How bacteria resist fluoride

Fluoride anion is everywhere.  Released into water through the natural weathering of rocks, it’s present to the tune of 5 mM in toothpaste, 30 μM in Cape Cod bay, and 17 μM in Massell pond at Brandeis.

Fluoride levels in our environment (graph).001

Fluoride in the environment, measurements by Ashley Brammer (Miller lab)

Since F is ancient, ubiquitous and toxic to microbes, it’s not surprising that bacteria have evolved defenses to expel it from their cytoplasm.   In an article published in eLife on August 27, 2013, Randy Stockbridge, Janice Robertson, and Luci Partensky from Chris Miller’s lab describe one of these microbial defenses, a fluoride channel called Fluc.  The channel provides a pathway for F to exit the cell across the membrane at a rate of 107 ions per second, while rigorously excluding Cl in order to avoid catastrophic membrane depolarization. The world-record 10,000-fold selectivity isn’t the only remarkable aspect of Fluc, however. The Fluc channel is built on an antiparallel dimer scaffold, with one of the subunits facing the exterior of the cell, and the other facing the interior. Only one other modern-day membrane protein is known to dimerize like this, but the arrangement recalls the inverted structural repeats that are a common, important motif for membrane transporters. Inverted repeats are the product of an antiparallel dimer, like Fluc, that duplicated and fused eons ago.  The sequences drifted over time until the duplication was undetectable by sequence similarity, and the plethora of membrane transport proteins built on this plan was only discovered when the 3-D structures were solved. The Fluc family provides the opportunity to study microorganism resistance to an ancient xenobiotic, as well as membrane protein architecture from an evolutionary origin.

For more, you should read the paper:

Stockbridge RB, Robertson JL, Kolmakova-Partensky L, Miller C. A family of fluoride-specific ion channels with dual-topology architecture. eLife. 2013;2(0):e01084. PMCID: 3755343.

PS: If you’re wondering about the tea on the bar graph, tea plants accumulate F in their leaves.  Cheap teas, made from older tea leaves, actually carry a lot of F, and if you drink a couple quarts of lousy tea a day, you can give yourself skeletal fluorosis.

Marder lab researchers win best paper contest

Alex Williams and Timothy O’Leary from the Marder Lab have won first place in the 2012  Brain Corporation Prize Competition in Computational Neuroscience  for their Scholarpedia article Homeostatic Regulation of Neuronal Excitability.  Williams, a Bowdoin College graduate currently working as post-baccalaureate research technician at Brandeis, and O’Leary, a postdoctoral fellow, won the worldwide competition to write the most popular review in the area of computational neuroscience, and gained a $5,000 prize, a feat that required not only superb writing but also mobilizing the audience to vote for paper. The award ceremony is today at the Computational Neuroscience (CNS’13) meeting in Paris.

Check out the winning entry online.

Summer Seminars Start on the Sixth

Science is a year-round endeavor, so science seminars will continue over the seminar, though the venues and times may shift.

D-Day for summer seminars this year is June 6, when the Biochemistry & Biophysics Summer Pizza Talks series kicks off with Dr Markus Grütter of the University of Zurich. Grütter will give a special summer on his recent breakthrough-structure of the first heterodimeric ABC transporter. This structure is important because the ABC transporter is a homologue of the CFTR channel (disrupted in cystic fibrosis, one of the most common human genetic diseases). The talk will be in Gerstenzang 121 at Noon on Thursday, June 6.

The Life Sciences Summer Research Seminar Series will start on Monday, June 24, with a talk by distinguished alumna Leslie Meltzer ’03, who has returned to the Boston area as Associate Director of U.S. Medical Affairs at Biogen IDEC, having paid a visit to the other coast to get a Ph.D. in Neuroscience at Stanford in 2008, working with Karl Deisseroth. The Life Sciences Summer Research Seminar Series is organized by the Brandeis University Postdoctoral Association and will be held on Mondays at noon in Gerstenzang 121.

How does the brain decide whether you like what you eat?

When we encounter a taste, we appreciate both its chemosensory properties and its palatability—the degree to which the taste is pleasurable or aversive. Recent work suggests that the processing of this complex taste experience may involve coordination between multiple brain areas. Dissecting these interactions help understand the organization and working of the taste system.

F4.largeThe lateral hypothalamus (LH) is a region of the brain important for feeding. In a rodent, damage the LH, and the rodent may starve itself to death; stimulate it, and you get a curious mix of voracious eating and expressions of disgust over what is being eaten. Such data suggest that LH plays a complex game of balancing escape and avoidance, palatability and aversion, during the evaluation of a taste stimulus. Little is known, however, about how neurons in LH actually respond to tastes of different valences.

Brandeis postdocs Jennifer Li and Takashi Yoshida. undergraduate Kevin Monk ’13, and Associate Professor of Psychology Don Katz have recently published a study of neuronal reponses in LH in the Journal of Neuroscience. They have shown that taste-responsive neurons in LH break neatly down into two groups–one that responds preferentially to palatable tastes and one to aversive tastes. Virtually every taste neuron in LH could be identified as a palatable- or aversive-preferring neuron. In addition, even without considering the specific tastes to which a particular neuron responded, these two groups of neurons could be differentiated according to their baseline firing rate, shape of response, and tuning width. While these neurons were spatially intermingled, several pieces of data (functional connectivity analysis, relationship to responses in amygdala and cortex) suggest that they are parts of distinct neural circuits. These results offer insights into the multiple feeding-related processes that LH manages, and how the hypothalamus’ role in these processes might be related to its connection to other parts of the taste system.

Li JX, Yoshida T, Monk KJ, Katz DB. Lateral Hypothalamus Contains Two Types of Palatability-Related Taste Responses with Distinct Dynamics. J Neurosci. 2013;33(22):9462-73.

Making new synapses with Sema4D

There are two main types of synaptic connections in the mammalian brain: excitatory glutamatergic synapses and inhibitory GABAergic synapses. The balance between excitatory and inhibitory inputs a neuron receives regulates the overall activity of neuronal networks; disruptions to this balance can cause epilepsy.

A new paper in J. Neuroscience from the Paradis lab shows that treatment of cultured neurons with the extracellular domain of the protein Sema4D causes a rapid increase (i.e. within 30 minutes) in the density of functional GABAergic synapses. Further, addition of Sema4D to neurons drives GABAergic synapse formation through a previously unappreciated mechanism: the splitting of pre-existing assemblies of the Gephyrin scaffolding protein. To our knowledge this is the fastest demonstration of synapse formation reported thus far and has significant implications for our understanding of the mechanisms of GABAergic synapse formation.

Screen Shot 2013-05-26 at 5.03.05 PMWhile the underlying mechanism of epileptogenesis is largely unknown, recurrent seizures emerge when there is an increase in network activity. One possible therapeutic treatment would be to restore normal network activity by increasing network inhibition. In an in vitro model of epilepsy, acute treatment with the protein Sema4D rapidly silences neuronal hyperexcitability, suggesting a possible use of Sema4D as a disease-modifying treatment for epilepsy.

Lead authors on the paper were Marissa Kuzirian, a grad student in the Neuroscience Ph.D. program, and Anna Moore, a Brandeis Neuroscience postdoctoral fellow.

The Genetics Training Grant hosts a panel discussion and lunch focused on careers outside academia

This past Monday, April 29th, students and post-docs, eager to learn more about careers outside of academia, had the opportunity to hear from, and question, panelist who have successfully harnessed their PhD experience to excel in non-academic careers. The event, hosted by the Genetics Training Grant, brought together panelists from several different fields, including scientific publishing, pharmaceutical research, consulting, and intellectual property law. The panelists were Priya Budde, Reviews Editor, The Journal of Cell Biology; Sadanand Vodala, Research Scientist, ARIAD Pharmaceuticals; Derek Buhl, Principal Scientist, Pfizer Neuroscience; Peter Bak, Consultant, Back Bay Life Science Advisors; and John Garvey, Partner, K&L Gates LLP. Each panelist spoke about their background in academia, how they made the transition to their current position, and fielded numerous questions from the audience both during the panel and at the networking lunch that followed.

The panelists gave the audience a sense of what their specific careers entail, and how skills they had acquired during their PhDs were highly relevant to their current work. Some of the transferable skills mentioned included critical thinking and the ability to quickly synthesize information and distill what is most important and interesting about a given scientific finding. These skills enabled them to be highly effective in their jobs, whether efficiently evaluating scientific manuscripts as an editor, or determining the crux of a client’s research as a consultant or intellectual property lawyer.

Current jobs for recent Brandeis Life Science PhDs (graduates 2002 and beyond, n=200)

Current jobs for recent Brandeis Life Science PhDs (Neuro, Mol Cell Biol, Biochem, Biophys graduates, 2002 and beyond, n=200)

Having completed their transition from academia to the business world, panelists were able to highlight some of key cultural and practical differences associated with working in a profit-driven industry. While Derek described his lab at Pfizer as largely mimicking an academic environment (minus the need to perpetually write grants), he and other panelists noted that, unlike academia, business evaluations are based almost exclusively on having achieved specific pre-determined goals. On the upside, for those who exceed expectations in business, there are lots of opportunities to move up the ladder. Other differences that panelists encountered in their non-academic professions included firmer deadlines, higher dressing standards, and less flexible hours.

While the majority of the discussion was specific to the panelists’ career paths, much of the advice applied to career searches in general. The importance of good networking was emphasized. Job seekers were encouraged to make the most of their networks – and their network’s network as well. Each panelist explained how he or she had acquired their job through a combination of effective networking, being proactive, and in some cases, luck. Panelists were quick to point out, though, that time and effort invested were positively correlated with “luck.”

Panelists stressed that effective networking required quickly following through with contacts, and being prepared to impress key contacts with excellent questions that demonstrate your research on a given company. They encouraged the audience to be proactive, and if needed persistent, in reaching out to people whose work they find interesting. Several panelists also emphasized the benefits of acquiring job-related experience. They noted this was a good way to both boost your resume and get a better sense of whether a given profession is the right fit for you. For example, John Garvey recommended joining a consulting or biotech club, and/or taking a business class. Getting involved in job-related activities is also excellent ways to establish good contacts for networking.

Overall the panelist presented several attractive alternatives to a traditional academic career. By carefully analyzing his or her personality, strengths, and working style, each of them had found a rewarding career that effectively utilized their scientific background/training. Priya, the editor, described how she enjoyed being able to see where scientific fields are going and staying up to date with the latest scientific breakthroughs. Derek, the pharmaceutical researcher, explained how it was gratifying for him to be working directly to develop drugs that could benefit people. John, the lawyer, explained how his work solving business problems was important because it helped provide pharmaceutical companies with the financial resources to bring new life-saving drugs to market. The general take-home message from all of the panelists was that, using the right career strategies, one can effectively use one’s PhD as a launching point to successfully pursue many different avenues outside of academia. Those interested in getting a better sense of what career might be a good fit for them are encouraged to visit and fill out the survey.

What do Brandeis life science PhD students go on to do?

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