Reasons You Should Meet with Your Congressional Representatives this August

congressional district mapAccording to a Pew Research Center Poll, 76% percent of Americans think that scientists act in the best interest of the public, and 67% think science has had a mostly positive effect on society.  In addition, despite recent headlines, the study shows that confidence in the scientific community has remained steady for the past 40 years.

At the same time, 70% of Americans can’t name a living scientist based on a 2013 poll conducted by Research!America.

In Congress, there is currently only one PhD level scientist, Bill Foster, a physicist representing Illinois i the House. There is one mathematician, Jerry McNerney from California, a handful of medical doctors, and a few political scientists.

Congress has several science-related policy issues on its plate including funding for science agencies, regulations and policies related to climate change, and support for renewable energy programs to name a few.

So what does this mean for you,, a practicing scientist?  It means that Congress needs to hear from you!

In particular, the Senators from your state and the Representative from your district need to hear from you. They need to know that you, a constituent, cares about these issues, that you,  your students, and your colleagues are affected by the policy choices they make in Washington, and that these choices can also affect the local economy.

They need to know that someone is watching and that someone cares.

The Biophysical Society wants to make it easy for you to connect with your elected officials.  This August, society staff will walk you through the process of setting up a meeting and preparing for that meeting.

All you have to do is sign up for the BPS Congressional District Visits program by July 26 and a BPS staff member will be in touch. You won’t have to travel far, and you can make a big difference.

Get out of the lab and be an advocate for biophysics!

 

 

 

 

Mesoscopic Adaptive Resolution Scheme toward understanding of interactions between sickle cell fibers

BPJ_113_1.c1.inddSickle cell disease (SCD) is a molecular disease that affects hemoglobin. To understand the altered morphologies and mechanical properties of sickle red blood cells in SCD, it is important to investigate polymerization of the mutated form of hemoglobin (HbS) and subsequent interaction with the red blood cell (RBC) membrane.

The cover image for the July 11 issue of the Biophysical Journal is an artistic rendering of several RBCs and a white blood cell in the blood flow. Some RBCs are sickle-like shape. The largest RBC in the bottom left corner is shown in the protein level. The red, blue, and green particles represent the lipid particles, spectrin proteins, and actin junctions in the RBC membrane, respectively. Inside the RBC,  a single HbS fiber consists of 14 chains of HbS tetramers arranged in a 7 double-stranded configuration. The 14 chains of HbS tetramers are twisted about a common axis in a rope-like fashion. In the image, one small yellow particle is one HbS molecule, and  56 small particles are coarse-grained as one large yellow particle.

As shown in the image, the proposed hybrid HbS fiber model seamlessly couples these two HbS fiber models at different length scales by applying a mesoscopic adaptive resolution scheme (MARS). The stiff HbS fibers interact with the RBC membrane and distort the RBC to the sickle shape. Sickle RBC morphologies are determined by the number of HbS fiber domains and the structure of each domain inside the cells. In return, the RBC membrane also suppresses the growth of the HbS fiber. In addition to irregular shapes, sickle RBCs are characterized by increased cell rigidity due to intracellular fiber structures, resulting in blood flow impairment and vaso-occlusive crises in the microcirculation.

This cover was inspired by the pressing need to understand the integrated process of HbS nucleation and polymerization, and subsequent alterations of cell morphology, which is a multi-scale process ranging from nanometers to micrometers. In order to accurately describe this process, the hybrid HbS fiber model is employed to capture the dynamic process of polymerization of HbS fibers, while maintaining the mechanical properties of polymerized HbS fibers, thus providing a means of bridging the subcellular and cellular phenomena in sickle cell disease.

—- Lu Lu, He Li, Xin Bian, Xuejin Li, and George Em Karniadakis

Alumni Spotlight -Jun Seok Lee


IMG_7233Tell us about where you are now in your academic career.

I recently graduated from Rutgers University with a double major in theoretical physics and mathematics. Come September, I will be starting a masters program in biophysics at the Université Pierre et Marie Curie (Paris VI) in France. I plan to continue towards a PhD at the end of my masters, either staying in Europe or maybe somewhere stateside where it’s always warm, like California.

What is your research focus?

I’ve spent most of my time as an undergrad exploring research options more than focusing on any specific thing. I’ve done research in high-energy experimental particle physics, in neurobiology, in genomics, and extremely briefly in optics. At the moment, I am not obligated to any specific field of research, but I am being drawn more and more towards neurophysics in regards to understanding and treating neurodegenerative diseases, as well as aspects of membrane biophysics.

When and how did you first become interested in this type of research?

I had some health issues regarding my nervous system a few years back and was really frustrated at the lack of answers and solid methodologies in diagnosis. While that frustration was more owed to my lack of patience, it did spark my curiosity in reading up on biophysics and neurophysics in general and prompted my desire to return to school to pursue my degree.

What was the most important thing you learned or took away from the summer program that helped you get where you are at now?

The summer program taught me that a PhD program is not some cutthroat outdo-your-peers competition, but rather it is a support group that is trying to help its members succeed academically, socially, and mentally. It showed me that people ranging from administrators, mentors, peers, and even unaffiliated people like professors from different departments are all willing to offer their time and support even if you don’t do anything related to what they are doing.

The program also exposed me to various types of work being done in biophysics. I had a better understanding of what work was being done in the field, and helped me both broaden and narrow my vision in the type of work I hope to pursue in my career in biophysics. The guest lecturers, the alumni, and the one-on-one counseling I received from various people both related directly and indirectly, was formative in creating the idea of what I believe is my future career goals.

What was your favorite thing about the summer program?

If not all the wonderful food (I’m not even joking here), it has to be all the people I met. My fellow students, the TAs, Mike, Barry, Lisa; everyone had a part in creating the awesome time I had during the program. I was exposed to so many types of personalities and lives a scientist could live, and I received so much good advice that has helped me get to where I am now and will probably continue to advance my growth as a scientist. I believe that during that short span of time, I was able to make connections, find new friends and mentors who I could depend on for support throughout my academic and professional career, and well into the rest of my life. Biophysics is such a broad field, and it requires a vast pool of knowledge to answer the questions posed in it. The program made it such that we all came from widely differing academic fields so that we could work together during our time in the program as well as call on each other for support for our individual work.

However, let me repeat once again, the food was great. I have cravings for that vinegar-based North Carolina barbecue sometimes.

What advice would you give for current undergraduates interested in pursuing a higher degree?

It’s not about how intelligent you are or how easily you can grasp the topic, but about persistence and consistency. Many people fall into this trap where they think just because they’re not the smartest or the fastest among their cohort, that they aren’t good enough for graduate school or beyond. Absolutely not true. You might have to put in some extra hours with the book or at the lab, but if you can hunker down and get working, consistently and diligently, you most definitely can reach that higher degree.

Have mentors played a role in your success? If so, how?

Absolutely, yes. I had multiple mentors during the program. Some were obvious mentors, and some not so much. I think you have to really take advantage of everything the program offers, whether that’s advice from your post-doc lab mentor about the research, or from a TA who was just recently in your shoes, or from a professor you sit down for conversation over lunch who tells you about how he got to where he is today, or even just passing by an office of one of the administrators and having a small chat that leads into something deeper. In whatever situation, summer program or not, there will be people out there who can help you figure out how to orient your compass.

What have been some of your toughest challenges so far in advancing your career?

Trying to figure out where my true passions lied in regards to the field I wanted to pursue. Luckily, the professors and programs I’ve applied to and been a part of have been more than helpful in guiding me towards my goal rather than trying to make me settle for any one specific thing.

Another tough thing is trying to get over what is commonly known as “imposter syndrome.” You study, you do your problem sets, you do research, but that fear of not being good enough makes you feel like you’re a fraud. That’s another thing the program helped with, is that I got to meet people along the various stages of a career path, whether in academia or industry, and it showed me that this is what everyone goes through, and as I said before, persistence and consistency are the keys to success.

BPS Summer Program Alumni spotlight


20170617_191504Hi, my name is Lonzie Hedgepeth. I am from Rocky Mount, North Carolina. I recently graduated with a Bachelor of Science in Chemistry from the University of North Carolina at Pembroke. Last year, summer of 2016, I attended the Biophysical Society Summer Research Program in Biophysics. I learned about the Biophysics Program through the help of a guest speaker in my genetics class.

My professor, Dr. Conner Sandefur, invited Patrick McCarter to talk about the biophysical properties of DNA, and how mutations in DNA can lead to diseases such as Cystic Fibrosis. Patrick’s lecture, which not only deepened my insight into the fields of biophysics and genetics, exuded vigor and confidence. After the talk, I approached Patrick. We talked about possible summer research opportunities that are available at University of North Carolina-Chapel Hill and then exchanged contact information. Later that day, I sent him an email, thanking him for a wonderful and informative seminar.

Soon after, Patrick contacted Dr. Sandefur, informing him about the Summer Research Program in Biophysics at the University of North Carolina at Chapel Hill. Dr. Sandefur and Patrick, who had attended the program himself, thought that this program would be an ideal program for a budding research scientist, such as myself, to gain extensive research experience in an environment that would mirror that of Biochemistry and Biophysics Ph.D. programs. Fortunately, I got accepted! After meeting with my cohort, I realized that we were a very diverse group, coming from different backgrounds. At first I was a little nervous, but over time the cohort and I became very close and connected like a family.

During the summer course, I was able to conduct graduate level research, attend lectures and seminars hosted by UNC-Chapel Hill faculty, participate in several professional developments activities, and also socialize with people at similar stages of their academic careers. I conducted my research in the lab of Dr. Timothy Elston, a professor in the department of Pharmacology. My direct research mentor was Patrick McCarter, who at the time was a graduate student in the Elston lab. I never expected to be working alongside Patrick, someone who I greatly admired. We worked on investigating Mitogen-Activated Protein Kinases (MAPKs) in budding yeast. We wanted to define time-dependent interactions between the Sln1 and Sho1 branches of the yeast (S. cerevisiae) High-Osmolar Glycerol (HOG) pathway. Each branch transmits hyper-osmotic stress through a MAPK cascade to Hog1 the terminal Mitogen-Activated Protein Kinase of the HOG pathway. My role in this project was to use mathematical models to investigate the time-dependent contribution of each branch to Hog1 phosphorylation (MAPK are typically active when phosphorylated). I defined a set of 24 mathematical models that each tested a different hypothesis about the time-dependent contributions to Hog1 activity. Mathematical models provide us with a way to investigate aspects of the biology that are currently not feasible with experiments alone. I then used UNC-Chapel Hill’s Killdevil High-Performance Research Cluster to ‘fit’ each model to an experimental Hog1 phosphorylation training data set. The best ‘fitting’ models were then used to predict how Hog1 phosphorylation would change under different experimental conditions including dynamic hyper-osmotic stress and/or with various genetic perturbations in key HOG pathway signaling proteins.

With the help of Dr. Elston, Patrick, and my colleagues, I was able to present my findings at Annual Biomedical Research Conference for Minority Students (ABRCMS). In addition to presenting my project, during ABRCMS I was also able to attend seminars, participate in networking, and learn about a variety of potential PhD programs.

While I mainly focused on computational science in the Elston lab, the interdisciplinary nature of the project and the collaborative research environment also allowed me to directly communicate with the experimental biologists who were gathering data needed to build the models. Thus, I learned a great deal about cellular and molecular biology, live-cell microscopy, and genetics.

Working in the lab allowed me to see how graduate students, post-docs, and senior professors manage their time, maintain organized lab spaces, and communicate their unique perspectives in an interdisciplinary research group. I was able to witness how modern scientists work together to solve some of the most interesting questions in the world. I am now using these experiences, along with the skills I accumulated from the Biophysics program, to further prepare myself to apply for Ph.D. programs in the fields of Pharmacology, Biophysics, and/or Systems Biology.

I am currently in a Post Baccalaureate Research Education Program (PREP) at Medical University of South Carolina (MUSC). I have kept in touch with Dr. Elston, Patrick, and also Dr. Sandefur! I have developed an invaluable relationship with them. They have become more than just mentors to me. I hope to emulate their perseverance and dedication to help others. They have inspired me to reach out and share my experiences to other young scientists, and to encourage them to pursue their dreams to conduct high-quality biomedical research. I am also extremely grateful to have attended the Summer Research Program in Biophysics. Through this experience, my aspirations of conducting high-quality research are immensely strengthened, and my relationships with scientists developed and flourished. I look forward to the day when I am able to help a young and budding scientist get started on their own journey in science!

New probes, singularities, and a reason for RNAi mismatches in vivo (Part 2)

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Me, Michael Shannon, in rainy Taipei

Takeharu Nagai (part 2/2): Singularities in cells: leaders, followers and citizens

Takeharu describes a familiar situation. Our results, whether its molecular behaviour or cellular behaviour are generally an averaged description of phenomena. We get an idea of what’s going on, but ignore the minority phenomena: the singularities that lead to group behaviours.

After a brief rundown of things he considers singularities: the big bang, the benign to malignant switch, formation of iPS stem cells with only 4 genes altered, populist fascism under Trump etc, he sets out to investigate this idea armed with a plethora of new fluorescent probes, and some cool model systems.

Here, he focuses on cAMP signalling in social amoeba, which transition from single celled entities to an intercommunicating mass, a multicellular being. To initiate this switch, all you have to do is starve them of nutrients.

By using two markers, Flamindo2 (Odaka) and R-FlincA (Horikawa, in press) he derives a ratiometric measurement for cAMP activity, known to be associated with this switch in amoeba behaviour. Combining this with a high speed microscope tiling technique, he is able to look at the behaviour of both single cells and the whole population of cells.

What he finds is amazing – single amoeba cells become leaders, displaying a burst of cAMP, before setting off their neighbours. “Early followers” then signal to “late followers”, and within a matter of hours, to “citizens”, setting off a continuous spiral of cAMP signalling which causes the amoeba to group together and become multicellular. The fluorescence videos of this are quite amazing – and while the paper isn’t out yet, you can view some similar behaviours online at Take’s website.

Interestingly, several leaders seem to be selected, but only one gains ultimate dominance as the seed of the spiral of signalling. One of the goals of the Nagai lab now is to find out how this leader is selected.

Okay, next up, Sua Myong

Sua Myong – How does RNAi actually work?

Sua employs FISH, a super resolution technique, to view RNA interference in single cells. What she finds is the first insight into the function of RNAi with reference to biologically relevant miRNAs since Fire and Mello won the nobel prize for the work and revolutionised the field.

The investigative technique works by targeting particular mRNAs with search RNAi strands loaded with 30 to 40 fluorophores each. By watching the transient binding of these RNAs in TIRF, the PSFs can be localised and the relative number of RNAs between conditions can be quantified.

The group tried to figure out which parts of shRNA were important in terms of its structure and its interactions with DICER and RISC, the proteins that bind it to genes of interest and cut the genes, respectively. To do this they altered the shRNA supplied to the cell by first changing the size of the hairpin loop, before measuring silencing using the FISH technique described above.

Longer loop size improved silencing, and it was found that this was dependent on better association with the DICER protein.

Introducing mismatches in the nucleotides was also trialled, as this is common in biological settings – many endogenous microRNAs have these mismatches which prevent them from binding the target gene perfectly.

What they found was that the altered shRNA had not problem binding DICER, but was inhibited in its handover to the RISC complex.

This is important, because it may be a way for cells to control the power of microRNAs, in cases where protein translation must be fine tuned.

Thanks for reading – that’s me over and out for this meeting.

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A local bicycle repair shack in Taipei

Michael Shannon (Dylan Owen lab, KCL)

Sensor and probe development, day 4 of the BPS conference in Taipei

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Michael Lawson, Amy Palmer, and Julie Biteen

 

Here are the talks on Sensor and Probe development, all on the last day of the conference (Part 1)

Amy Palmer probes the cellular ionosome

 

First up today, Amy Palmer develops new probes to investigate the ‘ionosome’* – the complex but under-recognised flow of metal ions within living cells. This is a relatively untapped field – 30 % of proteins in cells require a metal cofactor to function, yet only really Calcium has been addressed with fluorescent probes, or even recognised as a regulator of cell function.

Zinc ions are particularly interesting, and that’s the focus for today’s talk. It’s level is sensed by cells, which adjust their metabolism in response. 10% of proteins require Zinc, so it does a lot of different jobs.

OK so first of all the probe made by Amy and her team. This is a FRET probe, composed of two Zinc binding domains between the donor and acceptor. When Zinc binds, conformational change occurs and the probes come within the magic distance, facilitating energy transfer which can be detected. In addition, a signal sequence can be added to direct the construct to somewhere specific eg – membrane, nucleus, cytoplasm.

To prove the probe works, the group carried out in situ calibrations – within the same cells they will be testing. To soak up all the Zinc for a low signal readout, they used a chelator (in this case TPEN) and to get a high Zinc signal they used a Zinc carrier (Zinc Pyrithione). This works pretty nicely, and their yellow FRET signal is ratiometric with reference to the green donor signal alone. There also doesn’t seem to be any perturbation of endogenous Zinc concentration due to the probe itself, which is nice.

Next they looked at the kD values for binding of Zinc to some of the proteins it regulates, and it turns out that they are not fully occupied under physiological conditions. This is important as it points towards Zinc indeed being a regulator, functioning by binding on and off to the protein of interest.

One example of this is CDK2 in the cell cycle. Zn fluctuations accompany high CDK2 cytoplasmic recruitment/activity, when the cell has just exited mitosis. The group found that these zinc fluctuations are required for the decision to translocate CDK2 from nucleus (inactive) to cytoplasm (active).

One of the next steps for the group might be to target the probes to particular organelles, to investigate Zinc’s role there. Very interesting stuff.

*me and Amy agreed that this was a cooler name for this network than metallosome – what do you think?

Takeharu Nagai (part 1/2) – Acid resistant fluorescent protein for super resolution

Takeharu’s group looks in strange places for new fluorophores.

First up is the work of Hajime Shinoda, a “very handsome and cool student” in Take’s words. He has developed a new fluorescent protein, called Gamillus isolated from a flower hat jellyfish, which survives at low pH, where EGFP and others lose their signal.

That’s because it has a trans-isomeric conformation, instead of a cis one. It can’t gain H+ ions in a way that would disrupt the aromatic rings in the chromophores of the rest of the green cis proteins, so it is compatible for imaging low pH environments, like the inside of lysosomes. A nice control is shown: use GFP, you can’t see lysosomes, use Gamillus, and suddenly little polkadots appear in strategic cellular locations. It works!

Next, handsome Hajime altered the protein, so that it might be compatible for super resolution. He used the very problem that Gamillus solves, transition to cis isomerism, to achieve photoswitchability. Reversibly switchable Gamillus blinks on exposure to UV light, by switching between the inactive cis and active trans form. (Shinoda, unpublished data).

Michael Shannon

Day 3- Single-Cell Mechanobiology

After the wonderful talk during coffee break, coming back to our last session of today!

Megan Valentine- A new model system for cellular studies of mechanobiology

Megan introduced us a new model organism that is known is our  “closest vertebrate relative”, Botryllus schlosseri (commonly known as the golden star tunicate). It is a highly dynamic organism that needs constant angiogenesis, because it has a large and transparent extracorporeal vascular network, and their vessels are constantly remodeling. What is special about them is that their vessels are inverted with respect to vertebrate, so we can have direct access to extracellular matrix via microinjection.

With the model organism Botryllus, she can directly apply physical forces and monitor the downstream responses in a living organism in real time through manipulation of the blood vessels. She found that Lysyll oxidase (LOX, responsible for crosslinking collagen) expression is stimulated by the presence of collagen, and inhibiting LOX by adding a specific inhibitor, ß-aminopropionitrile (BAPN) causes massive retraction of vessels.

This is a pretty fascinating new model system for mechanobiology studies, and this talk was ended with a nice and amusing “slurp” video (a cell swallowed by the phagocyte)!

 

Chin-lin Guo- Spontaneous Patterning of Cytoskeleton in Single Epithelial Cell Apicobasal Polarity Formation

How does mammalian cells form the specific organs? Previously, people focused on the spatial patterning and the coordination of chemical signals. Recently, ChinLin and others have found that mechanical forces also play an important role in the organization of multicellular architectures.

He has shown that long-range mechanical force enables self-assembly of epithelial tubular patterns, and the  self-organization of epithelial morphology is dependent on rigidity. Moreover, he thinks that direct cell-cell contact induces the segregation of par complex and the formation of actin belt, which is how individual cells form apicobasal polarity.

The cool part of his talk is that he uses an ECM gel to see the spontaneous single-cell partitioning of cytoskeleton on 2D platform and 3D culture. Furthermore, to differentiate between actin band and belt and the role of microtubules, he implemented the lattice light sheet microscopy (LLSM, Bi-Chang Chen), which showed the conversion of actin from band to contractile belt, and he thinks that actin band can serve as a precursor to guide cell-cell interactions.

To sum up, he thinks that single epithelial cells can form a precursor state by spontaneous partitioning of cytoskeleton to guide multicellular epithelization and apicobasal polarity formation, and there could be an intermediate state between the mesenchymal state and the epithelial state.

 

Poul Bendix- Dynamics of Filopodia: Rotation, Twisting, and Pulling

Poul is interested in the question: do filopodia rotate around its own axis? His group has surprising evidence for a new pulling mechanism originating from twisting of the actin within the filopodium. Using labeled actin, he can have 3D visualization of filopodia in different cells to find the answer.

When visualizing actin polymerization inside membrane tube, he found that filopodia exhibit buckling of their actin shaft in conjunction with pulling. In HEK cells, he found that there is twist buckling transition of filopodia that buckling releases accumulated twist, which is a strong indication of twisting of actin. Moreover, they observed retrograde flow and rotation of the actin shaft, so there could be correlation between force and actin distribution, and also correlation between coil movement and force.

They have found helical buckling and rotational behavior in the filopodial actins in various cell lines, which may facilitate the sensing and interaction of the cell with its surroundings using filopodia.

 

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The banquet in Grand Hotel was AMAZING!! Grand hotel is one of the most famous landscapes of Taipei, with contemporary palatial architecture and delicious cuisines! After the wonderful meal, some of us went to the karaoke, and I heard it was also lots of fun!

Ivy (Howard Lab / Howard Lab facebook & Xiong Lab, Yale University)

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IMG_5640.JPG(Having a great meal at Grand Hotel, photo: Ivy)