Paradis and Van Hooser labs collaborate on eLife paper

Figure 3 from research paper

Figure 3. Rem2 is required for late-phase critical period ocular dominance plasticity.

“Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits.” Anna R Moore, Sarah E Richards, Katelyn Kenny, Leandro Royer, Urann Chan, Kelly Flavahan, Stephen D Van Hooser, Suzanne Paradis. eLife 2018;7:e33092.

Throughout our waking hours, we experience an ever-changing stream of input from our senses. The brain responds to this varying input by adjusting its own activity levels and even its own structure. It does this by changing the strength of the connections between neurons, or the properties of the neurons themselves. Known as plasticity, this process of continuous change enables the brain to develop, learn and to recover from injury.

The visual systems of mammals are particularly well suited to studying how sensory experience alters the brain. Studies in animals show that lack of sensory input to one or both eyes during a critical period in development causes long-lasting changes in the brain’s visual circuits. Similarly, children with the condition amblyopia or ‘lazy eye’ – in which one eye has impaired vision and the brain ignores input from that eye – can end up with permanent deficits in their vision if the condition is not treated during childhood. Changes in sensory input are thought to trigger plasticity in the brain by altering the activity of specific genes. But exactly how this process works is unclear.

Anna Moore, Sarah Richards et al. now show that a gene called Rem2 has an important role in regulating visual plasticity. In the key experiments, young mice had their vision in one eye blocked for a few days. Analysis of their brains showed that mice that had been genetically modified to lack the Rem2 gene responded differently to this change in their environment (i.e. the loss of input to one eye) than their normal counterparts. Further experiments suggest that Rem2 regulates the excitability of individual neurons: that is, how much the neurons respond to any given input. In the absence of Rem2, neurons in visual areas of the brain become hyperactive. This prevents them from adjusting their activity levels in response to changes in sensory input, which in turn leads to impaired plasticity.

Being able to harness the brain’s visual plasticity mechanisms on demand, for example by regulating Rem2 activity, could benefit individuals with disorders such as amblyopia. Rem2 is also active in many other parts of the brain besides those that support vision. This suggests that manipulating this gene could affect numerous forms of plasticity. However, various barriers must be overcome before we could use this approach to treat brain disorders. These include obtaining a more in depth understanding of the role of the Rem2 gene in the human brain.

Advanced spectroscopy reveals mechanism of vectorial action in a membrane pump

Judith Herzfeld research imageSome proteins in cell membranes are responsible for actively pumping desired molecules in or unwanted molecules out. Since their discovery, it has been expected that their vectorial action involves the existence of two protein conformations, one in which the active site has a low affinity for substrate and is open to the discharge side of the membrane and the other in which the active site has a high affinity for substrate and is open to the uptake side of the membrane. The driver of the pump is a source of energy that converts the pump from the lower energy state to the higher energy state, from which it can relax back and begin the cycle anew.

However, this model has never fit the longest-studied pump, the light-driven ion pump bacteriorhodopsin. At rest, the active site has a high proton affinity but is open to the discharge side of the membrane. Disruption of the active site by light reduces the proton affinity, but it has been a decades-long mystery how this occurs while maintaining access to the discharge side of the membrane. This mystery has now been solved through advanced spectroscopic studies of photocycle intermediates trapped at low temperatures. Obtained collaboratively by Judith Herzfeld’s group at Brandeis and Robert Griffin’s group at MIT, the spectra trace the establishment of an essential U-shaped pathway to the discharge side of the membrane. The results also explain how this pathway is broken as soon as the proton is released, thereby preventing back flow and enforcing the vectorial action of the pump.

“Primary transfer step in the light-driven ion pump bacteriorhodopsin: an irreversible U-turn revealed by DNP-enhanced MAS NMR.” Qing Zhe Ni, Thach Van Can, Eugenio Daviso, Marina Belenky, Robert G. Griffin, and Judith Herzfeld. J. Am. Chem. Soc., DOI: 10.1021/jacs.8b00022. Publication Date (Web): February 28, 2018

Papaemmanouil Receives Funding from Huawei Technologies

Olga PapaemmanouilShenzhen-based Huawei Technologies, the largest manufacturer of telecom equipment in the world, is supporting Associate Professor of Computer Science Olga Papaemmanouil‘s efforts to develop machine learning approaches for managing the performance of data management systems. The grant will support research on workload management, that is the task of query placement, query scheduling and resource allocation for database applications. Workload management is an extremely critical task for database systems as it can impact the execution time of incoming processing tasks as well as the overall perceived performance of the database  and the quality of the service (QoS) offered to end-clients. The complexity of the problem increases for applications that involve dynamically changing workloads and concurrently executing queries sharing the same underlying resources, as well as applications that are deployed on data clusters with fluctuating resource availability.

Dr. Papaemmanouil’s research aims to design frameworks that can be trained on application-specific properties and performance metrics  to automatically learn how to effectively dispatch incoming queries across a cluster of servers, implicitly solving the resource allocation challenge. These techniques will rely on machine learning algorithms (reinforcement learning and deep learning)  that model the interaction of concurrently running queries  as well as the relationship between database performance and the underlying resource availability in the cluster. The project will lead the way towards the development of workload management solutions that eliminate ad-hoc heuristics often used by database administrators to address these challenges and replace them with software modules capable of providing custom workload management strategies to end-clients.

Clocks, fruit flies, and Sweden

We mentioned previously that Rosbash, Hall and Young are getting the Nobel Prize in Physiology or Medicine this year “for their discoveries of molecular mechanisms controlling the circadian rhythm”.

The Physiology/Medicine lectures were on Thursday Dec 7 at 1 pm CET (7 am Brandeis time) and are still available to view. The Biology Department enjoyed watching the lectures on “tape delay”:

From and about the winners, via Cell:

About the science and its implications:

If you need to flesh out your fantasy of going to Sweden to collect your prize, see What to expect when you’re expecting a Nobel Prize

Video:

Circadian Rhythms and When to Eat (Swedish Television)

 

Rodal lab find surprising new link between inflammation and Lowe Syndrome

Could a disease with symptoms in the brain, eyes, and kidneys actually be caused by problems with immune cells? A team of scientists from the Rodal Lab, co-first authored by Steven Del Signore and Sarah Biber and including three Brandeis undergraduates (Katy Lehmann ‘16, Stephanie Heimler ‘17, and Ben Rosenfeld ’18), think this just might be the case with Lowe Syndrome, in a new paper published Oct 13th in PLOS Genetics.

Patients with Lowe Syndrome suffer from kidney failure, congenital cataracts, and several neurological problems including intellectual disability and seizures. Scientists have known for some time that the disease is caused by mutations in a gene called OCRL, but remain unsure how its loss causes such a diverse array of symptoms. A big problem has been that OCRL appears to do many different jobs inside cells, including controlling how they divide, how they sense their surroundings, and how they store and transport materials inside small packages called endosomes.

Fly immune cells showing the tracks of moving endosomes. Single tracks represent the path of individual endosomes over time.

To try to solve this mystery, a team of researchers from the Rodal lab used the fruit fly, which has its own version of the OCRL gene and allowed the investigators to perform powerful genetic experiments to figure out precisely what OCRL is doing, and where. To do this, the group created a fly missing its OCRL gene. They were surprised to find that, rather than eye or neurological defects, loss of OCRL hyper-activated cells of the innate immune system. The innate immune system is the first line of defense against infection in humans (and the only defense in fruit flies), when cells release inflammatory signals that mobilize specialized cells to attack invading pathogens.

The team determined that OCRL is required in one of these specialized immune cells in the fly, and that the immune-cell activation was caused by problems in a particular step of intracellular transport. Every cell of the body has its own postal service, which is used to pack and ship signals that tell the cell or its neighbors to grow, divide, or jump into action (see movie here to watch endosomes moving inside living fly immune cells). The OCRL mutant immune cells had a problem in a key step that controls whether signals get thrown in the trash or shipped outside the cell, and this caused the immune activation.

How do these findings relate to Lowe Syndrome? The authors think these results suggest a possible cause for the seizures that patients experience. When similar immune-like cells in the brain release excessive inflammatory signals, it can cause several forms of epilepsy. Further, OCRL has been linked to at least one mouse model of epilepsy. Going forward, the researchers will try to identify which immune signals are responsible, and how these findings translate to human cells.

Del Signore SJ (*), Biber SA (*), Lehmann KS, Heimler SR, Rosenfeld BH, Eskin TL, Sweeney ST, Rodal AA. dOCRL maintains immune cell quiescence by regulating endosomal traffic. Plos Genet. 2017;13(10):e1007052.

 

 

Ivanovic Receives 2017 NIH Director’s New Innovator Award

photo: Mike Lovett

Assistant Professor of Biochemistry Tijana Ivanovic has received a 2017 NIH Director’s New Innovator Award. This award is part of the NIH’s High-Risk, High-Reward Research program, designed to fund early career investigators who propose innovative and potentially transformative projects. Ivanovic will receive $1,500,000 in direct costs over five years to spearhead a research program aimed at comprehensively characterizing molecular changes in the viral cell-entry protein hemagglutinin (HA) that define pandemic influenza viruses. With the generated insights, Ivanovic hopes to ultimately be in a position to predict the pandemic potential of influenza viruses circulating in nature.

HA densely covers the influenza virion surface, where it allows the virus to both recognize and penetrate (fuse with) the cells of its host. HA is also a key target of neutralizing antibodies that protect us from influenza infection. An influenza pandemic is characterized by the adaptation of a new HA subtype to cell entry into human cells (of what was originally an avian virus). Without the pre-existing immunity to protect us, the virus quickly spreads around the globe. During pandemic adaptation, both HA functions in target-cell recognition and membrane fusion undergo key molecular changes. Ivanovic will use a custom-built Total Internal Reflection Fluorescence Microscope (TIRFM) to visualize, in real time, individual virus particles as they engage and fuse with target cell membranes. This system will allow her to obtain large-scale quantitative information about distinct HA functions at an unprecedented level of detail. She will compare avian viruses with their evolutionary offspring that infected humans, including past pandemic strains. She hopes to develop models for predicting which viruses will lead to a major flu outbreak.

Ivanovic obtained a PhD in virology from Harvard University and carried out postdoctoral research with Stephen Harrison in molecular biophysics. She integrates these diverse backgrounds in her laboratory, where members are trained across these two and other synergistic areas (such as laser microscope optics, and analytical and computational modeling). The funds from the New Innovator award have created new opportunities for hiring, and the lab is actively recruiting postdocs, PhD students (from the Biochemistry and Biophysics, Molecular and Cell Biology, and Physics graduate programs) and undergraduate researchers to undertake this ambitious program.

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