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Congratulations to BHS Animatronic Team:
The BHS Technology Students' Association (TSA) club animatronics team placed third at the Colorado state TSA competition
IC registration How to:
Students, want to request a course (Elective) now you can in Infinite Campus.Click here to find out how.
BHS Baseball Website:
Please check out our New BHS Baseball website. Stay up to date on all your baseball needs. Check Scores, dates, events, and player stats at: www.Brightonbaseball.net.
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Attention Students you can "test drive" potential careers
Are you a high school student wondering what the future holds or what career opportunities are out there for you?
The Adams County Education Consortium has teamed with more than 45 metro-area businesses and organizations to help students validate or elminate career options and explore new education pathways. Sessions start soon and includes hands-on activities, behind-the-scenes fun and Q&A opportunities with business leaders.
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Math Tutoring:
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Dear Brighton Students,
Parents and Community Members,
Welcome to Brighton High School, home of the Bulldogs. BHS is one of the first comprehensive high schools in Colorado dating back to the late 1800s. Our school is located in the heart of the Brighton community. The Brighton community is located northeast of Denver, Colorado.
Pioneer Summer Camp Registration Now Open
Summer Camp registration is now open. Summer Camp will be held at these four 27J elementary schools: Second Creek, Thimmig, Brantner and West Ridge. Click here for more information about Summer Childcare.
Student Open Enrollments & Registration being accepted for Reunion Elementary
Parents enrolling students for the 2017-2018 school year, can now send open enrollment forms and registration packets for students to attend the new Reunion Elementary School. Enrollment forms and registration packets can be emailed to Lisa Egan at email@example.com or dropped off at Second Creek Elementary School, 9950 Laredo Dr. Reunion Elementary School, is still under construction, but will be open for grades preschool through fifth starting in August. Reunion Elementary School is located at 11021 Landmark Dr. in Commerce City. For questions about enrolling at Reunion Elementary School, contact school secretary Lisa Egan at email@example.com or call 720-685-8505.
Applications accepted for ECARE free full-day kindergarten spots
School District 27J has been awarded funding from the Colorado Department of Education to implement ECARE (Early Childhood At-Risk Enhancement) Kindergarten for the 2017-2018 school year. This is an extension of the Colorado Preschool Program and will service students who are considered to have risk factors linked to potential academic failure. This program will offer full-day kindergarten free of charge to those families that qualify. Click here to learn more about qualifying factors and to download an application [Español]
Upcoming Kindergarten Round-Up Dates at 27J Elementary Schools
Parents are encouraged to attend upcoming informational Kindergarten Round-Up events at the elementary school where their child will attend kindergarten for the 2017-2018 school year. Here are some of the upcoming dates: Northeast Elementary School: Open House on April 12 during the school day; Thimmig Elementary School: Kindergarten Round-Up, March 22 (paperwork only); Pennock Elementary School: Kindergarten Round-Up, April 19, 5-6 p.m; Henderson Elementary School: Kindergarten Round-Up, March 16, 9-11 a.m and South Elementary School: Kindergarten Round-Up, April 13, 6-7 p.m.
Open Enrollment - Choice of Schools begins Jan. 10
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A light, refreshing cake filled with a sweet and zesty taste in every bite. Indulge in your favorite cakes you grew up with while maintaining your diet you've worked so hard on!
Our Bundts never stray away from that warm, familiar taste of baked goodness. If you would like to find out more about what goes into our Bundts check out our ingredients page.
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About the Book
The pictures in this book were taken in Spain between January and June of 2004, during which time the Madrid bombings occurred and the Spanish identity was shaken to its core.
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RepairPal is your advocate for car care advice and guidance
Q: how do i tell if it's the clutch fan oe waterpump making noise ???? on 2004 Chevrolet Trailblazer
my trailblazer runs fine. just started to make noise, either fan clutch or waterpump bearings nothing is leaking thermostate was replaced no engine light on ? the noise sounds like a diesel and seems to fade at higher revs,how &what do i check first?????? please help
Would definitely help you if you had a mechanics stethoscope and pinpointed the noise. Based off of what you say about the noise I would only guess and say fan clutch.
thanks for answer - forgot to say there is a little movement if you grab fan on each side?? I guess it,s time to pull the fan I think ??????
It is not unusual to have a little play in the fan clutch but it could very well be the source of the noise.
thanks 'i just got back from a dealer definetly a water pump !!!!lots of money!!!!!!!!that's why god made credit cards !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
I personally am working on a 94 Toyota pickup 22R-E engine that has a squawk noise when first start and just as shut off the negine. The noise I heard with my stethoscope was loudest at the idler/tensioner pulley bearing at top front bracket of engine for the p/s belt. I also know that noise can travel thru metal and start one place but be loudest at another. I removed that belt and started the engine and the noise was still there. The other belt ran the water pump/fan and alternator. I removed it and then on the restart the noise went away. I did hear the noise at front of w/p housing before but not as loud as the idler/tensioner bearing. When I physically grabbed the water pump pulley and turn it I could duplicate the squawk noise. Taa Daa. I found the noise source and likely the dealership went thru the same process as I did to pinpoint. I sold my job to my customer because I warned him that noise travels thru metal and untill the diag process I could not guarantee the source till step by step diag revealed the noise. My customers here in Oregon keep me busy because I don't charge like the big overhead shops and I let them buy the parts at my discounted price. Believe it or not, there are tons of us techs out there that work for shops or ourselves that are just as honest. This site helps us with the bad mistrust feelings that some customers have for techs. Anyways, good luck.
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Betty Dodson revisits the G Spot
January 6th, 2009
Dr Petra
There's been a lot of controversy over the G Spot over the past few years, and lots of bad journalism and poor science devoted to the topic. It's also led to confusion for women and their partners and a whole industry set up to plump, enhance and stimulate this area.
Welcome to this debate sex educator, activist and campaigner Betty Dodson who knows more about vaginas than I've had hot dinners. She's recently revamped her website (it looks fab!) and has a load of essays and interesting resources listed there. One that a colleague referred to me is Betty's take on the whole G Spot debate. It's interesting, challenging, and sums up much of what's going on in this area within the media. Not everyone will agree with Betty's conclusions, but her essay is definitely one to get you talking about female anatomy and related media coverage.Tweet
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Big Story
Separate names with a comma.
Discussion in 'The Vestibule' started by -The-Problem-, Dec 15, 2012.
Not sure if serious.
Fitted hat is Reynolds Wrap cuz I don't trust the government.
So Adam Lanza was a patsy? Seems about right.
MK Ultra'd lol
Maybe they gave Lanza and Holmes some crazy pills.
says the Illuminati plant
We're fine guys. This is just all confirmation bias and coincidence.
well there seems to be some misinformation about the number of guns being used:
one of the victims memorial facebook page was created on December 10th. WHAT????
at the very bottom.
It was removed
white people always getting caught up in money fraud. That's their gang banging.
Why did he kill the others but was unable to kill his presumptive target?
Was this legit?


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An investigation into how the Clintons have amassed millions in personal wealth through foreign contributions to the Clinton Foundation, a supposed charity, in exchange for political favors while Hillary Clinton was the US Secretary of State.
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Bellevue College offers associate degrees and certificate programs to more than 37,000 students at its campus near Seattle, Wash. The college also offers bachelor's degrees through educational partnerships with online colleges. The school's programs provide technical training that prepares students for careers after they graduate, as well as continued study at the bachelor's level. In academic year 2009-10, about 10% of community and technical college students that transferred to a Washington public four-year institution came from Bellevue College. That's more than any other state college, according to the school.
Programs Offered
Students can earn an associate degree, bachelor's degree or certificate online through Bellevue College. The school currently offers three associate degrees that can be taken online in arts, sciences, and business, which can directly transfer to a participating four-year university, and general studies, which is not transferable. Through educational partnerships with other universities, students can complete a bachelor's degree. They can earn a transferable associate degree through Bellevue and then put those credits towards an online bachelor's degree at Capella University, Washington State University Online, or Western Governor's University. Areas of study through this method include business management, healthcare, information technology, psychology, public safety, business administration, criminal justice, humanities, social sciences, and human development.
Bellevue College has been regionally accredited by the Northwest Commission on Colleges and Universities since 1970.
Bellevue College accepts applications from high school graduates, those who are 16 or 17 years old and have proof of GED completion, or those who are 18 years of age and older. The application process is fairly basic. Students must submit an application and pay an application fee. The school does not require or maintain transcripts for admissions. Out-of-state students applying for online credit classes must fill out a separate application form from the general admission form, as well as an application fee. Applications are available online or can be mailed to the admissions office.


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2870 Windside Court, Ann Arbor 48103
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This property has been Sold!
07/15/2016 at $385,000
Nestled on a quiet cul-de-sac this spacious home is move-in ready. Sit on the front porch swing and relax at the end of the day, or enjoy the brick-paver patio for family gatherings or dining al fresco. Two-story family room with fireplace, soaring ceiling and window-wall overlooking the private backyard and tree-lined common area. Freshly painted Living Room, Study and exterior. Hardwood floors in Living Room, Study and Foyer. Kitchen has maple cabinets and SS appliances. Ideal combination of Ann Arbor schools and Scio Township taxes. Buyer to assume $500 Road Assessment fee. View the Virtual Tour for more details. Association Fee covers maintenance of common grounds, pond & fountain, tennis courts, playground & baseball field, and pickup of trash & recycling.
Property Information
- Total Finished SqFt
- 2,278
- Above Grade SqFt
- 2,278
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- Attached, Door Opener, Electric
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- Public
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- 2000
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- 2 Story
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- $734
Rooms and Land
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UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation
The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 (also known as UBXD7) mediates p97 interaction with the transcription factor HIF1α that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.
We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1α, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1α. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1α carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.
Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1α. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1α.
Proteins destined for proteasome-mediated degradation are labeled with ubiquitin chains through the action of an enzymatic cascade consisting of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-ligase (E3)
Similar to ubiquitin, the ubiquitin-like (UBL) protein NEDD8 is attached to its substrates by specific E1, E2 and E3 enzymes. To date, cullins represent the major class of proteins that are targets for neddylation
We have previously identified HIF1α as a novel substrate of p97, with the UBA-UBX protein UBXN7 serving as the substrate-binding adaptor
Figure 1
Ubiquitin- and substrate-binding to UBXN7 do not correlate with CUL2 binding
Ubiquitin- and substrate-binding to UBXN7 do not correlate with CUL2 binding. (A) Illustration of the CRL2 ubiquitin-ligase bound to its substrate HIF1α. The core subunits of CRL2 are highlighted in blue. The UBA-UBX protein UBXN7 interacts with ubiquitylated HIF1α via its UBA domain. (B) CUL2 interaction with UBXN7 is independent of ubiquitin-binding. Flag-UBXN7 was immunoprecipitated from cells thermo-sensitive for the ubiquitin-E1. When these cells were grown at the restrictive temperature for 20 hours, there was a marked reduction in protein ubiquitylation (right panel). CUL2-binding to UBXN7 was not affected by the reduced ubiquitin-binding observed under these conditions (left panel). (C) Flag-UBXN7 stably interacts with the core subunits of the CRL2 complex. Flag-UBXN7 was immunoprecipitated from HeLa cells treated or not with 10 μM MG132 for two hours. Flag-UBXN7 stably interacted with CUL2, elongin C and RBX1. The interaction with HIF1α and VHL could only be detected upon proteasome inhibition (left panel). (D) Endogenous UBXN7 stably interacts with the core subunits of the CRL2 complex. As in (C), but endogenous UBXN7 was immunoprecipitated from HeLa cells using specific antibodies crosslinked to protein A-beads. (B-D) The indicated proteins were detected using specific antibodies in the immunoprecipitates (left) and the input cell extracts (right).
Here we show that UBXN7 interaction with cullins is not mediated by its ubiquitylated substrates, but involves the direct docking of the UIM motif in UBXN7 onto the neddylated cullins. UBXN7 over-expression causes non-ubiquitylated HIF1α to accumulate in a manner that is dependent on an intact UIM motif in UBXD7. Our data suggest that UBXN7 may act as a negative regulator of CRL2 and this would favor subsequent recruitment of p97.
Active ubiquitylation is not necessary for UBXN7 interaction with CUL2
Among human UBA-UBX proteins, UBXN7 is the most proficient in interacting with CRL subunits. Indeed, its ability to interact with CUL2 greatly outshines other UBA-UBX proteins
UBXN7 stably interacts with the core CRL2 complex
Next we examined UBXN7 interaction with other components of the CRL2 complex. Flag-UBXN7 effectively co-immunoprecipitated CUL2, elongin C and RBX1, which constitute the core CRL2 complex. In contrast, UBXN7 interaction with VHL and HIF1α could only be observed upon brief inhibition of the proteasome with MG132 (Figure
The data presented thus far indicated that UBXN7 binding to CUL2 was not mediated by its interaction with ubiquitylated-proteins that are CRL2 substrates. This raised the interesting hypothesis that UBXN7 might interact directly with the CRL2 core complex, irrespective of whether it is charged with a substrate (Figure
Cullin-neddylation is required for the interaction with UBXN7
We observed that UBXN7 interacted preferentially with the neddylated form of CUL2, which was largely depleted from the extracts after Flag-UBXN7 immunoprecipitation (Figure
Figure 2
UBXN7 exclusively interacts with neddylated cullins in cell extracts
UBXN7 exclusively interacts with neddylated cullins in cell extracts. (A) UBXN7 preferentially interacts with slower-migrating, neddylated CUL2. Input cell extracts and the supernatants after Flag-UBXN7 immunoprecipitation were compared. (B) Flag-UBXN7 over-expression causes an up-shift of CUL2 to its neddylated form. This effect was abolished when the cells were grown in the presence of the NEDD8-E1 inhibitor MLN4924 for two hours. (C) Alignment of human CUL2 with the yeast cullin Cdc53. The conserved neddylation site (K689) and a more C-terminal Lys residue involved in the interaction with Dcn1 (K719) are highlighted in red. (D) Neddylation-defective CUL2 variants are similarly defective in interacting with endogenous UBXN7. Wild-type or mutant Flag-CUL2 was immunoprecipitated from HeLa cells treated or not with 10 μM MG132 for two hours. (E) MLN4924 treatment abolishes UBXN7 interaction with several endogenous cullins. (F) MLN4924 treatment has no effect on UBXN7 interaction with ubiquitylated-proteins or with p97. (E, F) Flag-UBXN7 was immunoprecipitated from HeLa cells treated with MG132, MLN4924, or a combination of the two. The indicated proteins were detected using specific antibodies.
The UIM motif of UBXN7 is required to engage the NEDD8 modification on cullins
Because UBXN7 preferentially interacted with neddylated-CUL2 and cullin-neddylation was a prerequisite for the interaction to occur, we became intrigued with the possibility that the NEDD8 modification on cullins might be directly involved in recruiting UBXN7. We therefore turned our attention to UBXN7 and the various domains that are part of its structure. At the N-terminus of UBXN7 there is a UBA domain, followed by a UAS domain of unknown function, a UIM motif and a UBX domain at the C-terminus (Figure
Figure 3
An intact UIM motif is necessary for UBXN7 interaction with neddylated-CUL2
An intact UIM motif is necessary for UBXN7 interaction with neddylated-CUL2. (A) Schematic representation of human UBXN7 highlighting its various domains. (B-D) Wild-type or mutant Flag-UBXN7 was immunoprecipitated from HeLa cells. The indicated proteins were detected using specific antibodies in the immunoprecipitates (left) and the input cell extracts (right). (B) Either UBA- or UIM-deletion caused a reduction in ubiquitin-binding to UBXN7. UBX-deletion or a point mutation in this domain (P459G) abolished p97-binding and severely impaired the interaction with ubiquitylated proteins (left panel). (C) UIM-deletion, but not other mutations, caused a strong reduction in CUL2-binding to UBXN7 (left panel) and abolished the CUL2 up-shift caused by UBXN7 over-expression (right panel). (D) Point mutations within the UIM motif at Ser297 caused a defect in CUL2-binding to UBXN7 similar to UIM-deletion. p97-binding was not affected by these mutations (left panel).
As expected, both UBX-deletion and a point mutation in this domain (P459G) abolished p97 binding (Figure
Consistent with the reduced binding of UBXN7 ΔUIM to CUL2, over-expression of this mutant failed to cause an up-shift of CUL2 to the neddylated form (Figure
Various residues within the UIM motif are essential for its interaction with ubiquitin
To further substantiate the ability of the UIM motif in UBXN7 to interact with NEDD8 rather than ubiquitin we performed
Figure 4
UBXN7 directly interacts with NEDD8 and cullins
UBXN7 directly interacts with NEDD8 and cullins
UBXN7 interacts with cullin-RING complexes
To check whether UBXN7 could interact with cullin complexes
UBXN7 over-expression causes HIF1α accumulation in a UIM-dependent manner
Because various UBXN7 mutants had altered ability to interact with ubiquitylated-proteins or with CUL2, we checked whether their expression in the cell might have any consequence on the levels of HIF1α, which is a CRL2 substrate
Figure 5
UBXN7 over-expression causes HIF1α accumulation in a UIM-dependent manner
UBXN7 over-expression causes HIF1α accumulation in a UIM-dependent manner. (A) Non-ubiquitylated HIF1α accumulates in cells over-expressing wild-type Flag-UBXN7, but not in cells expressing a UIM-deleted version. 10 μM MG132 was added two hours prior to cell lysis to facilitate HIF1α detection. UBXN7 over-expression had no effect on CRL2 subunit levels. (B) Over-expression of another UIM-containing protein, PSMD4, does not alter HIF1α levels. (C, D) UIM-dependent accumulation of non-ubiquitylated HIF1α upon UBXN7 over-expression is also observed in the absence of proteasome inhibition (right panels). Wild-type UBXN7 interacted with HIF1α at various degrees of ubiquitylation, while UIM-defective UBXN7 (upon UIM deletion or point mutation at Ser297) only interacted with slow-migrating, poly-ubiquitylated HIF1α (left panels). The corresponding Flag, CUL2 and p97 western blots for the experiment in (C) are shown in figure 3D. (D) UBXN7 mutated at Ser288 within the UIM motif binds CUL2 (left panel) and causes HIF1α accumulation (right panel), similar to the wild-type protein. The indicated proteins were detected using specific antibodies.
To facilitate HIF1α detection, for the experiments shown in Figures
Previous reports identified a phosphorylation site within the UIM motif of human UBXN7 at Ser288
Interestingly, the defect in CUL2-binding observed for the UIM-defective mutants correlated with a complete loss of binding to non- or oligo-ubiquitylated HIF1α (Figure
Long ubiquitin-chains on HIF1α cause reduced ubiquitin-receptor selectivity
We previously observed that HIF1α carrying long ubiquitin-chains can interact, albeit inefficiently, with UBA-UBX proteins other than UBXN7
Figure 6
HIF1α carrying long ubiquitin-chains becomes promiscuous in its interaction with ubiquitin-receptors
HIF1α carrying long ubiquitin-chains becomes promiscuous in its interaction with ubiquitin-receptors. (A) FAF1 interacts, albeit inefficiently, with HIF1α carrying long ubiquitin-chains (top panel). Flag-UBXN7 or Flag-FAF1 was immunoprecipitated from HeLa cells treated with 10 μM MG132, 1 μM MLN4924, or a combination of the two for two hours. (B) Flag-UBXN7 (green) localizes to the nucleus of HeLa cells. The DNA was stained with DAPI (blue). The scale bar represents 15 μm. (C) RAD23B interacts with slower-migrating, poly-ubiquitylated HIF1α (top panel). Flag-UBXN7 or Flag-RAD23B was immunoprecipitated from HeLa cells using anti-Flag beads. The indicated proteins were detected by western blotting using specific antibodies.
Flag-UBXN7 was found exclusively in the nuclei of HeLa cells (Figure
UBXN7 interaction with cullins requires neddylation and is independent of the ubiquitylated substrate
Multiple lines of evidence indicate that ubiquitin/substrate-binding and cullin-binding to UBXN7 are two independent events: (1) inhibition of the ubiquitin-E1 strongly reduces ubiquitin-binding, but it has no effect on CUL2-binding to UBXN7; (2) UBXN7 interaction with HIF1α/VHL is transient and strongly enhanced upon proteasome inhibition while UBXN7 interaction with the core CRL2 complex is stable; (3) UBA-domain deletion reduces ubiquitin-binding to UBXN7, but it does not affect the interaction with CUL2.
Furthermore, several observations support the notion that neddylation is necessary for UBXN7 interaction with cullins: (1) CUL2 mutants defective to varying degrees in getting neddylated are similarly defective in UBXN7 binding; (2) chemical inhibition of the NEDD8-E1 abolishes the interaction of UBXN7 with multiple cullins; (3)
UBXN7, one domain for each interaction
The UBX domain has a ubiquitin-like structure
Both UBA and UIM have been characterized extensively as ubiquitin-binding modules
We show that within UBXN7, UBA and UIM play distinct roles. In cell extracts, the UBXN7 mutant lacking the UBA domain is fully competent in interacting with cullins, thus ruling out the involvement of this domain in cullin-binding. This mutant is the least competent in ubiquitin-binding, but it is not fully defective. It is possible that, in this case, ubiquitin-binding is not direct, but mediated by the UIM motif bound to cullins. In contrast, UBXN7 lacking the UIM motif or carrying point mutations therein is strongly defective in cullin-binding. The residual CUL2-binding observed for the ΔUIM mutant may be mediated by its UBA-dependent interaction with ubiquitylated substrates of CRL2. Indeed this mutant retains the ability to interact with HIF1α carrying long ubiquitin-chains. We argue that the UIM motif contributes to the direct binding of UBXN7 to neddylated-cullins. This conclusion is strongly supported by our
The data presented here suggest that each of the three domains found in UBXN7 enables a specific interaction to occur. Thus, the UIM motif allows docking of UBXN7 on neddylated-cullins, the UBA domain is required for binding ubiquitylated-protein substrates, and the UBX domain recruits the p97 complex (Figure
Figure 7
UBXN7 docks on neddylated cullins using its UIM motif
UBXN7 docks on neddylated cullins using its UIM motif. Each domain in UBXN7 mediates a specific interaction: the UBA domain interacts with ubiquitylated HIF1α, the UIM motif anchors the neddylated CRL complex and the UBX domain recruits the p97/NPL4/UFD1 complex.
Processivity versus selectivity in CRL-dependent degradation
Having established that UBXN7 can directly interact with neddylated CRL complexes, a key question is whether this interaction might have any effect on the ubiquitin-ligase activity of CRLs.
The data presented here lead us to speculate that UBXN7 is not only a ubiquitin-binding adaptor for p97, but it may also embody a novel mechanism of CRL inhibition. This would be in agreement with our previous observation that UBXN7 depletion by siRNA causes a reduction in HIF1α levels and not HIF1α accumulation as would be expected were it simply mediating HIF1α interaction with p97
Our finding that UBXN7 over-expression causes the accumulation of HIF1α mostly in its non-ubiquitylated form suggests that the UIM-NEDD8 interaction would have a negative effect on ubiquitin-chain elongation, that is, reduce the processivity of the CRL ubiquitin-ligase. UBXN7 over-expression causes not only HIF1α accumulation, but also converts CUL2 to its neddylated form. Because both effects are entirely dependent on the UIM motif, it is tempting to propose that by sequestering CUL2 in its neddylated form, UBXN7 might sterically hinder the transition of the CRL complex to an open conformation and thereby mitigate the positive effect NEDD8 has on CRL E3 activity.
We find that ubiquitin-receptor selectivity is compromised when HIF1α carries long ubiquitin-chains. Hence, we suggest that reduced CRL processivity would favor p97 recruitment to the UBX-domain of UBXN7 rather than recruitment of alternative ubiquitin-receptors to a fast-growing ubiquitin chain. Through its prior docking on the neddylated-CRL, UBXN7 would be ideally poised to modulate substrate-ubiquitylation and to shift the balance towards p97 recruitment.
UBXN7 recruits p97 to nuclear HIF1α
Employing p97 complexes as the ubiquitin-receptor of choice is particularly important in the nucleus, where HIF1α forms complexes with HIF1β and associates with the promoters of its target genes
Herein we show that among the ubiquitin-binding adaptors of p97, UBXN7 has the unique ability to directly dock onto neddylated cullins. This function depends on the UIM motif that is only found in the UBXN7 co-factor of p97. Furthermore, UBXN7 interaction with neddylated CUL2 appears to negatively affect its ubiquitin-ligase activity as UBXN7 over-expression causes the accumulation of non-ubiquitylated HIF1α in a UIM-dependent manner.
It has been puzzling why p97 has such a multitude of ubiquitin-binding co-factors, for example, NPL4, UFD1, various UBA-UBX proteins, PLAA. Our data indicate that the role of UBXN7 as a substrate-binding adaptor for p97 is secondary to its ability to interact with CRLs and possibly to modulate their activity. UBXN7 interaction with cullins does not require p97, while UBXN7 interaction with NPL4/UFD1 is mediated by p97
Cloning Information
Human UBXN7 [GenBank:
PCR reactions were carried out using KOD Hot Start DNA Polymerase (Merck Millipore, Darmstadt, Germany). All full-length PCR products were cloned into pSc-B (Agilent Technologies, Santa Clara, CA, USA) and fully sequenced prior to further subcloning. All mutations and deletions were made following the Quickchange method (Agilent Technologies), but using KOD Hot Start DNA Polymerase. DNA sequencing was performed by the Sequencing Service at the College of Life Sciences (CLS), University of Dundee.
Cell Extracts and Immunoprecipitation
For immunoprecipitation experiments, the cells were lysed in buffer A (50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)/KOH, pH 7.2; 5 mM Mg(OAc)2; 70 mM KOAc; 0.2% Triton X-100; 10% glycerol; 0.2 mM ethylenediaminetetraacetic acid (EDTA); protease inhibitors) and incubated with anti-UBXN7 antibodies crosslinked to Protein A-agarose or anti-Flag beads (Sigma, Saint Louis, MO, USA). For the experiment in Figure
Total extracts were prepared using buffer B (50 mM HEPES/KOH, pH 7.2; 400 mM NaCl; 1% NP-40; 0.2 mM EDTA; 10% glycerol; protease inhibitors) to facilitate extraction of nuclear HIF1α.
Antibodies and Chemicals
The following antibodies were used for protein detection by western blotting: mouse anti-Flag M2 (Sigma), mouse anti-ubiquitin FK2 (Enzo, Farmingdale, NY, USA), mouse anti-p97 (Fitzgerald, North Acton, MA, USA), mouse anti-CUL3, mouse anti-elongin C (BD Transduction Laboratories, San Jose, CA, USA), rabbit anti-CUL4A (Cell Signalling, Danvers, MA, USA), rabbit and mouse anti-CUL1, rabbit anti-CUL2, rabbit anti-NEDD8 (Invitrogen, Camarillo, CA, USA), rabbit anti-RBX1 (Thermo, Fremont, CA, USA), rabbit anti-VHL (Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit anti-HIF1α (Novus, Littleton, CO, USA), rabbit anti-UBXN7 (courtesy of Millipore, Billerica, MA, USA). MG132 (Enzo) was added at 10 μM to the tissue culture media for two hours prior to cell lysis. The Division of Signal Transduction Therapy (DSTT) at the CLS, University of Dundee synthesized MLN4924, as described previously
Recombinant Protein Expression and Purification
The Protein Production and Assay Development Team (PPADT) at SCILLS produced the various recombinant proteins in bacteria, as follows. Expression vectors for full length, UBA- or UIM-deleted UBXN7 were transformed into BL21 DE3 cells. Overnight cultures were grown in LB medium (1% tryptone, 0.5% yeast extract, 1% NaCl) supplemented with carbenicillin. Autoinduction medium was inoculated and the cells were left to grow at 37°C until the OD600 reached about 1.5. The temperature was then dropped to 15°C and the cells were left for about 16 hours to express the protein. The cells were collected by centrifugation and resuspended in 50 mM Tris-HCl pH 7.5, 250 mM NaCl, 0.4% Triton X-100, 0.1 mM EDTA, 0.1 mM ethylene glycol tetraacetic acid (EGTA), 1 mM dithiothreitol (DTT) and protease inhibitors. The suspension was sonicated and the insoluble material was sedimented by centrifugation at 4°C, 28,000 g for 20 minutes. The supernatant was incubated with GSH-sepharose for one hour. The sepharose was washed four times and UBXN7 was recovered upon cleavage with TEV protease. The proteins were further purified by chromatography over a Superdex 75 column after which protein purity exceeded 90%.
The vector expressing Flag-CUL1(324-776)/GST-HA-RBX1
The dual expression vector encoding GST-CUL2/HIS6-RBX1 was used to generate recombinant baculoviruses using the Bac-to-Bac system (Invitrogen) following the manufacturer's protocol. These baculoviruses were used to infect
The Flag-CUL1(324-776)/GST-HA-RBX1 complex was immobilized on GSH-sepharose (GE). For each binding assay, 10 μl beads carrying approximately 1 μg CUL1/RBX1 were incubated for 30 minutes at 30°C with a neddylation reaction mix containing NEDD8 E1 (PPADT, SCILLS), NEDD8 E2 (Ubiquigent, Dundee, UK), NEDD8 and ERS (BostonBiochem, Cambridge, MA, USA) in buffer C (50 mM HEPES/KOH, pH 7.5; 60 mM KOAc; 5 mM MgCl2; 5% glycerol, 1 mM DTT). Mock neddylation reactions were performed in parallel by omitting NEDD8 from the mixture. The beads were then washed and incubated for one hour with 3 μg of wild-type or mutant Flag-UBXN7 in buffer C without DTT and supplemented with 0.1% Triton X-100 (buffer D). After washing the beads, the bound proteins were eluted with Laemmli buffer. The binding assays were also performed using naked beads to account for non-specific UBXN7 binding to the beads.
GST was cleaved off CUL2 with PreScission protease and the resulting CUL2/RBX1 was neddylated as above. CUL2/RBX1 (1.5 μg) was pre-incubated with 1.5 μg Flag-UBXN7 (approximately 1.5 times molar excess to CUL2) for 30 minutes, followed by one hour incubation with 10 μl anti-Flag beads in buffer D. The proteins bound to beads were eluted by boiling in Laemmli buffer.
Wild-type or mutant UBXN7 (25 μg) was incubated for one hour with 10 μl NEDD8- or ubiquitin-agarose (BostonBiochem) in buffer D and the bound proteins were eluted as above.
Immunofluorescence Staining and Microscopy
For Flag-UBXN7 immunostaining, cells were grown on coverslips and fixed with ice-cold methanol for six minutes at -20°C. Cells were then blocked in 1% BSA/PBS for 30 minutes and subsequently incubated with mouse anti-Flag M2 (Sigma) antibodies in 3% BSA/PBS, for one hour at room temperature. After washing with PBS, cells were incubated with donkey anti-mouse FITC-conjugated antibodies (Jackson ImmunoResearch, West Grove, PA, USA) for 45 minutes. The cell nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI, Invitrogen). The coverslips were mounted onto glass slides using hydromount (National Diagnostics, Atlanta, GA, USA).
Images were obtained with a DeltaVision Spectris microscope (Applied Precision), using a CoolSNAP HQ camera (Roper) and a 60 × 1.4 NA objective (Olympus). The SoftWorx software (Applied Precision) was used for acquisition and deconvolution.
ATP: adenosine triphosphate; BSA: bovine serum albumin; CLS: College of Life Sciences; CRL: cullin-RING E3 ligase; CRL2: CUL2-based CRL; DAPI: 4',6-diamidino-2-phenylindole; DSTT: Division of Signal Transduction Therapy; DTT: dithiothreitol; EDTA: ethylenediaminetetraacetic acid; EGTA: ethylene glycol tetraacetic acid; ERS: energy regeneration solution; FITC: fluorescein isothiocyanate; GSH: glutathione; GST: glutathione S-transferase; HECT: homologous to E6-AP carboxyl terminus: HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; IPTG: isopropyl-beta-D-thiogalactopyranoside; KOAc: potassium acetate; KOH: potassium hydroxide; LB: Luria-Bertani media; Mg(OAc)2: magnesium acetate; NaCl: sodium chloride; OD: optical density; PBS: phosphate buffered saline; PCR: polymerase chain reaction; PMSF: phenylmethylsulfonyl fluoride; PPADT: Protein Production and Assay Development Team; RING: really interesting new gene; SCILLS: Scottish Institute for Cell Signalling; siRNA: small interfering RNA; TEV: Tobacco Etch virus; UAS: domain of unknown function; UBA: ubiquitin-associated domain; UBL: ubiquitin-like protein; UBX: ubiquitin regulatory X domain; UIM: ubiquitin-interacting motif.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
SB performed the experiments shown in Figures
We would like to thank J. Hastie and the PPAD team for recombinant protein expression and purification, N. Shpiro for MLN4924 synthesis, T. Kurz lab, J. Bett, S. Rocha, and Ubiquigent for sharing reagents, S. Swift for help with microscopy, and D. Wright for tissue culture assistance. We are grateful to P. Cohen for critical comments on the manuscript and to D. Alessi, R. Hjerpe, and T. Kurz for helpful advice. The research in G.A. lab is supported by a grant from the Scottish Government to SCILLS.
Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown
Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system
A 26 S protease subunit that binds ubiquitin conjugates
Proteasome subunit Rpn13 is a novel ubiquitin receptor
Delivery of ubiquitinated substrates to protein-unfolding machines
Role of the ubiquitin-selective CDC48(UFD1/NPL4)chaperone (segregase) in ERAD of OLE1 and other substrates
Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone
Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle
The role of p97/Cdc48p in endoplasmic reticulum-associated degradation: from the immune system to yeast
Cdc48p(Npl4p/Ufd1p) binds and segregates membrane-anchored/tethered complexes via a polyubiquitin signal present on the anchors
Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4
Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains
UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97
Ubiquitin-binding domains
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover
Nedd8 on cullin: building an expressway to protein destruction
Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation
The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae
A dual E3 mechanism for Rub1 ligation to Cdc53
The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2
Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex
Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability
Function and regulation of cullin-RING ubiquitin ligases
Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation
Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation
Integration of oxygen signaling at the consensus HRE
The von Hippel-Lindau tumor suppressor protein
Molecular characterization of the thermosensitive E1 ubiquitin-activating enzyme cell mutant A31N-ts20. Requirements upon different levels of E1 for the ubiquitination/degradation of the various protein substrates in vivo
Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ
Identification of NEDD8-conjugation site in human cullin-2
The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting
Double-sided ubiquitin binding of Hrs-UIM in endosomal protein sorting
Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization
Global phosphoproteome of HT-29 human colon adenocarcinoma cells
Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column
Studies on the intracellular localization of hHR23B
XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes
The UBX domain: a widespread ubiquitin-like module
Ubiquitin-binding domains
Structure of the UBA domain of Dsk2p in complex with ubiquitin molecular determinants for ubiquitin recognition
Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation
Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes
Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases
Regulation of the NEDD8 conjugation system by a splicing variant, NUB1L
Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension
Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor
Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1
HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia
The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages
Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases
Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer


text:
It seems Star Wars never gets old. And with Disney buying Lucasfilm a few years back, a new generation of kids gets to experience Star Wars movies, action figures, games and other toys. There are even plans to build a Star Wars Land inside Disneyland. The Air Hogs Star Wars RC X-wing Starfighter is another product of the marketing machine that is Disney. The Air Hogs name has been known for reasonably-priced, remote-controlled aircraft. But the X-wing version has to be one of the coolest ones that they make, well, next to the Air Hogs Millennium Falcon, that is. The only one I saw at our Costco was the X-wing, however. Either way, you will find the Air Hogs Star Wars RC X-wing Starfighter as a fun toy that you can enjoy along with your kid. You too can evade imperial gunfire while racing to launch your torpedos into the Death Star with the Air Hogs Star Wars RC X-wing Starfighter.
|Dog fight with the best of them with the Air Hogs Star Wars X-wing
Here are the specs:
Air Hogs Star Wars RC X-wing Starfighter Product InfoCostco Item#: 944805
Costco Price: $49.99
Found at: Costco in Redwood City, CA (2300 Middlefield Rd)
(price and availability may vary per Costco location)
|Air Hogs Star Wars RC X-wing Starfighter – Durable foam body
|Air Hogs Star Wars RC X-wing Starfighter – 250 ft flying range
|Deal for the Star Wars Remote Control X-wing Starfighter at Costco
Air Hogs Star Wars RC X-wing Starfighter – The X-wing is a versatile Rebel Alliance starfighter that balances speed with firepower. Armed with four laser cannons and two proton torpedo launchers, the X-wing can take on anything that the Empire throws at it. Nimble engines give the X-wing an edge during dogfights, and it can make long range jumps with its hyperdrive and its Astromech Droid co-pilot. Luke Skywalker is famous for destroying the Death Star behind the control of the X-wing.
Key Features:
- 250-ft flying range
- Crash-resistant, durable foam body
- Remote controlled


text:
DGLM has had some technological challenges this past week; the cable that carries the internet into our office was somehow severed. (Sabotage obviously. I blame the North Koreans, fresh from their triumph hacking into the Sony Pictures system, exposing the unguessed-at truth that Hollywood folks can be small-minded and mean.) Anyway, my inability to access email, our office network, or the majority of my saved files was disorienting. Then Sharon, tech genius that she is, showed me how to access my e-mail via my spam filter. This seemed to me thrillingly covert–a bit like crawling into a locked building through its garbage chute–but the interface was so basic. There was no "undo" button, no save. The result was ugly. Outlook Express and iOS have been saving me from myself. I see that now.
Our computer troubles also allowed me some time to muse on my fraught relationship with technology. I grew up in a family of late (to never) adopters. My parents were unmoved by cable, video games, computers, VCRS, or even color televisions. I had mixed feelings about this when I was a kid. I cultivated a friendship with a kindly agoraphobic neighbor who watched TV all the day long. To her I owe any knowledge of the A-Team, daytime talk-shows and soap operas that I may possess.
Still, I've followed in my parents footsteps. My sons have had comparatively little exposure to technology. Given my line of work and benign but inchoate ideas about child-rearing, it seemed natural to favor books over tablets, paper over gaming devices, outdoors over indoors. But this year—specifically this Christmas–that's about to change. We're buying our sons their own computer.
We are: a) caving or b) emerging from the rock under which we've been living, because as it turns out, the standardized tests that kids in our town will take later this year require them to type. And so it seems cruel not to allow them to build the skills that they will so obviously need.
I can still remember the day when I realized that a computer, not a pencil, was a truer, faster connection between my thoughts and the page. I felt a little sad, because I still love the physical act of writing. For me, a good fine line felt tip pen is a source of pleasure. Today, however, few kids are taught cursive at all. I'm no Luddite, but part of me finds it awfully sad that reading script will be a skill reserved to archivists. Or–who am I kidding?–an app.
Technology is a great boon—it facilitates so much—but I'm curious about your relationship with it. Or, in the words of Ali G, "Tech-mology: Is it Good, or is it Whack?"


text: Good news for owners of the Samsung Galaxy S4 and Galaxy Note 3 in the UK, your new operating system is currently rolling out.It is rolling out for some of you anyway. Android 4.4.2 KitKat is heading to unlocked models of the Galaxy S4 and Galaxy Note 3 right now, which is good news for some of you, not so if you have a contract. No idea when that will come through, as it will be dictated by your network giving the nod after testing. But if you bought outright, you should see a notification on your phone offering you the new OS.When you do get offered it, make sure you are in a Wi-Fi zone before you download. It is said to be between 300 and 400MB in size, so not something you want out of your data allowance.The update isn't a huge one in terms of features, although you will see some changes with the likes of the phone dialler (with contacts also arranged in terms of popularity), an improved Hangouts app, voice control via 'Okay Google', native cloud printing, tweaks to notification bars and lock screen album art, for example. It's also a more efficient operating system, so less stress on your phone's memory too.Which means it is well worth downloading when it is offered to you. Which should be now or in the very near future.


text:
1 Fine Dining Restaurant in Claremont
Showing 1 result
Bentley Oyster Bar & Bistro
Where? Claremont
This classy and very trendy restaurant is the place where you can indulge on phenomenally prepared oysters and fabulous fine dining dishes. Prepare yourself for a taste sensation and gulp down deep fried ...


text:
Open Windows
After winning a contest that nets him a date with actress Jill Goddard, Nick Chambers is crushed when she cancels. He's offered a consolation prize -- a spy's-eye look into her personal life -- but there's more to the proposition than meets the eye.
Rent DVDs for only $4.99 a month.
Movie Details
- Director
- Nacho Vigalondo
- Genres
- Thrillers, Action Thrillers, Showbiz Dramas, Crime Dramas
- This movie is
- Suspenseful
- Format
- DVD and streaming
- Ratings
NRNot rated. This movie has not been rated by the MPAA.
17Common Sense rating OK for kids 17+
Widescreen Anamorphic 1.78:1Subtitles
NoClosed captioned
NoLanguage and sound
English: Dolby Digital 5.1Other features
Color; interactive menus; scene access.
Open WindowsClose
For Parents
Common Sense Note
Parents need to know that Open Windows is a thriller that takes place almost entirely on a laptop -- through webcams, streaming videos, and video chats. It features the former porn star Sasha Grey, who's the object of a male character's obsession and is viewed as a sexual object. She exposes her breasts in one scene. Language is strong, with many uses of "f--k" and "s--t," as well as other words. Grey's character is kidnapped and tied up; other violence includes a man being bound and given electric shocks, shooting, a Taser gun, car chases, crashes, and explosions. A minor character can be seen snorting cocaine, and drugs are discussed. The story is set in the movie industry, where a new zombie film is being promoted. A clip from the fake "movie" is shown, with some violence.
- Sexual Content
- A woman is forced to open her robe, exposing her breasts. A camera zooms in on her cleavage. She goes to a hotel room for sex; kissing noises are heard. Reference to a sex tape/porn movie. Reference to masturbating on a webcam. Innuendo. Sexy photos.
- Violence
- A woman is grabbed and taken hostage; she's slapped off screen and tied to a chair. A man is tied up, gagged, and given electric shocks. A man is shot and seemingly killed. Taser gun. Explosions. Car chase and crash. A clip from a zombie movie, with bowling balls to the head.
- Language
- "F--k" and "s--t" are used several times. Also "t-ts," "ass," "schlong," "damn," "son of a bitch," "bastard," "bitch," "bimbo."
- Social Behavior
- Vague warning about Internet safety and trusting everything you see. Food for thought: A man holds a woman hostage and threatens to blow her up unless Internet surfers log off the site; less than 10% do it -- the rest stay on to watch.
- Consumerism
- The movie begins at a sci-fi convention panel where a new movie is being teased. No real-life products are mentioned.
- Drugs / Tobacco / Alcohol
- A man is seen snorting cocaine from a distance. Drugs are mentioned.
- Age appropriate
- Not an issue
- Depends on your kid and your family
- Not appropriate for kids of the age most likely to want to see it


text:
Simplicity 3015; ca. 1939; Misses' Dress. You'll attract attention in this stunning dress. Neckline is square, emphasized by ribbon or clips. The panel-like skirt front and yoke are in one. The full side and back skirt joins backyoke and skirt front at hipline. Sleeves are long or short.
Links to reviews/blog postsEdit
Add a photo to the gallery by clicking the "modify" button below.
[insert your username, and make sure your preferences allow for people to contact you via e-mail. Do not list your email address here!]


text:
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News, Interviews, Live Streams, Upcoming Events, Tweets..
Thursday, December 31, 2015
Donald Trump Coming To Clear Lake, IA on Jan 9, 2016
Sat, Jan 9, 2016 at 4:00 PM (CST)
Doors open at 2:00 PM
Surf Ballroom and Museum - 460 North Shore Drive Clear Lake, IA 50428
Tickets: https://www.eventbrite.com/e/donald-j-trump-in-clear-lake-ia-tickets-20288718102
4 comments:
- AnonymousJanuary 9, 2016 at 1:13 PM
Are there ever videos of the entire event for Mr. Trump? Most of the time there are great speakers that open for him and we never get to see that? would love to know if anyone is posting full video's of the eventsReplyDelete
- AnonymousJanuary 10, 2016 at 7:35 AM
Gotta disagree. The very times we see an introductory speaker, it's a local guy or gal who most likely helped with the rally or state organization. It's rare to see a celebrity (e.g., Herman Cain). Name a few of these so-called 'great speakers' you're talking about?ReplyDeleteReplies
- AnonymousJanuary 10, 2016 at 7:37 AM
...very few times...Delete
- AnonymousJanuary 10, 2016 at 1:13 PM
Guess I need to clarify... I did not mean necessarily celebrities but he has had senators, and local to the area well known people who give great speeches about him and prior to his taking the stage. I have seen young people from the local churches singing the national anthem as well as local pastors. We also do not see how Trump goes into the crowd to autograph books, etc and take pics with voters. There were a FEW videos that showed everything but not lately. I think it is great to see his interaction with the voters and how anxious they are to meet and speak to him.Delete


text:
Swap your brush for a blender sponge to get an Instagram finish
Forget the standard foundation brush, to get an Instagram ready finish on your make-up, it's all about the beauty blender sponge. We run through how best to use this hot new tool.
There are a huge array of sponges on the market these days, all boasting different properties. But one thing that is the same regardless of the brand is just how you should use these sponges.
Once you take the sponge out of its packing, you'd be forgiven for wondering what all the fuss is about. This small, hard object doesn't look like it can give you a flawless finish.
However, run it under the tap and it's a different story. Make sure the sponge is entirely saturated in water (it will also almost double in size), and then squeeze out the excess fluid to give you a damp surface to work with. You can use these sponges regardless of which base you choose – whether you opt for a high coverage dense foundation or a light coverage tinted moisturiser. Whatever your choice, dab the damp sponge into your make-up and then use the sponge in short sharp "bouncing" motions to apply the make-up onto your face. The most important thing is not to use the sponge to wipe the make-up onto your visage, but to use it to dab it on. If you prefer a lengthier make-up routine, you can use the sponge to apply your primer or base, before putting on your foundation and then setting with powder. If you're a fan of strobing, use the sponge to apply your highlighter either pre-foundation or at the end of your regime.
It's not just for make-up either – you can also use these sponges to apply your moisturisers and face creams. The design means that you get a much more even coverage on your complexion than if you apply the cream using your fingers.
If you are a beauty blender sponge virgin, then follow the steps above to get a gorgeous finish that even the Kardashians would be proud of.
When it comes to choosing a blender sponge, our favourites are Real Techniques' Bold Metals Collection Miracle Diamond Sponge, which has 13 faceted areas to work on every area of the face, and BrushWorks' HD Blender sponge set - a high quality, affordable alternative to more expensive blenders on the market.
Lord & Berry's Luxury Bell Sponge is also a good option, as its clever shape and pointed tip means you can reach the otherwise difficult to reach areas – such as the sides of the nose and around the eyes.
Cover Media


text:
Related quotes
"It was a game of two halves. We didn't come out and compete in the first half. We're not a great team playing from behind. We outscored them 50-39 in the second half, but we have to play a complete game."
"He was all-square stood on the 18th, then finished with a par to win his game and halve the match overall."
"It was a game of two different halves, ... They made good on almost all of their chances in the second half."
"It's a game of two halves. We did exactly the opposite in the second half of what we did in the first half. We were nowhere in the zip code with Smith on his first two shots. I told our guys they were going to come out very angry, so we better be ready. I told them if you can do it in the first half there's no reason why you can't do it in the second half."
"That was a good game for us offensively, we scored 76 points and got 38 in both halves. They just had a more solid second half. They closed it out. We didn't hit the shots."


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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Noirin Plunkett <noi...@apache.org>
|Re: [PATCH] mod/mod_usertrack.xml
|Tue, 13 Jun 2006 09:19:34 GMT
On Mon, Jun 12, 2006 at 06:19:01PM -0700, Matt Lewandowsky wrote: > I was reviewing the mod_usertrack docs and a few things jumped out at > me as "this should be corrected". So, I took it upon myself to do so > and the patch is attached. First off, thanks a mill for this! =) > Changes: > > Index: mod_usertrack.xml > =================================================================== > @@ -123,6 +123,16 @@ > + > + <note> > +
Most browsers in use today will disallow cookies to be set for > + a "two-part top level domain" such as .co.uk. This I'd prefer "will not allow cookies to be set", rather than "will disallow" - if you want to keep disallow, you'll have to change the wording a little - "will disallow cookies from being [...]" > + is because a two-part top level domain is equivalent to a top level > + domain such as .com. Allowing such cookies may be I had to read this several times before I understood what it meant. It's definitely a useful piece of info to have in the docs, but perhaps we could rephrase it a bit. My patch is attached, let me know if it's any clearer, or if I've just been staring at this so long that I get it now =) > + users' browsers. As of mid-2006, most browsers only fully support > + CookieStyle Netscape.
 I've also changed this to "At the time of writing" - if these docs don't get updated for another seven or eight years, at least then the reader has to dig back to see how old and crufty they are, rather than having it printed there before them =) Noirin
|View raw message


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The chances of seeing Kaka playing in the colours of Paris Saint-Germain receded slightly further on Friday when Real Madrid coach Jose Mourinho said the Brazilian still featured in his plans for the rest of the season.
Sources close to PSG owners Qatar Sports Investments (QSI) have told AFP that the Ligue 1 leaders are lining up a bid for the playmaker, but Mourinho said: "I'm counting on him for the season."
New PSG coach Carlo Ancelotti is reportedly eager to bring Kaka to Parc des Princes, having enjoyed success with the Brazilian during his tenure as coach of AC Milan.
Mourinho also addressed the competition for places at the tip of the Madrid attack, where Karim Benzema and Gonzalo Higuain continue to scrap over a single starting place.
Both players have been in fine form this season - with Higuain having netted 12 goals in the league and Benzema eight - but Mourinho intends to keep faith with his habitual 4-2-3-1 formation.
"I prefer to play with one central striker and wingers who cut inside into the middle," he told reporters at a press conference.
"But I also know that there is a possibility of playing Higuain and Benzema. In any case, in each match, the two of them have given me what I wanted."
The half-time introduction of Benzema to play alongside Higuain turned the tide in Madrid's favour in Tuesday's Copa del Rey last 16 first leg against Malaga, with the Frenchman inspiring his side to fight back from two goals down to claim a 3-2 victory.
Madrid, who lead La Liga by three points from title rivals Barcelona, resume their league campaign at home to Granada on Saturday.
Sergio Ramos is available to play after tearing a muscle in his left thigh during the 6-2 win at Sevilla last month, but full-backs Alvaro Arbeloa and Fabio Coentrao have been left out of the matchday squad.
Madrid's website said that Arbeloa and Coentrao had been "left out at the coach's behest", while centre-back Pepe (suspended) and Argentine winger Angel di Maria (thigh injury) will also be missing.


text:
Define evaluation
Define evaluation
1.An assessment, such as an annual personnel performance review used as the basis for a salary increase or bonus, or a summary of a particular situation.
2.(mathematics) A completion of a mathematical operation; a valuation.
3.(computing) Determination of the value of a variable or expression.
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text: Ms. Powers refers to Northwest Bio CEO Linda Powers, who owns approximately 40% of the company via some intertwined entities, including the company that manufactures DCVax. Smith believes Power's large ownership stake in Northwest Bio proves she has "skin in the game." A more believable and less optimistic explanation: Powers can't convince institutional investors to buy the stock because they've checked out DCVax and found it lacking credibility. Retail investors, on the other hand, are more easily persuaded, thanks in part to articles promoting the company like those written by Smith. Smith should know better given his past experience working on Wall Street. Hidden gems in the biotech sector, if they exist at all, don't remain hidden for long. Northwest Bio has been toiling in the dark for years -- and for good reason. Adjust for last fall's 1-for-16 reverse stock split and Northwest Bio today is a 21-cent stock. The company's market value is a measly $85 million even with DCVax in a phase III study for GBM. Investors have looked at Northwest Bio and passed. Potential development and marketing partners -- Big Pharma companies eager and willing to write big checks for licensing promising new drugs -- have also looked over Northwest Bio and passed. The Feuerstein-Ratain Rule hasn't been proven wrong yet and is unambiguous about Northwest Bio: DCVax will fail. Smith believes otherwise. We'll see who's right eventually. -- Reported by Adam Feuerstein in Boston. Follow @AdamFeuerstein


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dotloop provides online software that handles real estate transactions from offer to close.
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Keladi Kanmani 15-09-2016 is a Tamil serial being shown on Sun Television. This program begins right after the afternoon movie is done on the channel. Keladi Kanmani 15.09.16. It involves many famous characters who have already been in other serials or movies in the past. Keladi Kanmani 15/09/2016 Tamil drama from Sun TV do not miss today's episode.
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BIDDEFORD, Maine – The 23rd annual Maine Geriatrics Conference will be held June 13-14, at the Harborside Hotel and Marina in Bar Harbor.
Co-hosted by the University of New England College of Osteopathic Medicine Department of Geriatric Medicine and the Maine Gerontological Society, the meeting gathers health professionals and para-professionals, geriatrics administrators, social workers, care givers, policy makers and others invested in enhancing the health and lives of Maine's elders.
The annual conference offers a wide range of workshops and networking opportunities. Continuing professional education credits are available for physicians and physicians assistants, nursing home administrators, and nurses.
A sampling of this year's workshops led by regional and national leaders in elder care includes:
- It's Not About Sex…It's About Intimacy
- Hearing Their Voices: How Older Consumers Experience Health Care and Can Help Change It
- From the Inside Out: Undercover Feedback Prompts Nursing Home Staff Response
- Fitness-to-Drive Screening Measure for At-Risk Older Adults
- Estate and Public Benefits Planning for Seniors: Potential Pitfalls and Remedies
- Just Say Know: Helping Patients Become Better Consumers
- Oral Health Impact on Systemic Disease in Seniors
The Maine Health Access Foundation awarded the conference a $2,000 grant to advance education and teaching on aging in Maine. The conference also includes numerous exhibitors, including Lunder-Dineen Health Education Alliance of Maine, the event's Diamond Sponsor.
Health care professionals attending the Geriatrics Conference can stay an extra day to participate in a free educational training program called "Preparing for the Future: Alzheimer's Disease & Related Dementias." Presented by the UNE Maine Geriatric Education Center, the program is funded with a grant from the U.S. Department of Health and Human Services Health Resources and Services Administration. To register, visit http://www.une.edu/com/cme/
For a full listing of Maine Geriatrics Conference workshops and exhibitors, or to register, visit the UNE Continuing Medical Education website at http://www.une.edu/com/cme/


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I have actually always wanted an albero di natale for my home. I love the concept of setting a manger scene under the tree as well as loading the evergreen with angels that rise to the top resulting in a big, shining superstar. It makes the ideal portrayal of the vacation party and an Angel Xmas tree actually helps us focus on the suggestion behind the party as well.
I'm quite old-fashioned when it pertains to this vacation yet several could still take pleasure in an angel Xmas tree without leaning in the direction of a particularly religious style. These attractive objects are excellent for any holiday event not basically for those of us that wish to keep the definition of the vacation traditional for our households.
There is a significant obstacle to developing such a display. Numerous people have emotional personalized Xmas accessories that indicate the world to us. I despise to put them aside to create an angel Xmas tree style. These ornaments are necessary due to the fact that they represent really special times in our lives and I don't intend to leave them in the box.
My spouse and I created a solution to the problem. We had a couple of alternatives that I will certainly share in instance you are torn in between producing an angel Xmas tree and also using your personalized ornaments also. These are basic and also you might find that you truly like the concept of showcasing your emotional embellishments separately from the angel motif tree.
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COLUMBUS, Ohio — When star quarterback Braxton Miller cried out in pain and crumpled to the ground during No. 5 Ohio State's practice on Monday, coach Urban Meyer wasn't certain what had happened.
"Oh, it was devastating. It was a bad deal," Meyer said glumly on Wednesday. "First of all, I didn't see exactly what happened and I thought someone hit him. I went berserk, saying, 'What happened?' (The coaches) looked at me and I said, 'No one hit him?' "
No, no one tackled or was even rushing the two-time Big Ten player of the year and Heisman Trophy candidate. Still coming back slowly from February surgery on his right shoulder, it took just a 7-yard pass — with no one around — to sideline Miller for the season. This time, he had sustained a torn labrum.
Rabid Buckeyes fans have had a mournful look on their faces ever since word leaked out about Miller's injury.
The Buckeyes will get through it by replacing Miller — with 8,346 yards of total offense and 84 passing and running touchdowns in his Ohio State career — with redshirt freshman J.T. Barrett, who has never taken a snap in a college game.
Barrett has the backing of his teammates.
"He's very focused," linebacker Curtis Grant said. "He's a very mature kid. He's going to be fine. He just has to get his rhythm down with everybody and keep going forward."
Player dies at 21: Kent State football player Jason Bitsko, who was slated to start at center for the Golden Flashes this season, died Wednesday.
Police believe he passed away from an undetermined medical issue, the school said. The school said in a release the 21-year-old Bitsko was found unresponsive in the bedroom of his off-campus apartment shortly before 9 a.m.
When Bitsko failed to show up at practice, calls were placed to Bitsko's roommate, who called 911 after finding Bitsko in his bed. Brimfield Police arrived on the scene within three minutes of the call.
The school said it is providing counseling services and support to student-athletes and athletic staff members to cope with the tragedy.
Teams will play in 2020, 2021: Michigan and Washington have decided to renew their rivalry.
The Wolverines will play the Huskies in Seattle in 2020 and will host them at the Big House in Ann Arbor the next year.
The agreement announced Wednesday by both schools marks their fifth home-and-home series. They have also played each other in the Rose Bowl four times.
Michigan leads the all-time series 7-5 and won the last matchup in 2002 on Philip Brabbs' 44-yard field goal as time expired.
Swilling denied waiver to play: The NCAA denied former Tulsa basketball player Patrick Swilling's request for a progress-toward-degree waiver to play football based on academic eligibility.
Tulsa made the announcement Wednesday.
Swilling was accused of sexual assault earlier this year, but no charges were filed. He was suspended from the basketball team in February and did not play again. The university eventually cleared him of any violations of the student code of conduct. The student involved in the assault accusation is suing Tulsa for failing to protect her.
Swilling averaged 8.6 points per game for the Tulsa basketball team last season. His father, Pat, is a former All-Pro linebacker who played with the Saints from 1986-92.


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THQ's Troubles Could Be Bad For All Of Us
THQ might be in trouble. Then again, THQ might not be in trouble. THQ might just be coasting along, for all I know – I'm not privy to their latest financial forecasts. Yet.
But word has spread over the weekend that the company may well be 'not doing that well'. Rumours of a dropped MMO, a slate for 2014 cleared and the company offering its services for sale to Asian firms.
The company came in to deny things, if only slightly and not entirely, and it hasn't really stopped the speculation. Is THQ on the ropes? I don't know. But I hope not.
Even though this is the company that killed Red Faction, even though it's the company that thought the MX vs ATV: Alive business model was a good idea, even though this is the publisher that releases the greatest example of diminishing returns I've ever seen in the shape of the Smackdown/WWE series – even though they're perennial cock-up merchants, at least in 2011, I wish the publisher nothing but well.
That might be slight insanity on my part, but there is some logic at work. THQ is a publisher that encourages creativity and is willing to experiment. Yes, Homefront was just another militaristic manshooter, but it was new IP. Yes, Red Faction Armageddon was (in the main part) a pile of pump, but it was mixing things up in an established franchise. Yes, WWE '12 turned out to be a pile of half-truths and broken physics, but at least… actually, no. That one was just poor.
But THQ is a publisher that allows its devs to make things like Saints Row The Third. It's a publisher that hires Guillermo del Toro and lets him loose, free to create what he wants. It's a publisher that sticks with a shooter based on a fairly obscure Russian post-apocalyptic literary series. It openly makes a statement it is dropping its licensed output – something THQ was commonly mocked for during my youth – and focusing more on original ideas and establishing new series.
Regardless of quality, that's the kind of thinking I can get behind. And that's why I wish nothing but good things for THQ in the future. Unless it goes evil, in which case I will retract that statement.
I was sat in a presentation this time last year – it was in New York, but frankly it could have been anywhere in the world such was the dark warehouse location of said presentation – in which Danny Bilson revealed the new logo for THQ. On revealing it, he pointed out what he thought 'THQ' stood for: "THe Quality".
Yes, that is true.
Yes, we – the British contingent – had to stifle some pretty massive giggles.
But Bilson seems to be a man who truly believes these sorts of things. He seemed to truly believe what he said; he seems to truly believe that THQ – 'THe Quality' – is home to some great games that will do well. He truly believes a slow and steady pursuit of establishing new IPs and focusing on creativity will reap rewards. He truly believes all of this.
And if there's one thing I know, regardless of what you think about THQ's output: you never write off a true believer.
Similar posts
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Will PlayStation 4 Bring About The Death Of The 'AA' Game? »
Darksiders: The Overlooked Gem »
THQ: How To Save The Business »
Publishers: Please Be Quiet »
Red Faction Armageddon: "One Flaw Was Interference" – Ex-Volition Staffer »
Homefront 2 Has Killed Timesplitters »
THQ Drops MX vs ATV For Obvious Reasons »


text:
Droplet Like It's Hot
Wednesday, December 11, 2013 from 6:00 PM to 11:30 PM (PST)
Who's Going
San Francisco, California
London, United Kingdom
Florence, Italy
Event Details
Since the first Droplet was spun up, we have been dedicated to creating the ideal environment for developers. Sponsoring the Node Summit was our little way of reinforcing our support for the javascript community, and your support of us has been essential to our success.
To show our appreciation, DigitalOcean will be hosting a party at Rosewood Bar in San Francisco exactly one week after Node Summit 2013. This is an exclusive event with a guest list of only 100 people, meant for our closest friends and dearest customers.
There will be an open bar, delicious hors d'oeuvres, and the best of company. The dress code is sohpisticated developer - what others may call their "best hoodie". Each attendee has a +1 of their choosing.
We look forward to seeing you and celebrating all of the exciting things happening within the community.
When & Where
Rosewood Bar
732 Broadway Street
San Francisco,
Wednesday, December 11, 2013 from 6:00 PM to 11:30 PM (PST)
Add to my calendar
DigitalOcean is a simple cloud hosting provider built for developers. Easily deploy a working SSD cloud server with a dedicated IP in less than 55 seconds. DigitalOcean has an active community where developers can openly communicate within a Q&A forum, chat room, and tutorials. The DigitalOcean team graduated in 2012 from the TechStars accelerator program in Boulder, CO. Since graduating, DigitalOcean has been experiencing serious traction and growth with over 200,000 virtual servers launched since inception. DigitalOcean has been featured on Forbes, TechCrunch, PandoDaily, and TheNextWeb.


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Bigger and better than ever, MatzoBall, the nations leading Jewish single's event, kicks off its 30th year with an unforgettable Jewcy adventure. With almost three decades of experience, nobody can do it bigger or better than Matzoball and this year will prove to be no different. Matzoball sets the stage for the ultimate party experience that you do not want to miss out on!!
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If an item you ordered from TextbookRush does not meet your expectations due to an error on our part, simply fill out a return request and then return it by mail within 30 days of ordering it for a full refund of item cost.
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Description: Many pastors find it easier to preach on the New Testament than the Old Testament, with its powerful and often shocking narrative, prophetic warnings and calls to holiness. For many preachers seeking to make the Bible relevant, it's far easier--and safer--to stay out of the woods and plow the well-worn fields of the newer canon.Preaching the Old Testament equips pastors to journey into the forest and find a passion and confidence for preaching on the Old Testament. This book helps them keep up on their Hebrew, understand the themes of the Old Testament, and unpack Jesus' foundational text to take their congregations to a deeper understanding of Christ himself.
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Welcome to the New Zealand Parachute Industry
Association's Website
Initial Issue Certificates
Temporary Certificate
Commercial Certificate
Ratings & Courses
Drop Pilots
As of 01 January 2017, the NZPIA no longer issues plastic certificate cards. New certificates are issued in PDF, and are also downloadable to a PC or smart phone, as a PDF or Apple Wallet pass, from the certificate holder's account page on this website. Certificates have a QR code so drop zone operators anywhere in the world can verify their authenticity. The downloadable certificate will also be made available to all current affiliated certificate holders in the coming months. This is a work in progress, though, so please be patient. Check your account page to see if this is available to you, and contact the NZPIA if you need this urgently. The option of a physical card is still available, but as we have to outsource the card production, there will be an extra charge of $25.
The NZPIA standards and procedures review has been completed, and we are in the process of finalising the manual amendments. The updated Documents, Standards and Procedures Manual will be published in mid-2017.
There is now a Comments/Suggestion Form available for download from the All Docs and Forms page. Not all comments/suggestions will be actioned but all will be given due consideration; if an action is practical and supported industry-wide, we will do our best to address it. All un-actioned submissions will be kept on file and reviewed periodically for possible action in future. Please note this is the only acceptable format for suggestions for changes to our approved procedures.


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SpacePilot PRO
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The challenges for today's CAD-intensive business are many.
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What is JotForm?
JotForm is a free online form builder which helps you create online forms without writing a single line of code. No sign-up required.
At JotForm, we want to make sure that you're getting the online form builder help that you need. Our friendly customer support team is available 24/7.
We believe that if one user has a question, there could be more users who may have the same question. This is why many of our support forum threads are public and available to be searched and viewed. If you'd like help immediately, feel free to search for a similar question, or submit your question or concern.
Create two column formAsked by dominologic on May 21, 2014 at 11:37 PM
JotForm Support
Hello dominologic,
Do you want to make your form "Get Estimate" in two columns?
You can take advantage of our "Shrink" feature to position your form field in such a way that it makes a two column form. The following guide should help you: http://www.jotform.com/help/90-Form-Field-Positioning
It is also possible to inject custom css code in your form to change the position of your form field and place them as desired.
Please take a look at the following cloned form where I have used shrink feature to reposition the fields: http://form.jotform.me/form/41411442270441? There are some alignment problem which can be resolved by injecting some custom css code. If this form looks good to you, we will make the further changes. Do get back to us if you need any other changes.
We will wait for your response.
Thank you!


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If you have never had a credit card, you probably have no or little credit history, and offers most suitable for you can be found on the page with credit cards for no credit.
A good option for someone establishing credit history is a secured credit card. There is a cash deposit required for approval, it serves as a guarantee that the bank gets repaid, and the credit line often equals this deposit. As a rule secured cards are less expensive and have lower interest rates compared to unsecured credit cards for no credit. No credit check is a common policy for secured credit cards as well, and this is a great benefit for people with limited history.
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And remember that it starts with choosing the right credit card and then continues with the wise management of it. Making payments on time and staying below credit limits are essential if you intend to establish good credit history.
Other Popular No Credit Card FAQs
Store credit cards are not easier to get than traditional credit cards. The important factor is when you apply for a card make sure you apply for one that has criteria that fits your creditworthiness. Store credit cards will generally not approve those with bad credit. If you have bad credit or your credit is […]Continue »
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You can apply for a credit card or for a loan. If you have never had a credit card or a loan, look at the credit cards for people with no or limited credit. You can also use our card match tool to see credit cards you can apply. You may need an active bank […]Continue »
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