Gene Therapy Trials With Nrtn And Gdnf
In contrast to the immense logistical challenges and potential safety concerns associated with continuous or repeated long-term delivery of recombinant GDNF protein, gene therapy promises sustained, durable and localized production of properly folded biologically active GDNF following a one-time dosing procedure. Several clinical studies have now been conducted in PD, including a multi-phase program of NRTN gene transfer, a homolog of GDNF, and more recently a Phase 1 clinical safety trial of GDNF gene transfer. Both the NRTN and GDNF gene therapy programs utilized gene transfer vectors derived from the non-pathogenic adeno-associated virus serotype 2 with a constitutive CMV promoter. These vectors appear to have a favourable safety profile for neurotrophic factor gene delivery in PD, in addition to which AAV2 has an exclusive neuronal tropism and restricted distribution when directly delivered to the brain , thus minimising off target side effects.
Several key changes were made as part of the AAV2-GDNF Phase 1 study design compared to prior direct infusion studies in PD conducted in the early 2000s, including:
Fig.1
Structure And Physiological Function Of The Miro1 Protein
In mammals, two Miro GTPases, named as Miro1 and Miro2, are encoded by the RHOT1 and RHOT2 genes located on chromosome 17. Miro1 and Miro2 are both ubiquitously expressed, consisting of 662 amino acid residues, and display a 60% peptide sequence homology . Miro GTPases are conserved in almost all eukaryotes containing mitochondria , and they were first considered as atypical members of the RAS superfamily of GTPases, particularly as two of the 23 members of the RHO protein subfamily .
However, in contrast to other RHO family members, Miro GTPases contain no C-terminal cysteine and they also lack the typical RHO insert, which led to their classification as a definite subfamily of small GTPases .
Structurally distinct N-terminal and C-terminal GTP-binding motifs are present in both Miro proteins, with a linker region connecting two EF-hand domains to the C-terminal GTPase domain .
Further reinforcing this hypothesis, only mutations in the N-terminal GTPase domain led to the disruption of the mitochondrial network in mammalian cells . Moreover, recent work developed by Kalinski et al. describes that the deacetylation of the lysine 105 on the N-terminal GTPase domain of Miro1 could inhibit mitochondrial transport in primary mouse neurons, subsequently affecting axonal growth .
Foreign Policy And National Security
In 2003, Collins voted in favor of the Iraq War Resolution authorizing President Bush to go to war against Iraq. In November 2007, she was one of four Republicans to vote for a Democratic proposal of $50 billion that would condition further spending on a timeline for withdrawing troops, mandating that a withdrawal begin 30 days after the bill was enacted as part of a goal of removing all U.S. troops in Iraq by December 15, 2008. The bill failed to get the 60 votes needed to overcome a filibuster. In April 2008, Collins and Senators Ben Nelson and Evan Bayh met with Bush’s advisor on Iraq and Afghanistan, Douglas Lute, and expressed support for a prohibition on spending for major reconstruction projects, the proposal requiring Iraqis to pay for its security forces to be trained and equipped and reimburse the American military for the estimated $153 million a month the military spent on fueling in combat operations in Iraq. Collins said after the meeting that while the administration did not have a view entirely similar to the senators’, it at least seemed open to their proposal. In June 2014, while growing violence erupted in Iraq under the leadership of Prime Minister Nouri al-Maliki, Collins said the violence would have been slower had a residual NATO force been present in Iraq and that the question was whether airstrikes were effective.
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Comparison Of Effect Size Estimates
Five gene loci where both Caucasians and Asian populations were represented showed no difference in effect size estimates that were different beyond chance . Conversely for BST1, the effects were different beyond chance for Asian and Caucasian populations with stronger genetic effects in the former.
Forest plot showing the comparison of effect of each single nucleotide polymorphism in Caucasian and Asian population
Boxes indicate the summary effect estimate. SNPs in 3 loci were monomorphic in the Asian population and thus are not included in the graph. GAK SNP showed deviation from Hardy-Weinberg equilibrium in Asian series and thus excluded from the graph.
The Initial Open Label Trials Of Intraputaminal Injections Of Gdnf Protein
To ensure that GDNF reached the DA terminal plexus within the posterior-dorsal striatum, two small open label studies evaluated direct-to-putamen continuous catheter infusions of GDNF . To effect continuous infusions, GDNF was administered from subcutaneous pumps placed in the abdomen connected to a single catheter to each putamen in a 5-patient cohort in Bristol, UK and to a single-sided unilateral catheter only in a 10-patient cohort studied in Kentucky, USA. The Bristol group initially reported after 6 and 12 months as did the Kentucky group . Doses in the Kentucky study were escalated to 30 g per day and in the Bristol trial, patients doses were on average 30 g per day. Some patients did receive even higher doses but this produced high signal changes on MRI in the putamenchanges which resolved with dose reduction.
Both of these small open label studies reported marked benefits in UPDRS motor scores in the practically defined OFF state with a mean reported improvement of approximately 30%40%. Changes in diary fluctuations were equally encouraging at this open-label stage although it should be noted that the changes were bilateral even in patients who had been in receipt of unilateral infusions for reasons that are not clear.
Based on these encouraging open label observations, a prospective, double-blind, placebo-controlled trial of continuously infusing GDNF to the putamen was initiated.
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Miro1 As A Regulator Of Cellular Calcium Homeostasis
Calcium ions act as important second messengers that control several cellular mechanisms. Therefore, cytosolic calcium levels need to be tightly regulated, and cells manage to maintain calcium homeostasis mainly via buffering calcium by specific organelles, such as the ER and mitochondria .
One of the main functions of Miro1 is to orchestrate calcium homeostasis in mitochondria and calcium-dependent mitochondrial positioning. To fulfill this function, calcium-binding is facilitated via both of its EF-hand domains and the C-terminal GTPase domain . Miro1 was suggested to have a high calcium-binding affinity and consequently binds calcium only upon elevation of cytosolic calcium levels .
Interestingly, Chang et al. found in 2011 that intra-mitochondrial calcium levels correlated with mitochondrial transport speed, suggesting that mitochondrial transport was not only controlled by cytosolic calcium transients but also by mitochondrial matrix calcium levels . Furthermore, primary mouse neurons overexpressing Miro1 with calcium-insensitive EF-hand domains showed a decreased influx of calcium into the mitochondrial matrix, suggesting that Miro1 also regulates intra-mitochondrial calcium levels .
Analysis Including Only Asian Sites
In the Asian series, not only the SYT11 SNP, but also the ACMSD and MAPT SNPs were monomorphic . Summary effect estimates for the remaining SNPs are shown in . We again observed consistent nominally significant evidence of association for all loci except for STK39 and HLA-DRB5 , which still had an effect size estimate consistent with what was seen in the overall analysis. Results were generally consistent across sites, with the exception of STK39 that showed very large heterogeneity .
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I Never Saw A Survivor
Sen. Susan Collins, Republican of Maine, is renowned as a force of bipartisanship in Washington, and sometimes as a voice of reason. Introducing Collins at the Harvard Kennedy School on Thursday night, Harvard President Drew Faust characterized her as a problem-solver who can look beyond ideology. She sees her role on the Hill in terms that are becoming increasingly and unfortunately rare. Through this tumultuous and transfixing election season, she has instilled the value of treating people with respect.
Moderated by HKS Dean Douglas W. Elmendorf, the hourlong talk often brought out Collins differences with the current GOP. Yet she noted that she still sees herself as a traditional New England Republican.
I believe in the traditional values of personal responsibility, individual freedom, free markets, and a strong national defense, she said. And I believe in keeping government out of certain aspects of our lives. Today I feel that the party is in a state of chaos, but the pendulum always rights itself. And I think that sticking with the core values is the best way to make that happen.
Prior to the HKS talk, which ended her day on campus, Collins toured labs to learn more about Harvard research, meeting with Kit Parker, Tarr Family Professor of Bioengineering and Applied Physics, whose work ranges from bioengineered wound dressings to traumatic brain injury.
The winning candidate needs to work quickly to win public trust, Collins said.
Miro1 As A Regulator Of Mitochondrial
MERCs are discrete areas of proximity between mitochondria and the ER that coordinate essential physiological processes, such as lipid biosynthesis, cellular calcium handling, and mitochondrial homeostasis . These mechanisms are reported to be affected in neurodegeneration hence, MERCs are one of the most studied organelle juxtapositions and a current spotlight in PD research .
The relationship between Miro proteins and MERCs started to be investigated when, in 2011, two research groups identified Gem1p, the yeast ortholog of mammalian Miro1, as a crucial regulator of the ER-mitochondrial encounter structure , a protein complex that tethers mitochondria and ER in yeast . Association of Gem1p to ERMES controls phospholipid exchange for lipid biosynthesis between mitochondria and ER and regulates mitochondrial division and morphology . The localization of dMiro at MERCs was also demonstrated in Drosophila neural stem cells and dopaminergic neurons , as well as mammalian Miro1 in COS-7 cells, HeLa cells, MEFs, human fibroblasts, and human iPSC-derived neurons .
Moreover, based on the increased amount of overall MERCs and impaired CCCP-induced mitochondrial clearance observed in iPSC-derived Miro1-R272Q neurons, we speculate that damaged mitochondria may not uncouple from the ER, consequently hampering the initiation and flux of mitophagy .
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What Is Spasmodic Dysphonia
Spasmodic dysphonia is a medical disorder in which the voice box or larynx muscles go into periods of spasm.
When spasming, the muscles create breaks or interruptions in the voice. The sound produced can also be strained or strangled, often making one difficult to understand.
According to Johns Hopkins: Spasmodic dysphonia can cause problems ranging from trouble saying a word or two to being not able to talk at all.
It is a lifelong condition which largely affects women, with symptoms starting in your 30s.
Does Susan Collins Have Parkinson’s
Why doesn’t anyone get to the bottom of this bobble-headed bitch’s ailment already? Does she think she’s Katherine Hepburn or some shit with that ridiculous voice?
The shaking.
| reply 1 |
It is the physical manifestation of the mostly suppressed shred of decency inside of her, fighting to prevent her from being a cunt 100% of the time.
Her moral compass is wobbly.
Heavy drinker. The shaking indicates she needs a quart .. BAD.
| reply 4 |
She’s already been sexually assaulted by Kavanaugh and enjoyed his small penis. This is why she is going to vote for him.
| reply 5 |
I only know that old bag of gas has the biggest schnoz since Jimmy Durante. You could land a 777 on that grotesque snout of hers and damn she is a spineless old puss.
Spasmodic dysphonia
R4 is right. Susan Collins really LIKES BEER.
I believe she has survived a stroke or several mini-strokes.
| reply 9 |
N. It’s actually a vibrator that got lost inside her some years ago. The shaking used to be more violent, but the batteries are finally running down.
Duracell I believe.
| reply 10 |
I don’t give a shit if she has Parkinson’s. I never want to hear from her or those other two hand-wringing ‘holdouts’ again since they are going to vote in lockstep with the other Republicans for Kavanaugh. Just like they always do. Spare us your reservations next time, bitches, and just do what McConnell orders you to do. You never intended to do otherwise. You just didn’t want to seem happy to do it like the other Republican reptiles.
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Is Susan Collins Married Does She Have Children
GettySusan Collins’ husband is Thomas Daffron.
With all eyes on Susan Collins, the Maine Senator and moderate Republican whose vote will be crucial in the Brett Kavanaugh vote, some are wondering about her own family.
Is Susan Collins married? Does she have children? Susan Collins is married. She married later in life in 2012, and she does not have children. Collins is married to Thomas Daffron, who was well-known for decades in the halls of Congress, working as a chief of staff for top Republican Senators, including Alaskas Lisa Murkowski, the other moderate Republican on whose vote the Kavanaugh confirmation partly hinges.
Collins announced on Friday that she is voting yes for Kavanaughs nomination. Kavanaugh was confirmed with a vote of 50-48-1. Collins did vote to confirm Kavanaugh.
Heres what you need to know:
Characteristics Of Sites And Overall Database
Twenty-one sites contributed a total of 8,750 cases and 8,955 controls. Characteristics of all participating sites are shown in . Most sites contributed participants of Caucasian ancestry 5 sites included participants of Asian ancestry. We excluded 1 site with 114 cases and 67 controls from the analysis due to a plate layout error. The median age at onset was 59 years and median age at examination was 67 years.
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Does Susan Collins Have A Medical Condition Voice Tremors Explored
What medical condition does Susan Collins have? We explore the health of the longstanding Maine Senator.
Sen. Susan Collins, 68, has represented Maine in the Senate since 1997. She is a member of the Republican party. Collins has been re-elected to the Senate four times over the past couple of decades, in 2002, 2008, 2014, and 2020.
Collins was born on 7 December 1952 in Caribou, Maine.
Collins & Her Husband Married In 2012 When She Was 59
Collins and Daffron 2012. Their marriage occurred when Collins was already a Senator. The ceremony was performed by Rev. Dr. Thomas Bentum at Gray Memorial United Methodist Church in Caribou, Maine, according to The New York Times wedding announcement.
GettyU.S. Senators Susan Collins and Claire McCaskill , the Chairman and Ranking Member of the Senate Aging Committee studied prescription drug price gouging and released a report in 2016. Her theyre with then-President Obama
Collins was 59 at the time. Hillary Clinton held a women-only dinner at her house for Collins that The Washington Post dubbed a bachelorette party. The wedding was described by The Post as a small family wedding.
Collins is the daughter of a former Maine state senator named Donald F. Collins, and his wife, Patricia M. Collins, who served as mayor of Caribou, Maine. It was Daffrons second marriage.
According to Bloomberg, Thomas Daffron served as the Chief Operating Officer of Jefferson Consulting Group, LLC since September 2006. Mr. Daffron oversaw Jefferson Consulting Groups administrative and financial functions as well as the day-to-day operations of the firm.
According to Bloomberg, Daffron once worked for Democratic Arizona Rep. Morris Udall and was a speech writer for Illinois Senator Charles Percy, a Republican.
GettySusan Collins and Brett Kavanaugh
GettySusan Collins is one of two pro-choice Republicans in the Senate.
You can see the lobbying profile for the Jefferson firm here.
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Collins: Trump ‘encouraged’ New Health Care Deal
Collins said that she was stopped everywhere she went in Maine over the past few weeks, saying most wanted her to stay in the Senate.
The people who argued for me to stay in the Senate told me that they felt I was playing such a vital role right now and the times were so tumultuous an contentious that they were worried if I were to leave that the center would sink, Collins said.
At Mass on Saturday, the day after she announced her decision, people stopped her on her walk back to her seat after Communion to thank her. That was an interesting development, she said, laughing.
The women who serve in the Senate hold regular, bipartisan dinners together. While they agree to never discuss what they talk about at those dinners, two attendees admitted that all the women encouraged Collins to remain a legislator.
Were not supposed to talk about what the women talk about when the women have dinner together but we love her service here, Sen. Tammy Baldwin, D-Wisc., said laughing.
Heitkamp, the North Dakota Democrat, feels an affinity for Collins. Both are moderates, albeit from different parties, who have felt both isolated from their party and embraced by the other at times.
Heitkamp, for example, is currently being lobbied by Republicans and the White House to support tax reform, putting her at odds with her own party that remains mostly united in opposition to the Republicans tax framework.
Leigh Ann Caldwell is an NBC News correspondent.
Susan Collins First Met Her Husband Tom Daffron When She Was An Intern Years Ago
Thomas Daffron and Susan Collins go back decades as friends and, in the beginning, there was a mentorship type of situation between them. According to a story on Central Maine.com, Collins first met Tom Daffron when he hired her as an intern for former Senator Bill Cohen.
She was 21. It was 1974. According to the article Daffron acted as Collinss mentor both then and as her own political career began to ascend. Somebody once said that the best person to marry is your best friend, says Daffron to the newspaper. This evolved from a working relationship to a friendship when I was working on her campaigns and now to husband and wife.
Hes extraordinarily smart, has a wonderful sense of humor and is a great friend, Collins said to the Bangor Daily News. Those qualities matter a lot to me. Collins does not have children, and it was her first marriage at age 59. Daffron has described himself as a moderate Republican as well and most of the politicians he has worked for belonged to the GOP.
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