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Chromatin Accessibility of human mitral valves and functional assessment of MVP Risk Loci

rs6723013 is a potential causal variant at IGFBP5/TNS1 MVP-associated locus

WHAT IS KNOWN?

  1. Mitral valve prolapse (MVP) is a common valvopathy that can lead to heart failure and sudden death. However, the causes of MVP development are still poorly understood.
  2. Functional genomic studies are needed to better characterize MVP associated variants and target genes

WHAT DOES THIS STUDY ADD?

  1. We used ATAC-Seq (assay for transposes-accessible chromatin using sequencing) genomic annotation technique in combination with 4C-Seq (circular chromosome conformation capture, coupled to high-throughput sequencing), to describe unprecedented genome-wide chromatin profiles from human pathogenic and non-pathogenic mitral valves.
  2. The experiments also provided evidence for plausible causal variants for rs2641440 at SMG6/SRR locus and rs6723013 at IGFBP2/IGFBP5/TNS1 locus. In addition, we also identified several target genes including SRR, HIC1, and DPH1 at SMG6/SRR locus.

LINK TO THE ARTICLE

Kyryachenko S, Georges A, Yu M, Berrandou T, Guo L, Bruneval P, Rubio T, Gronwald J, Baraki H, Kutschka I, Aras K, Efimov IR, Norris RA, Voigt N, Bouatia-Naji N. Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci. Circ Res. 2021 Jan 28;. doi: 10.1161/CIRCRESAHA.120.317581. [Epub ahead of print] PubMed PMID: 33508947.

Catheter -integrated soft multilayer electronic arrays for multiplexed sensing and actuation during cardiac surgery

Multimodal multiplexed soft sensors and actuators for minimally invasive surgery

WHAT IS KNOWN?

  1. Catheters are widely used for minimally invasive therapies such as atrial fibrillation ablation, intravascular stents, etc. In addition, they are also used for capturing information during procedures such as measuring temperature, pressure, electrograms etc.
  2. However, these catheters are limited by mechanical rigidity, low spatial densities, single function capability necessitating use of multiple catheters to acquire critical information.

WHAT THIS STUDY ADDS?

  1. We have designed a novel flexible, stretchable and tissue conforming electronics device integrated with a balloon catheter that supports simultaneous high-density spatiotemporal mapping of temperature, pressure, and electrograms.
  2. In addition, our device allows for programmable electrical stimulation, radio frequency ablation and irreversible electroporation.
  3. This novel device, the first of its kind, anywhere in the world, will eventually enable physicians to acquire a rich set of physiological information and complete surgeries and deliver therapies in shorter times than currently possible, with a single instrumented catheter system.

LINK TO THE ARTICLE

Mengdi Han*, Lin Chen*, Kedar Aras*, Cunman Liang, Xuexian Chen, Hangbo Zhao, Kan Li, Ndeye Rokhaya Faye, Bohan Sun, Jae-Hwan Kim, Wubin Bai, Quansan Yang, Yuhang Ma, Wei Lu, Enming Song, Janice Mihyun Baek, Yujin Lee, Clifford Liu, Jeffrey B. Model, Guanjun Yang, Roozbeh Ghaffari, Yonggang Huang, Igor R. Efimov, John A. Rogers. Catheter-integrated soft multilayer electronic arrays for multiplexed sensing and actuation during cardiac surgery. Nature Biomedical Engineering (2020). https://doi.org/10.1038/s41551-020-00604-w.

Research in the time of covid-19 (part 2 of 2), July 11, 2020

The COVID-19 pandemic has created a global health emergency upending people’s lives and impacting them socially, economically in addition to being a health and human crisis. From the perspective of scientists, it has disrupted the typical functioning of academic research labs and hampered the ability to do research. For example, researchers who may have been in the process of collecting data to submit with their grant application or a manuscript for publication now could face inordinate delays. For a lucky few, this delay may be annoying but not debilitating to their academic careers. For others, this could result in the window closing on time critical experiments and needing to start all over again, if at all possible. And for the early career scientists, who are especially vulnerable with the tenure clock ticking, this delay could jeopardize their ability to secure tenure. I’d count myself as among the lucky few, who has his own funding for the next few years. In addition, I work in a lab where my mentor also has funding for the next few years. This has allowed me to stay patient and flexible with my plans, while also exploring other ways to be productive. 

As mentioned in an earlier blog post, I have been focused on the major K99 deliverables that include Postdoctoral Training, K99 Research Project, R01 Grant Preparation, Manuscript Publications, and Tenure Track Faculty Job Search. With COVID-19 pandemic, my planned approach for each of the deliverables has changed as follows:

  1. Postdoctoral Training: Over the next year or so, I am hoping to pick up skills in bioinformatics and adipose tissue biology to complement my cardiac electrophysiology and scientific computing & visualization background. The pre-covid19 plan was to spend 4-6 months in each of two mentors’ labs (Bioinformatics: Prof Crandall, Adipose Biology: Prof Li) and learn from them. However, with university and lab closures, the timeline has been delayed. But rather than wait for the labs to open back up, I have been attending online seminars, watching and/or reading online tutorials, textbooks and current literature to get conceptual and theoretical knowledge of these skills. Obviously, this approach is not ideal or perfect, and no substitute for hands on learning. But my hope is that when things open back up, I can use the conceptual knowledge gained now to accelerate the learning in the labs. Current Risk Level: Moderate
  2. K99 Research Project: The pre-covid19 plan was to conduct experiments and generate enough data for validating research hypotheses and eventually publish the results as journal papers. With Covid-19, there has been a delay of at least 4 months, which while concerning has not been debilitating, yet. With the labs opening slowly and in phases, I have been able to restart my experiments, albeit at a slow rate. If things continue to improve, I am cautiously optimistic that the delay will be overcome, and I will get back on track with my project timeline. On the other hand, if the Covid-19 pandemic worsens, it could elevate the risk level for this deliverable. Current Risk Level: Moderate.
  3. R01 Grant Preparation: I will be expected to submit a R01 grant application during my 3rd year of the award, at the earliest, giving me 3 years to prepare the application. As such there is no time sensitive work that needs to be accomplished immediately. Even so, my approach has been to do copious amounts of reading including current literature and attend online seminars and presentations to formulate and flesh out new grant ideas.  Pre-covid19, I would be inclined to attend more conferences in person and talk to resident experts and explore opportunities for future collaborations. This would also be in conjunction with doing proof of concept experiments to gather preliminary data for grant applications. With Covid-19, these activities are on hold. But there is still time and I don’t necessarily feel the pressure to try and force the issue. At this time, I am mostly engaged in lot of reading and thought experiments. Current Risk Level: Mild.
  4. Manuscript Publications: The pre-Covid19 plan was to design and conduct experiments, process and analyze data, present results at conferences and publish findings in peer reviewed journals. Rinse and Repeat. With Covid-19 the inability to conduct experiments has put a damper on this process. Thankfully, there are projects in the pipeline where data was already collected, and I was in the various stages of data processing and analysis, or manuscript preparation and revision. These tasks can still continue, and I have been busy on this front. I am hoping by the time these projects are completed and the findings published, the university and the labs will open up for normal function and I will be able to restart experiments on new projects and repopulate my projects pipeline for the future. Current Risk Level: Mild
  5. Tenure Track Faculty Job Search: Professional networking is a never-ending process. Typically, you meet people at scientific conferences and/or put the word out through your professional networking channels that you are looking for a faculty position in the near future. The best time to look for a job is when you already are employed. Even so, finding the right opportunity is a matter of timing and serendipity. Thankfully, I have couple of years to find a TT faculty position. The COVID-19 pandemic has slowed down the professional networking process. Even so, I have used this time to refresh my social media presence and activated a passive job search process. In addition, my mentors are aware of the tentative timeline and are putting out feelers on my behalf. My role at this point is to stay prepared so that when the opportunity does arrive, I will be ready.  Current Risk Level: Mild.

At the end of the day, these plans are not set in stone. I will continually tweak them as needed until I get the expected results. The concept is similar to an airline pilot responsible for flying from one location to another. The pilot sets the initial destination coordinates and takes off. But during the flight, he/she makes continual course corrections to account for wind, turbulence, and storm patterns and eventually lands the plane safely at its destination. I intend to do the same :).

Research in the time of Covid-19 (Part I) – JUly 01, 2020

The official start date of my K99 award was May 07, 2020 and the official end date for the K99 phase of the award is April 30, 2022. As mentioned in an earlier blog post, the K99 award entails two years of additional training as a postdoctoral fellow followed by transition to a tenure track faculty position with three additional years of funding. The NIH award comes with expectations that include: One, picking up additional technical skills during the first two years of the award and Two, successfully applying for an R01 grant during the latter phase (R00) of the award. It also goes without saying that you need to be productive relative to publications throughout the duration of the award. 

Given the clearly defined NIH expectations commiserate with allocated resources, my planned approach has been twofold: First, chart out the timelines for each of the major deliverables including: Postdoctoral Training, K99 Research Project, R01 Grant Preparation, Tenure Track Faculty Job Search, and Manuscript Publications. Second, keep a daily log to track my progress relative to each of the deliverables. In addition, I also set aside time once a week to evaluate the effectiveness of my approach and make course corrections as needed. (There are lot of free online project management tools you can use to track the progress of your projects, if so inclined )

While the official notification of the award came in May, I had an inkling that my application was likely to be funded back in January, given the overall score assigned to my K99 application and the past history of applications with similar scores receiving funding. As such I had already started the planning process with the intent to hit the ground running. But as Mike Tyson once famously said, “Everybody has a plan until they get punched in the mouth.” My planning did not account for the COVID-19 pandemic. 

 It’s taken a little bit of time to assess the new reality of things and recalibrate my approach and project timelines accordingly. It is likely that there will be project delays and the research and training tasks that were straightforward pre COVID-19 will no longer be that, especially since the universities and research labs have been shut down and are only now beginning to reopen in phases. But as with life, we make do with what we have. The key is to stay nimble and be flexible without losing sight of the overall aim and objective. 

My story: not winning the aha early career award (ECA)… well, not yet :) (June 21, 2020)

I had mentioned during my earlier posts on winning the K99/R00 award that I had a plan B in motion in case I did not get the award. That plan B was applying for the AHA early career award (ECA). The award is designed to fund new faculty appointments (assistant professors) for 3 years. It is equivalent to the R00 phase of the K award, although with a little less money available for research. Even so, getting the AHA ECA is pretty impressive and can fast track your research career.

You would assume that if my plan B was the AHA ECA, I would be fairly confident about getting the award. Well, you would assume wrong :). To put it mildly, I have not had much success with AHA. I have applied for AHA postdoctoral fellowships three different times and gotten rejected every time. The only reason I considered AHA ECA as plan B was the timeline. The K99 application deadline was earlier (July 2019) than the AHA ECA application deadline (Oct 2019).

The documentation required for the AHA ECA is fairly similar to that required for the K99 application. Even so, there are a few things unique to the AHA ECA. First, unlike the K99 award which is given to postdocs, the AHA ECA requires the applicant to be in an independent faculty position (e.g., research assistant professor or such) to be eligible for the award. Second, unlike the K99 award, where the training component is extensive with university courses, lab training etc. , the AHA ECA training focuses primarily on training needed as a research faculty. In other words, its more about how you are going to secure resources to help with your research (e.g., through mentors etc.,). Third, while the K99 application assigns equal weightage to the 5 criteria: candidacy, career development and training plan, research plan, mentors, and environment, my sense is that the AHA ECA assigns a lot more weight to the research plan compared to the other criteria.

I will admit that when I submitted the AHA application I was still recovering from the K99 application submission fatigue as well as adjusting to the life as a father to a beautiful boy. As it was, I repackaged my K99 application for AHA but did not spend too much time customizing it. I would strongly recommend against this approach. While the documentation is similar, there are still enough differences in terms of content requirements that it is best to spend equal amount of time preparing the AHA application as you would a K99 application.

The application was submitted in Oct 2019 and the results were out in June 2020. I did not get the award. To be honest, after finding out that I had won the K99 award, I was not really concerned about the AHA ECA results one way or other. If I had gotten the award, I would have had to decline it as the award cannot run concurrently during the K99 phase of the K-award. However, you can apply for and accept the award during the R00 phase of the K award. That said, I was curious to read the comments from reviewers. Of the 5 criteria, they thought my candidacy, mentors, career development plan, and environment were very strong or exceptional. One of the reviewers brought up the point that I was still a post doc and not an independent faculty, which could be an issue. So of the 5 criteria, I scored strong to exceptional on 4 of them. However, they found my research plan relatively weak and identified from their point of view gaps in my research design that if addressed would make the proposal strong. I am thankful for that feedback as I can now use that knowledge to strengthen my K99 research plan.

I do plan to apply for the AHA ECA in the future. However, it will be for another project as I cannot use the current project which is already funded through NIH to apply for the AHA ECA. They do not allow for double dipping, which is fair. If you have been paying attention, my current success rate with AHA remains at 0% (0/4). However, I have not given up hope yet :). I will continue to refine my grant writing skills, come up with research ideas that I think are awesome and apply again. Hopefully, the next time, I will breakthrough and get the award 🙂