TGF-β1, and adiponectin in matched NAF and plasma samples. Interestingly, none of the three biomarkers in NAF were correlated to levels in plasma. Further, in postmenopausal women, levels of all three potential breast cancer biomarkers in plasma were inversely correlated with BMI, but there was no relationship between BMI and these biomarkers in NAF. With our small sample size, correlation coefficients ≥ 0.45 are necessary to determine statistically significant correlations between NAF and plasma or between biomarkers and BMI with 80% power. Our sample size, however, was sufficient to determine a statistically significant relationship between plasma adiponectin levels and BMI, a well-known association [13]. Therefore, this preliminary evidence suggests that NAF contains biological information distinct from plasma, despite the small sample size.
We are aware of only one other study reporting adiponectin levels in the NAF; Sauter et al. observed that 3 and 6 months after bariatric surgery, NAF adiponectin levels significantly increased in premenopausal women, but were unchanged in postmenopausal women [14]. Given the known inverse association between plasma adiponectin levels and BMI [15] and epidemiological evidence indicating an inverse relationship between adiponectin levels and breast cancer risk [11], it is interesting that NAF adiponectin levels in postmenopausal women appear to be independent of BMI in our work as well as that of Sauter et al.
To our knowledge, this is the first study to quantify TGF-β1 in NAF. Here TGF-β1 levels in NAF of premenopausal women were significantly higher than post-menopausal women, whereas plasma levels were similar between the two groups. These results likely reflect differential hormone levels in the breast by menopausal status.
NAF EGF levels in healthy, pre and postmenopausal women were similar to those previously reported [16–18]. Our finding of higher EGF levels in NAF of premenopausal women relative to postmenopausal women is consistent with a positive effect of sex hormones on EGF exposure in the breast [16]; as well as with other studies which have shown differences in plasma and NAF biomarkers by sex steroid hormone concentrations [19, 20].
While our data suggests that circulating EGF, TGF-β1 and adiponectin in plasma are regulated differently from NAF protein levels, the main study limitation is the small sample size. Further, the premenopausal women enrolled in this study had, on average, a higher BMI compared to the postmenopausal women. This differs from the age expected BMI distribution [21], suggesting a participation bias. We attempted to adjust for this bias using adiponectin as a surrogate of metabolic disturbance [22]. After adjustment for BMI alone, adiponectin alone, or BMI and adiponectin, there were still significant differences in the NAF levels of the study proteins between pre and post-menopausal women, which were not observed in plasma. Reproductive variables such as time since lactation or last full birth may also affect NAF components [23], however, were not collected as part of the clinical study. Timing of sample collection for phase in the menstrual cycle poses another potential source of variation that was not controlled in this study. Chatterton et al., however, has demonstrated that levels of NAF proteins including EGF, cathepsin D, and interleukin-6 were consistent throughout the phases of the menstrual cycle [24]. Therefore, it is likely that the variation in NAF protein levels in premenopausal women is a reflection of long-term hormonal (and environmental) exposures. Taken together, our findings suggest that the underlying biological factors associated with both BMI and menopausal status differentially influence protein expression in plasma as compared NAF. Future studies with larger sample sizes are warranted to develop the use of NAF as a minimally invasive strategy to identify risk factors and novel drug/prevention targets in the breast.
We would like to thank Donna Vining and Heidi Fritz their assistance in the conduct of the clinical study.
Grant support
Department of Defense grant # BC061529.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Helena Gomez Clothing Designer
Cynthia A PModel Female Hayward, California, US My MM URL: http://www.modelmayhem.com/cynthiababy
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Our Story
The Down Syndrome Association of Central Florida is an accredited and award-winning not-for-profit association founded in 1991 by parents of children with Down syndrome. It has grown from a few families to over 1,200 individuals with DS and their families. We serve families in an area of over 10 counties with help from more than 17,000 friends, professionals, volunteers and other supporters. We are governed by a volunteer board of directors. More than 50% of our board members have family members with Down syndrome.
DSACF is the leading voice for all individuals with Down syndrome and their families. We offer hope, encouragement and acceptance through advocacy, education and awareness as we guide individuals with Down syndrome through life's transitions. Together, we create a Central Florida community composed of and dedicated to individuals with Down syndrome – and those who love them – so that each may realize their potential.
Amy Van Bergen Executive Director
Susan Forster Administration
Katie DeHart Program Coordinator
Board of Directors
Mary Beth Eliason, President/Community Volunteer
Adam Pickett, Vice President/My One Resource
Pablo Abreu, Treasurer/Moore Stephens Lovelace
Bradford Gornto, Secretary/Gorto Law PLLC
Joe Gavigan, Walt Disney World Resorts
Rev. Chris Chandler, Christ Presbyterian Church
Ryan Hayes, Yonfa Hayes PA
Kieran Hill, City of Orlando
Kristi Koester, Walt Disney World Resorts
James Walson, Lowndes, Drosdick, Doster, Kantor & Reed PA
Medical Advisory Board
Sam Smith, DO, Chair, pediatrician, Interlachen Pediatrics
Julie Denham, MD, gastroenterologist, Nemours Children's Hospital
Sheryl Logan, MD, obstetrician-gynecologist, Women's Care Florida
Lynda Pollack, MD, geneticist/pediatrician, Orlando Health
Jennifer Tucker, DPT, University of Central Florida
Julie Wei, MD, otolaryngologist, Nemours Children's Hospital
Affilations & Sponsors
- National Down Syndrome Congress
- National Down Syndrome Society
- Down Syndrome Affiliates in Action
- Global Down Syndrome Foundation
Dates, locations, and agendas are subject to change, so please see our calendar or call 407-478-5621 for the most up-to-date information.
We also offer monthly DADS (Dads Appreciating Down Syndrome) meetings, Sibshops, playgroups, and more!
Click Here to Become a Member or to Renew Your Membership
Down Syndrome Association of Central Florida
204 N. Wymore Rd.
Winter Park, FL 32789
Phone: 407-478-5621
Fax: 407-478-5698
DADS Voicemail: 407-504-1747
Email: email@example.com


text:
NARS Exhibit A
362 reviews
85% would repurchase
Package Quality: 4.3
Price: $$$$
Package Quality: 4.3
Price: $$$$
on 4/29/2007 8:58:00 AM
Age: 19-24
Skin: Combination, Other, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
I ordered this after lemming it for a long time, and then reading all of the positive reviews on MUA. I am a pale brunette with mostly cool undertones. So far, I LOVE this stuff. Everyone is right about the amount -- I just barely touch my SK powder brush to the surface of the powder and then blend it into my cheeks. However, after blending, I usually do it again in order to get that pop of color on the apples of my cheeks. I also used my finger to put some on my lips and covered it with a clear gloss -- perfection. This was my first NARS blush, and undoubtedly, will not be my last. Also -- I would repurchase this glowing blush, but because of how little it takes to achieve the desired affect, I can't imagine ever having to!
on 4/23/2007 9:33:00 PM
Age: Unknown
Skin: Combination, Other, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
Very scary looking at first. EXTREMELY pigmented. You will be amazed at how natural this looks once you learn how to apply it. It is the EXACT shade that you flush. I don't know how they did it, but they did it! I put it on my lips with some balm too. I've found my HG blush.
on 4/19/2007 1:48:00 AM
Age: 25-29
Skin: Acne-prone, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I received this in a swap, I have long been curious about this. I don't know if I'm applying it wrong, too little or probably pairing it with the wrong lip shades? I guess it looks good if you have those fiery red orange lipsticks or similar to that and most of my lipsticks are leaning towards pinkish brown, nude, peach or reds like Clinique's Black Honey (I can't imagine it going well with that). Being so, I haven't really reached out for it, only did to experiment and double check if it's worth keeping or not. So far, verdict is it's okay but most of the time it will just be in my drawer waiting for its turn to be used - which will be verrrry seldom. For reference I'm MAC C3/ Chanel DPC Med Beige.
on 4/18/2007 9:28:00 PM
Age: 19-24
Skin: Combination, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Black
So people aren't kidding that you really really have to use a minimal amount of blush to get the right effect, otherwise it just looks a little freaky. By little amount, I mean, I tap my brush very very lightly on the color, blow on the brush, and tap it lightly on my cheeks because I don't leave one darker area of color than other parts of my cheeks. HOWEVER, once all this careful application is done, it has a very natural beautiful glow. This blush is awesome, I'll be old old old when I'm done with it :)
on 4/13/2007 11:06:00 AM
Age: 36-43
Skin: Oily, Other, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
This is IT! I have medium to fair skin, with dark eyes and dark hair, and this blush is divine. Yes, it is a bit tricky to apply. As others have said...a little goes a long way. But when you figure out the application (be light-handed!), it's gorgeous. I love it as an eyeshadow as well. I doubt I'll have to repurchase any time soon (huge pan!), but I would if need be.
on 3/25/2007 4:11:00 PM
Age: 25-29
Skin: Combination, Other, Not Sure
Hair: Black, Other, Other
Eyes: Brown
Nars exhibit A is the combinatin of red and orange. It's matte which is rare for nars blush The color is very intense so it's not easy to use it. You have to apply it carefully or else it will be too bright. However, once you apply it appropriately. The color is quite good. It's the same color as when you blush.
on 3/10/2007 6:49:00 PM
Age: 19-24
Skin: Acne-prone, Tan, Not Sure
Hair: Brown, Curly, Coarse
Eyes: Brown
Ok so, I researched this website looking for a bold blush to buy and I stumbled across these reviews. I saw pics and read great things and decided to check it out at sephora. When I actually saw Exhibit A in person, I was in shock and thought 'noooooooooooooooooo way'...I kept these reviews in mind anyway and asked a floor person to apply it to my face for me. Since the sephora was just opened, I think the girl had no idea what she was doing and turned me into a clown so I decided I didn't want it.
I walked around the store for a good half hour nad wound up wiping off half of what she applied on me with a tissue and IT LOOKED AMAZING. This stuff definitely+++++ needs to be applied lightly. I ended up buying this and I'm so happy I did. I even came home washed my face and reapplied to make sure. Applied correctly this is a warm natural flush that will transform ur entire face. I'm so glad I read the reviews on this website, it really pushed me to try this.
I marked that i would buy this again only because it's so great, but I really don't see this stuff finishing on me in the next 10 or 15 years.
My best advice is to go to a store and check the stuff out if you can, but if you have to order online, take these reviews into full account!
on 2/2/2007 4:13:00 PM
Age: 19-24
Skin: Combination, Olive, Warm
Hair: Blond, Curly, Medium
Eyes: Brown
beautiful blush... it looks beautiful on darker complexions... although im fair i wear a light dusting of it and it gives a beautiful peachy flush.... use sparingly... dust off your brush first!
on 1/14/2007 8:37:00 PM
Age: 30-35
Skin: Normal, Fair-Medium, Not Sure
Hair: Red, Other, Other
Eyes: Blue
I usually only use MAC blushes, but I had purchased NARS Orgasm & Sin a few years ago, and remembered liking them a lot. I got a gift card to Sephora for X-mas, so I though I would give NARS another try.
I got Exhibit-A and Indian red lip stain. Exhibit-A looked exciting in the case. I have to use it very sparingly. It looks so great! It's like Benetint on steroids!
The Indian Red lip stain goes perfectly with it...Exhibit-A is great... I can't wait to try more of the fabulously pigmented shades!
on 1/7/2007 10:39:00 PM
Age: 25-29
Skin: Other, Other, Not Sure
Hair: Other, Other, Other
Eyes: Other
Before buying this blush, I had studied many of the reviews here so I knew what to expect. I appreciate the reviews especially since I can't see Sephora products in person so I have to buy on faith that you lovely gals won't lead me astray! Thankfully, Exhibit A is a keeper. As most everyone has mentioned, use a liiiiight hand. Just a dab'll do ya. Haha. I dab my brash on it then kinda tap that off, which seems silly as there's hardly anything there (so it seems) and then I apply. It gives me the perfect flush. I'm young and cute and slightly embarrassed at something a cute boy just told me! Well, not really, but I look like it thanks to Exhibit A! ;)
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December 9, 2011
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Page 1
published: 17 February 2012
doi: 10.3389/fphys.2012.00008
The membrane-bound aspartyl protease BACE1: molecular
and functional properties in Alzheimer's disease and
Bastian Dislich and Stefan F. Lichtenthaler*
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Edited by:
Raquel Marin, Universidad de La
Laguna, Spain
Reviewed by:
GiuseppinaTesco,Tufts University,
Mikko Hiltunen, University of Eastern
Finland, Finland
Stefan F . Lichtenthaler, German
Center for Neurodegenerative
Diseases (DZNE), site Munich,
Schillerstrasse 44, 80336 Munich,
e-mail: stefan.lichtenthaler@
The β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease involved
in Alzheimer's disease (AD) pathogenesis and in myelination. BACE1 initiates the genera-
tion of the pathogenic amyloid β-peptide, which makes BACE1 a major drug target for AD.
BACE1 also cleaves and activates neuregulin 1, thereby contributing to postnatal myeli-
nation, in particular in the peripheral nervous system. Additional proteins are also cleaved
by BACE1, but less is known about the physiological consequences of their cleavage.
Recently, new phenotypes were described in BACE1-deficient mice. Although it remains
unclear through which BACE1 substrates they are mediated, the phenotypes suggest a
versatile role of this protease for diverse physiological processes.This review summarizes
the enzymatic and cellular properties of BACE1 as well as its regulation by lipids, by tran-
scriptional, and by translational mechanisms.The main focus will be on the recent progress
in understanding BACE1 function and its implication for potential mechanism-based side
effects upon therapeutic inhibition.
aspartic protease
neurodegeneration,amyloid-beta,regulated intramembrane proteolysis,beta-secretase,
Alzheimer's disease (AD) represents the leading cause of demen-
tia worldwide. It is the most common neurodegenerative disease
cellular amyloid plaques and intracellular neurofibrillary tangles
(Ballard et al., 2011). The amyloid hypothesis states that the
main constituent of amyloid plaques, the 39–43 amino acid long
amyloid-β-peptide (Aβ), is responsible for the initiation of a
neurotoxic cascade that ultimately leads to neuronal death and
dementia (Hardy and Selkoe, 2002; Haass and Selkoe, 2007). Aβ
cursor protein (APP) in a stepwise process referred to as regulated
intramembrane proteolysis (RIP). RIP in general controls intra-
and intercellular communication through the release of extracel-
signaling molecules or are further degraded (Brown et al., 2000;
Lichtenthaler et al., 2011). Ectodomain shedding, the first step of
RIP, results in the release of the soluble APP ectodomain (APPs)
into the extracellular space and is carried out by either one of two
alternativeproteaseactivities.Themolecularidentityof thesepro-
tease activities was unknown for many years,which led to the still
established terminology of α- and β-secretase.
In the amyloidogenic, β-secretase dependent pathway, shed-
ding occurs within the ectodomain of APP in close proximity to
the membrane and is mediated by the membrane-bound aspartyl
protease β-site APP cleaving enzyme 1 (BACE1, β-secretase,
memapsin-2, ASP-2; Hussain et al., 1999; Sinha et al., 1999; Vas-
sar et al., 1999; Yan et al., 1999; Lin et al., 2000; Figure 1). The
remaining membrane-bound APP C-terminal fragment (CTF)
bears the N-terminus of Aβ and is processed in a second step
within its transmembrane domain by the GxGD-type aspartyl
and is able to cleave its substrates within the hydrophobic envi-
ronment of the lipid bilayer (Steiner et al., 2008). This cleavage
generates theAβ C-terminus and liberates theAβ peptide into the
extracellular space, whereas the APP intracellular domain (ICD)
is released into the cytosol. Due to the heterogeneous nature of
γ-secretase cleavage, Aβ species of different length are produced,
including the pathogenic 42-amino acid long Aβ42, whose toxic
properties have been summarized in a recent review (O'Brien and
Wong, 2011). In the non-amyloidogenic pathway, a third prote-
precludes Aβ formation by cleaving APP within the Aβ domain,
and releasing the soluble APPsα fragment into the extracellular
space (Esch et al., 1990; Figure 1). ADAM10, a member of the
ADAM (a disintegrin and metalloprotease) family of proteases,
has α-secretase activity in vitro and in vivo and has been identified
as the constitutively cleaving α-secretase in neurons (Lammich
et al., 1999; Postina et al., 2004; Jorissen et al., 2010; Kuhn et al.,
2010). Other metalloproteases may also act as α-secretases, but
appear to cleave APP only after pharmacological activation or
overexpression (Buxbaum et al., 1998; Koike et al., 1999; Naus
et al., 2006). BACE1 is the rate-limiting and principal enzyme
responsible for Aβ generation in neurons. Deletion of BACE1 via
homologous recombination in mouse models of AD completely
abolishes Aβ generation in the brain (Cai et al., 2001; Luo et al.,
February 2012 | Volume 3 | Article 8 | 1
Page 2
Dislich and Lichtenthaler BACE1 function and enzymatic properties
FIGURE 1 | Proteolytic processing of the BACE1 substratesAPP and
NRG1. (A) Regulated intramembrane proteolysis of APP occurs by two
alternative pathways. In the amyloidogenic pathway, ectodomain shedding
by BACE1 releases the soluble APP ectodomain and generates the
N-terminus of the Aβ peptide.The membrane-bound CTF (C99) is then
further processed by γ-secretase, which releases the Aβ peptide into the
extracellular space and the APP intracellular domain (AICD) into the cytosol
where it is rapidly degraded. In the alternative, anti-amyloidogenic pathway,
ectodomain shedding is mediated by ADAM10. Cleavage occurs in the
middle of the Aβ domain and yields the soluble APP ectodomain and a CTF
(C83), which is further processed by γ-secretase to generate the secreted
p3 peptide (not shown). (B) Ectodomain shedding of type III NRG1 by
BACE1 or ADAM10 occurs C-terminally of the EGF-like domain and
generates a large NTF as well as a shorter CTF . Cleavage by BACE1 leads to
a slightly larger NTF , that exerts signaling function. Cleavage within the
EGF-like domain by ADAM17 appears to render the resulting NTF inactive
(not shown).The remaining CTF is further processed by γ-secretase in
order to yield the NRG1-ICD.
fore prevent the formation of all Aβ species and be beneficial for
the treatment of AD. Besides BACE1, additional proteases with
minor,regulated β-secretase activity,such as the cysteine-protease
cathepsin B, may contribute to Aβ levels in the brain, suggest-
ing that their inhibition may be of additional therapeutic benefit
(Haque et al., 2008; Hook et al., 2008, 2011). However, much less
is known about the pathophysiological relevance of cathepsin B
compared to BACE1.
Since its discovery in 1999 by five independent research groups
(Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan
et al.,1999; Lin et al.,2000),BACE1 is a major drug target forAD.
Extensive efforts toward an understanding of BACE1 physiology
and pathophysiology as well as the development of potent BACE1
inhibitors have been made. This review focuses on the latest find-
ings and current developments in BACE1 research. We will first
describe the role of BACE1 in AD as well as the basic cell biol-
ogy of this protease. Next we summarize the transcriptional and
translational regulation of BACE1 in health and disease.After dis-
cussing the role of lipid microdomains on BACE1 activity,we will
turn to BACE1 substrates with a focus on the functional conse-
quences of the generated proteolytic fragments. In order to safely
reduce Aβ levels in AD, a detailed understanding of BACE1 sub-
strate processing and its implications upon therapeutic inhibition
is necessary. Different approaches toward therapeutic inhibition
as well as future perspectives of BACE1 research will be addressed
in the last part of our review.
The 501 amino acid long type I transmembrane protein BACE1,
together with its homolog BACE2,belongs to the family of pepsin
and retroviral aspartic proteases. The single transmembrane
domain, a unique feature amongst aspartic proteases, exposes the
active site toward the luminal side and links the ectodomain to
the 21 amino acid long cytosolic tail (Figure 2). The active site
features the critical aspartic acid residues within two character-
istic D-T/S-G-T/S motifs. Like other aspartyl proteases, BACE1
requires both aspartates for its activity (Hussain et al., 1999; Vas-
sar et al., 1999; Bennett et al., 2000b). However, because BACE1
forms dimers, it appears possible that the two monomers pro-
vide one aspartate each. Evidence for this scenario comes from
a study showing that mutation of the aspartate within the C-
terminal DSGT motif does not affect BACE1 activity (Schmechel
et al., 2004). In the endoplasmic reticulum (ER), BACE1 is ini-
tially synthesized as a zymogen and subjected to N-glycosylation,
palmitoylation, transient acetylation, and disulfide bridge forma-
tion (Haniu et al., 2000; Benjannet et al., 2001; Costantini et al.,
2007; Ko and Puglielli, 2009; Vetrivel et al., 2009; Figure 2). Full
cosylation and removal of the prodomain by furin prohormone
protein convertases lead to the 70kDa form (Bennett et al.,2000b;
Capell et al., 2000; Benjannet et al., 2001). The zymogen form
about twofold after removal of the prodomain (Creemers et al.,
2001; Benjannet et al., 2004). Rather than suppressing enzymatic
activity, the prodomain facilitates correct folding of the protease
domain (Shi et al.,2001).
Frontiers in Physiology | Membrane Physiology and Biophysics
February 2012 | Volume 3 | Article 8 | 2
Page 3
Dislich and Lichtenthaler BACE1 function and enzymatic properties
FIGURE 2 | Structural organization of BACE1 (active isoform of 501
amino acids). Schematic diagram of the domain structure,
post-translational modifications and interaction motifs of BACE1.The active
sites motifs DTGS and DSGT at position 92–95 and 289–292 are marked as
stars, the critical aspartic residues are highlighted in red.The DISLL motif at
the cytosolic domain is recognized by GGA proteins and serves as an
endosomal targeting signal. Glycosylation sites are depicted as sugar
"trees," palmitoylation sites as fatty acid chains. S–S, disulfide bond
(connecting amino acids 216–420, 278–443, 330–380); P , phosphorylation
site; Ub, ubiquitination site.
After transport to the plasma membrane, the dileucine motif
DISLL at position 496–500 in the cytoplasmic domain promotes
BACE1 trafficking to early endosomal compartments (Huse et al.,
2000). A recent study suggests that this sorting event is controlled
by the small GTPase ARF6 in a clathrin-independent fashion,
in contrast to the clathrin-dependent endosomal sorting of APP
(Sannerud et al.,2011). Phosphorylation of the dileucine motif at
serine 498 and interaction with Golgi-localized γ-ear-containing
early endosomes to late endosomes and the trans-Golgi-network
(TGN; He et al., 2002, 2003, 2005; von Arnim et al., 2004, 2006;
Wahle et al., 2005). In addition, retrograde BACE1 trafficking
depends on the cytosolic domain of the Vps10p homolog Sor-
tilin,most likely via retromer complex or GGA dependent sorting
mechanisms (Finan et al., 2011). Recycling of BACE1 from the
tributestotherelativelyslowturnoverrateof BACE1(Walteretal.,
2001;He et al.,2005;Wahle et al.,2005). Finally,monoubiquitina-
tion at lysine 501 promotes lysosomal degradation, a process that
depends on the recognition of the ubiquitinated lysine residue by
GGA3 (Kang et al., 2010). Depletion of GGA3 enhances BACE1
activityandAβgenerationinvitro andreducedGGA3proteinlev-
els correlate inversely with BACE1 protein levels in AD patients
(Tesco et al.,2007; Santosa et al.,2011). GGA3 depletion and sub-
sequent stabilization of BACE1 have been proposed to follow the
reducedexpressionof theneuroprotectiveproteinseladin-1under
stress conditions (Sarajarvi et al., 2009). Shedding by ADAMs,
et al., 2004). However, the inhibition of BACE1 shedding after
treatment with metalloprotease inhibitors does not influence Aβ
generation (Hussain et al., 2003).
β-Site APP cleaving enzyme 1 has an acidic pH-optimum (Vassar
et al., 1999; Gruninger-Leitch et al., 2002; Shimizu et al., 2008)
and cleaves its substrates mostly in the acidic early endosomal and
trans-Golgi compartments, where also Aβ generation takes place
(Haass et al., 1993; Koo and Squazzo, 1994; Vassar et al., 1999;
Capell et al., 2000; Gruninger-Leitch et al., 2002). After internal-
ization from the plasma membrane, wild-type APP is processed
in early endosomes. As indicated above, endocytosis and endo-
somal transport of APP and BACE1 occur via distinct pathways.
Interfering with either one, e.g., by knockdown of ARF6 or mod-
ulation of APP endocytosis via clathrin-dependent mechanisms,
alters the shedding of APP by BACE1 (Chyung and Selkoe, 2003;
Neumann et al., 2006; Schobel et al., 2006, 2008; Sannerud et al.,
2011). In contrast, the processing of Swedish APP (APPSWE), a
rare genetic double mutation leading to familial early-onset AD
(Mullan et al., 1992) occurs along the secretory pathway (Haass
et al., 1995). The responsible amino acid changes at position-1
and -2 of Aβ enhance the proteolytic activity of BACE1 and there-
fore Aβ production (Citron et al., 1992). Although the secreted
form of BACE1 processes peptide substrates in vitro,efficient pro-
cessing of APP by BACE1 requires the membrane-bound form,
ensuring the proper spatial interaction between protease and sub-
strate at the membrane surface (Yan et al.,2001;Gruninger-Leitch
et al., 2002). In mouse and human brain, native BACE1 occurs as
a dimer. Dimerization via the ectodomain is dependent on mem-
brane attachment and increases BACE1 affinity and turnover rate
toward APPSWE-like peptides when compared to the monomeric,
February 2012 | Volume 3 | Article 8 | 3
Page 4
Dislich and Lichtenthaler BACE1 function and enzymatic properties
soluble form (Schmechel et al.,2004;Westmeyer et al.,2004). The
different enzymatic properties of monomeric and dimeric BACE1
need to be considered in future drug screening and development
The protease domain of BACE1 features the typical bilobal struc-
ture of aspartic proteases, showing a high degree of conservation
N- and C-terminal lobes and partially shielded by an antiparallel
hairpin loop known as"flap,"which controls substrate access and
proteolytic specificity (Hong et al., 2000; Ostermann et al., 2006).
The main structural feature that sets BACE1 and BACE2 aside
from other aspartic proteases is the enlarged molecular bound-
ary of the catalytic domain. This is due to four helical or loop-like
possibly mediating associations with other cell surface molecules.
Overall the BACE1 active cleft is broader, less hydrophobic, and
more open when compared to other aspartic proteases, allowing
the accommodation of up to 11 substrate residues (Hong et al.,
2000; Turner et al., 2005). The unusually large active site poses
a major challenge in the development of potent small molecule
inhibitors in drug development.
Consistent with its role as β-secretase, the highest expression lev-
els and enzymatic activity of BACE1 are found in brain (Sinha
et al., 1999; Vassar et al., 1999; Yan et al., 1999). This is mainly
due to neuronal expression, as expression levels in glial cells are
very low (Laird et al.,2005; Harada et al.,2006; Zhao et al.,2007).
In mouse brain, BACE1 expression peaks during early postnatal
stages, with highest expression levels found in the cortex, hip-
pocampus, and cerebellum (Irizarry et al., 2001; Willem et al.,
2006). Disruption of entorhinal cortex afferents to the hippocam-
to axonal membranes within neurons and is actively transported
to synaptic nerve terminals, resulting in the release of Aβ at the
synaptic cleft (Lazarov et al.,2002; Sheng et al.,2003). In contrast,
BACE1 within cultured polarized hippocampal neurons and finds
that the bulk of APPsβ andAβ fragments is recovered from soma-
Besides brain tissue, high BACE1 mRNA levels are also found in
the pancreas. Due to alternative splicing and post-transcriptional
inactivation enzymatic activity is comparatively low (Sinha et al.,
1999; Bodendorf et al., 2001; Ehehalt et al., 2002; Molinari et al.,
2002; Mowrer and Wolfe, 2008). The pancreatic isoforms of
BACE1 may not cleave APP, but other substrates instead, such as
substrate in pancreas (Bodendorf et al., 2001; Hoffmeister et al.,
2009). Low expression levels are found in the remainder of the
A complex interplay of transcriptional, translational, and post-
translational mechanisms regulates BACE1 activity. At the
transcriptional level, numerous mechanisms regulating BACE1
activity have been described. Hypoxic and oxidative cell stress,
idation product hydroxy-non-enal (HNE), the c-JUN N-terminal
kinase (JNK)/c-JUN pathway, and others, has been shown to
increase BACE1 mRNA levels (Yasojima et al., 2001; Holsinger
et al., 2002; Tamagno et al., 2005, 2008, 2009; Zhang et al., 2007).
ulationof BACE1canbecitedatthispointandwereferthereader
to two excellent reviews for further information (Rossner et al.,
2006; Stockley and O'Neill,2008). However,most of these studies
are based on in vitro observations. The physiological relevance for
AD pathogenesis remains unclear, as BACE1 transcript levels are
not significantly altered in AD brains (Preece et al., 2003; Matsui
et al., 2007; Hebert et al., 2008). On the contrary, BACE1 protein
levels are increased two- to fivefold in about 30% of patients with
sporadicAD,supporting the assumption of disease-relevant post-
transcriptional regulatory mechanisms (Fukumoto et al., 2002;
Holsinger et al.,2002; Preece et al.,2003;Yang et al.,2003; Li et al.,
2004; Hebert et al.,2008).
Indeed, three distinct mechanisms have been described con-
trolling the translation of BACE1. First, the large 5?untranslated
region(5?UTR)of theBACE1transcriptrepressestranslationina
(De Pietri Tonelli et al., 2004; Lammich et al., 2004; Rogers et al.,
studies identified the GC-rich strand of the 5?UTR as an effec-
et al., 2004). Further mechanisms such as ribosomal shunting by
binding of ribosomes to upstream ORFs and subsequent prema-
ture ribosomal dissociation have been proposed (Rogers et al.,
2004). It is currently unknown whether regulatory proteins bind
to and therefore modulate the extent of 5?UTR mediated trans-
lational repression. However, a recent study demonstrated that
the translational block can be partly relieved under conditions
of energy deprivation in the brain, which suggests a direct link
between reduced brain metabolism and sporadic AD (Velliquette
et al., 2005). Post-transcriptionally elevated BACE1 and Aβ lev-
els were found upon acute pharmacologic reduction of energy
metabolism in mice overexpressing APPSWE.In vitro and in vivo,
phosphorylation of the translation initiation factor eIF2a results
in the increased translation of BACE1 mRNA, in a mechanism
that bypasses the repressive features of the 5?UTR and that is typ-
ical of genes involved in the cellular stress response (Schroder and
Kaufman, 2006; O'Connor et al., 2008). A pathogenic increase in
neuronal stress response.
A second mechanism of BACE1 translational regulation is
based on studies of miRNA expression profiles in patients with
sporadic AD, where a link between the downregulation of the
increase in BACE1 protein levels was suggested. A direct relation-
shipissupportedbythepresenceof bindingsitesfortheidentified
(Hebert et al.,2008; Wang et al.,2008).
A third mechanism regulating BACE1 translation in vitro and
in vivo is a non-coding BACE1 antisense transcript (BACE1-AS).
Frontiers in Physiology | Membrane Physiology and Biophysics
February 2012 | Volume 3 | Article 8 | 4
Page 5
Dislich and LichtenthalerBACE1 function and enzymatic properties
mRNA,resulting in increased BACE1 protein levels and enhanced
Aβ42 production (Faghihi et al.,2008). Furthermore,Aβ42stimu-
lates BACE1-AS expression, resulting in a feed-forward loop that
potentially drives disease progression.
microenvironment and the related consequences toward BACE1
activity remain controversial. On the one hand, BACE1 and APP
invivo andinvitro partiallylocalizetolipidraftdomainsenriched
to these microdomains via addition of a GPI-anchor enhancesAβ
Ehehalt et al., 2003; Kawarabayashi et al., 2004; Crameri et al.,
2006; Hattori et al., 2006). Feeding mice a high cholesterol diet,
which promotes lipid raft formation, increases Aβ levels, whereas
the disruption of lipid rafts upon depletion of cellular cholesterol
2001; Refolo et al., 2001; Cordy et al., 2003). On the other hand,
a study focusing on endogenous APP and BACE1 in hippocam-
pal neurons suggests that the main pool of APP resides outside
of lipid rafts, unable to be accessed by BACE1 (Abad-Rodriguez
cholesterol decrease Aβ production presumably as result of direct
BACE1/γ-secretase inhibition (Kaether and Haass, 2004).
Lipid raft association of BACE1 is dependent on the S-
palmitoylation of four cysteine (Cys474/478/482/485) residues
at the boundary between the cytoplasmic and transmembrane
domain (Benjannet et al., 2001; Vetrivel et al., 2009). After muta-
tion of these residues, raft association is lost, without affecting
protein stability, subcellular localization, and proteolytic activity
toward APP in neuronal and non-neuronal cultured cells, sug-
gesting that BACE1 efficiently cleaves APP in raft and non-raft
environments. These results challenge the previous studies that
are based on cholesterol depletion (Simons et al., 1998; Fassben-
der et al., 2001; Refolo et al., 2001; Cordy et al., 2003), which has
pleiotropic effects on membrane morphology and vesicular traf-
ficking (Rodal et al., 1999; Wang et al., 2000; Hao et al., 2004).
More in vivo studies focusing on endogenous APP and selectively
these contradictory issues.
A direct effect on BACE1 activity by the active lipid metabolite
sphingosine-1-phosphate has been shown. Sphingosine is phos-
1-phosphate that ultimately binds to the C-terminal and trans-
membrane region of BACE1, activating its proteolytic activity
(Takasugi et al., 2011). Knockdown or inhibition of sphingo-
sine kinase 2 as well as overexpression of S1P degrading enzyme
reduced Aβ levels in cultured cells. In line with in vitro results,
stereotaxic injection of sphingosine kinase inhibitors reduced
brainAβ loads in wild-type andAPP transgenic mouse lines. Fur-
thermore,levels of sphingosine kinase 2 were found to be elevated
in AD brain.
Two years after the discovery of BACE1,the first knockout mouse
lines were generated. These mice do not produce C99 or Aβ, fur-
ther validating BACE1 as the sole β-secretase in vivo. Initially,
overt developmental or adult phenotypes in BACE1−/− mice
were not detected, encouraging treatment of AD by therapeu-
tic inhibition of BACE1 without significant adverse effects (Cai
et al., 2001; Luo et al., 2001; Roberds et al., 2001; Dominguez
et al., 2005). However, later studies uncovered multiple devel-
opmental and behavioral changes, suggesting that BACE1 has
diverse physiological roles.As the function of a protease is defined
by its substrates, the identification and characterization of novel
BACE1 substrates remains one of the key challenges in current
AD research,providing insights into BACE1 physiology,substrate
specificity, potential side effects upon therapeutic inhibition, and
biomarker development. So far,all known BACE1 substrates have
been identified by candidate approaches, some of them under
overexpressing conditions, where BACE1 may cleave substrates
that are not processed in vivo, for example proteins that reside in
the ER. Known BACE1 substrates (summarized in Table 1) will
be discussed below, in order of evidence regarding their in vivo
cleavage and the related functional consequences of the resulting
proteolytic fragments. APP, type III neuregulin 1, the β-subunits
2 and 4 of voltage-gated sodium channels (VGSCs), and the β-
galactoside α2, 6-sialyltransferase belong to the group of BACE1
substrateswherethefunctionalrelevanceof substratecleavagehas
been demonstrated in vivo.
Despite being a prominent substrate, the physiological func-
tion of APP and its shedding by BACE1 remains unclear. Genetic
deletion of full length APP in mice leads to a reduction in brain
and body weight, memory deficits and reduced grip strength,
and can be rescued by APPsα (Ring et al., 2007). The addi-
tional knockout of the APP homolog amyloid precursor pro-
tein 2 (APLP2) results in perinatal lethality and neuromuscu-
lar synapse defects (Muller et al., 1994; von Koch et al., 1997).
APPsβ actively regulates transthyretin and Klotho expression lev-
els, but fails to rescue the lethality and neuromuscular synapse
defects present in APP/APLP2 knockout mice (Li et al., 2010).
Upon trophic withdrawal, APPsβ is processed by a yet uniden-
tified mechanism to yield a 35kDa fragment (N-APP) that
binds to death receptor 6 and triggers a widespread proapop-
totic signal that may speed up neurodegeneration (Nikolaev et al.,
2009). Thus, APPsα and APPsβ apparently have different func-
tions. Future studies on the biology of APP and its homologs
could provide links to the complex phenotype of BACE1−/−
mice. Besides APP, APLP1 and 2 are also processed by BACE1
in vivo and in vitro (Yanagida et al., 2009; Sala Frigerio et al.,
2010; Hogl et al., 2011). The physiological function of APLP1
and APLP2 shedding by BACE1 is currently unknown. Wild-
type APP and its homologs are considered relatively poor sub-
strates, as BACE1 binds preferably to APPSWE-like peptides,
which feature bulky hydrophobic residues such as leucine and
phenylalanine at position P1 (reviewed in Stockley and O'Neill,
2008). However, this assumption is based on in vitro assays
using peptide substrates and neglects the proper spatial orien-
tation of the full length substrate and protease within the lipid
February 2012 | Volume 3 | Article 8 | 5