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uğur akın
Why does not mature neurons duplicate themselves? can anybody explain me?
William Gunn
William Gunn uğur, I think it might be easier for someone to provide a response if they knew how much you already understand about cellular response to injury. Perhaps you could fill out your Mendeley profile with more details, such as where you go to school (if you do) and what you have published?
21st January
Cell Press
Cell Press added a document to this group
Sri Narasimhan
Sri Narasimhan This study by Hsiao, Mazmanian and colleagues (FREE paper @ http://ow.ly/rw3eF) identifies gastrointestinal and behavioral abnormalities in the offspring of mice with maternal immune activation (MIA). An imbalance of the gut microbiome is thought to be the driving factor for some of these abnormalities. Remarkably, oral treatment with Bacteroides f...
6th December
Martin Canizales
Martin Canizales The effect of the microbiota increased PI3K pathway activity in the moderate lead to abnormal physiological bechavioral and autistic disorder. This is a good document that informs the principal protein in autism is not absent due to mutation or deletion but by defects or in signaling pathways that are restored by changes in the microbiota in the sa...
7th December
Hameed Aslam
Hameed Aslam Hello,
Happy Christmas & New year God Bless All
I'm a journalist & Media person to identify why the world is not peaceful and unity among all the communities. Jewish, Christians & Muslims of the world are following prophet Abraham, but we are not co-operating with each others. God created trouble with each other to fight...
25th December
Niaz Oliazadeh
did any body read this paper? its amazing work, how can we add it to the discussion?
"Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects on Development"
Ruben Drews
The KSR2-paper is a great piece of work, covering different levels of scientific research: from different biochemical research approaches, via the extensive work with mice to humans. Especially the investigation of KSR2-mutations among affected family members and their subsequent medical examination (BMR, RQ, heart-rate...) was surprisingly exciting for me. Altough the anecdode with metformin wasn't solved entirely, it gave me a good forecast of what may come.

Though two questions concerns me:
1.) I didn't understand how exactly the cases and the controls are composed? Is it like this:
Cases = 1,770 (from GOOS) + 331 (WES from GOOS) + 238 (replication of GOOS) = 2,339? From these 2,101 have a severe obesity?
Controls = 1,536 (from ELY) + 1,117 (replicates from ELY) = 2,653? And from these 1,353 controls are nonobese?

2) What is the sensitivity of the test for the KSR2 mutations within the two cohorts?
The p-value of 0.036 could be easily become non-significant if only one out of 1,350 more nonobese control would carry said mutation (for 4 nonobese: p-value = 0.072).

Thanks in advance!
Neli Atanassova
Neli Atanassova Thank you Ruben,
1. The total number of GOOS cases (all of whom have severe obesity) studied was 1770 (by Sanger sequencing) + 331 by whole exome sequencing + 238 by whole exome sequencing (in the replication set). Total = 2339 cases.
We compared the data to 1536 controls (Ely study) + 1117 (different controls in the replication set) = 2653 c...
2nd December
Cell Press
Cell Press added a document to this group
Robert Kruger and Mirna Kvajo like this.
Robert Kruger
Robert Kruger Your question is a good one and certainly something that we are thinking about as this group gets off the ground. One thing we tested out with the latest issue came was to mention the discussion group in the email alert. We are considering other ways to spread the word. What do you think would be the most effective way to get interested readers ...
25th November
Mirna Kvajo
Mirna Kvajo Hi everyone!
To start off the discussion I’ll ask a question that is likely on the minds of many people that heard this story. The authors show that in flies olfaction can influence the function of the blood and immune systems. Is there any evidence that something similar may be happening in vertebrates? Can the authors speculate about the possible...
27th November
Ruben Drews
Ruben Drews Hi guys, what do you think of a multichannel approach? So maybe a Facebook campagn ("Cell goes Mendeley"?!) combined with a Website Banner, this email alert and Twitter. So you may reach two important groups: the casual scientific reader (undergrads, interested people...) and the scientists.
Especially for students (which may not have an email aler...
28th November
Michael Urzo
I'm just a bit curious if there's a known cause why mutation occurs in the KSR2, and could this mutation be presnt in all individuals exhibiting obesity and diabetes.
Robert Kruger likes this.
Neli Atanassova
Neli Atanassova KSR2 mutations are present only in proportion of patients with obesity. There is no inherent reason in the KSR2 sequence to suggest higher mutation rate.
22nd November
Marta Murcia
I have a quick question for the more avid Mendeley users in the group. Is there any way to set things up so that any time a paper is posted an automatic alert is sent to one's email? Thanks in advance.
Robert Kruger
Robert Kruger Good suggestion! I don't know, but will find out. Someone chime in here if you know the answer
20th November
Cell Press
Cell Press Hi Marta, great question. On the top-right corner of your Mendeley window, click on the "My Account" box. A dropdown menu will appear. Select "Account Details" in that menu. A window titled "My Account" will appear. In that window, select the "Notifications" tab and then check the box under the "Someone posts an update or a comment in a group" entr...
20th November
Marta Murcia
Marta Murcia Hi Robert and Cell Press. Thank you for your comments. I have followed the instructions from Cell Press and should be all set now. (This particular notification setting was not a default setting.) Thanks again
21st November
Marta Murcia
The authors elaborated on the therapeutic potential of AMPK activation to ameliorate the effects of KSR2 mutations on substrate utilization. Could they comment a bit more on the potential use of strategies, if any, to manipulate the Raf-MEK-ERK pathway to help rescue KSR2 loss of activity? Would ERK be the preferred candidate for such approached? Also, I was curious to know if the authors have any data on mutations leading to overly active KSR2 and potential phenotypes associated with those. Thanks
Robert Kruger likes this.
Neli Atanassova
Neli Atanassova Modification of ERK signalling is unlikely to be the preferred candidate because it has been demonstrated that disrupting the interaction of KSR2 and ERK does not alter the biological action of KSR2 in transfected cells (Fernandez et al, 2013). We haven’t found mutations leading to overly active KSR2 – these would be predicted to lead to leanness.
22nd November
Gianpaolo Rando
Just wondering if any of the identified KSR2 mutations is currently genotyped by 23andMe. If so, you may be able to get access to an even wider population.
Neli Atanassova
Neli Atanassova A small proportion of the rare KSR2 variants identified in our study were found in the control individuals we screened, so it is possible that other sequencing efforts (including 23andme) may yield variants. The challenge is whether there is consent to recruit these individuals for additional studies on the basis of genotype. This may be possible i...
16th November
Adrian Sim
This paper is a nice piece of work that extensively cover the mechanisms, genetics, mice work and human samples! The authors had painfully ensure that the various ways of measuring metabolism was carried out. The clinical observation of metformin treatment was a nice cherry on top. And i will be waiting eagerly for any study that comes out of that treatment.

I am just curious about a few things.
1. It was stated that the "KSR2 protein is detectable by western blot only in the brain". It seemed interesting and I was wondering if the authors had tried doing the same experiments they did on HEK293 and Cos7 cells in neuronal cells such as SK-N-SH or SH-SY5Y. Just curious. I do understand that such cells are difficult to work with.

2. Do the authors think that there is an interplay between the mechanism that they showed with the much talked about gut microbiome? Like the one stated in Ridaura et al., 2013 (Science 341:p1241214) where it would seem that gut microbiome plays a important role in metabolism.
Neli Atanassova
Neli Atanassova Thank you, Adrian.
1. We did not use any neuronal cell lines in our experiments because they endogenously express KSR2 and so it would have been difficult to investigate the effects of KSR2 mutations. However, we are planning to try NG108-15 and SH-SY5Y cells in planned studies that address the effect of KSR2 on cell signalling.
2. Studies on the g...
13th November
Adrian Sim
Adrian Sim Dear Neil, Thank you for the reply. Nice piece of work! Will await eagerly on any further development on this piece of work.
14th November
Cell Press
Cell Press added a document to this group
Robert Kruger and Mirna Kvajo like this.
Robert Kruger
Robert Kruger This study reports mutations linked to energy intake, metabolic rate, and obesity in humans---you might have seen it in the news (e.g. http://www.bbc.co.uk/news/health-24610296 . Here's the link to access the paper directly from Cell: http://www.cell.com/fulltext/S0092-8674(13)01276-2 . Neli Atanassova, lead author on the study, will be taking p...
12th November
Adrian Sim
This paper is extremely interesting. The number of samples that the group plough through is very labour intensive but important. The study is significant as it also looked into various types of cancer and not just a single type of malignancies. It also point out that the extra chromosome is not necessary a silent bystander. Wonderful piece of work!
Michael Urzo and Robert Kruger like this.
Roland Eils
Roland Eils Thanks, Adrian, for this supportive comment!
11th November
Michael Urzo
Hypermutation in the Xi is indeed a very revolutionizing discovery in cancer treatment and therapy. I'm just wondering, is there any known mechanism why this mutations seem to exist and why it exist in Xi? Why hypermutation is very prominent in the Xi and not in other autosomes? If mutation already occurred, can this still be reversed in order to cure cancer? Can you tell me what is the significance of this research? I also noticed that there is a significant alteration of cytosine to thymine in all types of cancer presented, have you already explore this area on why this mutation occurs? Thanks in advance, kudos for a very interesting research.
Robert Kruger likes this.
Roland Eils
Roland Eils Michael, the mechanism we believe accounts for Xi hypermutation is DNA replication stress. Xi is the latest replicating chromosome and it also replicates with double the speed compared to the other chromosomes. Thus, we believe mutation occuring on Xi cannot as efficiently repaired as on the autosomes. Interestingly, we see a somewhat different eff...
11th November
Marta Murcia
Heads up to all group members. Yesterday, I logged in and wrote my comment under the Dashboard tab without realizing that for it to show in this feed I should have posted it here, under the Groups tab and then clicking Cell Press: Latest Research. Just wanted to share this with the group in case someone has had the same issue.
Robert Kruger and Cell Press like this.
Cell Press
Cell Press Thanks for the heads up, Marta!
9th November
Marta Murcia
I wonder if the authors could briefly comment on their plans to explore the clinical significance of these findings. Could the hypermutation of the Xi chromosome become a biomarker of replication stress, stage of evolution, and/or aggressiveness of the tumor type in female patients? How can these findings aid ongoing therapy development efforts targeting the replication stress–signaling pathways? Thank you much.
Robert Kruger likes this.
Roland Eils
Roland Eils X chromosome hypermutation could indeed become a biomarker of
replication stress, but so far, we have no data to support that it could
also be a marker of aggressiveness of the tumor type.We checked all obvious pathological and clinical parameters but there was no obvious correlation with e.g. tumor stage, survival etc. I believe that the major con...
10th November
Marta Murcia
Marta Murcia Thank you!
11th November
David Wiener
I think that paper shows an important pattern for women cancers, it will be intriguing to know if these affect for activation of particular oncogenes especially on the late replicating zones. I wonder if you have looked differences between the genomes who has an X hypermutation and the other who do not have, it appears a particular difference in a mutated gene ?, or within the samples with X hypermutation appears some particular gene related with DNA repair affected?.
Robert Kruger likes this.
Roland Eils
Roland Eils We have looked into the differences between different female cancer genomes. Apparently, there does not seem to be any particular mutated gene or (DNA repair) pathway common to only
X-hypermutated cases. In many female cases without X hypermutation, the
inactive X chromosome was lost in the cancer, thus no X chromosome
hypermutation appeared. This ...
10th November
David Wiener
David Wiener Thanks for your answer.
Related with the loss of chromosome X in patients without X hypermutation, have you looked if these phenomena also occurs on similar rate in the late replication regions of autosomes?
10th November
Roland Eils
Roland Eils I am not quite sure whether I understood your question correctly. We looked into the correlation of replication timing and hypermutation. Indeed, we find that all regions on autosomes that are hypermutated are also late replicating. However, the opposite does not hold true. There are many regions that are late replicating but not hypermutated. Whet...
11th November
Laurie Herviou
I think that the paper from Jager et al. is really interesting and rich in term of the amount of samples studied and tested. My first question is : Do you think that, being an early event in tumorigenesis, hypermutation of Xi is essential for tumor progression or treatment resistance in female patients (in cancers that have this feature)? Even if the regions that are mutated are not transcribed?
My second question is : Do you think that this hypermutation feature on Xi could alter XIST recruitment and thus lead to a reactivation of Xi in cancers?
Roland Eils
Roland Eils We don't think that hypermutation is essential for tumor progression or treatment resistance in female patients. Note that we have observed X hypermutation in essentially all female tumors, however, we could not observe any correlation between X hypermutation and diagnosis or clinical outcome. Further, as you already noted, the inactive X chromosom...
6th November
Robert Kruger
Robert Kruger That will definitely be interesting to probe further. I'm curious if the frequency of mutation on the inactive X is higher than in autosomal regions with low transcriptional activity or is it similar?
8th November
Natalie Jaeger
Natalie Jaeger Regarding the transcriptional activity, we haven't analyzed this in full detail, however, the mutations on the inactive X are mainly intergenic, i.e. basically no transcriptional activity in these regions, thus lack of transcrition-coupled repair should not explain X hypermutation.
Some autosomal regions, which are late-replicating (and hence also ...
8th November
David Wiener
The paper is intriguing especially by the issue related with the difficulty to cure the HIV infection. I was wondering if the place where the HIV genes are inserted in the human genome can affect the reactivation of the LR viruses. And if where the virus is inserted affects the kind of mutations?
Robert Kruger and John Davies like this.
Robert Siliciano
Robert Siliciano The integration sites definately affect reactivation. HIV normally intergrates within active host genes and thus behaves as a gene within a gene. Transcription of the host gene can interfere with HIV gene expression. The defects in the HIV genome arise during reverse transcription prior to integration.
6th November
Ruben Drews
The paper from Ho et al. is great! Especially the wet-lab intensive derivation of their conclusions is remarkable.
Since they showed that both the VOA and the new VOA (Laird et al. 2013) are not capable of estimating the correct LR size I'm wondering whether this has or will have any real life impact of HIV / AIDS diagnoses or treatments?
My other thought was if culture assays seem to fail are there any other alternatives published?
Robert Kruger likes this.
Robert Siliciano
Robert Siliciano Measuring the reservoir is really important only for patients who are participating in clinical trials of eradication strategies. We clearly need new and better ways to do this. The NIH is encouraging research on new ways to measure the reservoir.
6th November
Michael Urzo
With regards to the first article posted, all I can say is that this journal article is very interesting. My question is that, is it feasible if targeting this latent provirus within the human genome be a possible cure for HIV-1 and possibly eradicate the disease in the future? Is there any possible mean (Example: induced mutation or permanent deactivation) to permanently damage the provirus and have it deactivated so that even T Cells were reactivated the virus is not thereby inhibiting the recurrence of the disease?
Robert Kruger likes this.
Robert Siliciano
Robert Siliciano There is now exciting research on a type of engineered nuclease enzymes that can specifically detect and inactivate the provirus. The problem with this approach is figuring out how to deliver the enzyme into every infected cell in the body.
6th November
Michael Urzo
Michael Urzo Sir, can you tell me what are the current mechanisms beingstudied in delivering this nuclease enzyme? My suggestion would be exploiting the properties of nanocrystals like gold nanoparticles. Can this enzyme be modified in such a way that it will automatically attack only the infected cells thereby allowing us to just inject the nuclease enzymes?
7th November

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