TNFα Signaling Maintains the Ability of Cortical Synapses to Express Synaptic Scaling

The brain has billions of neurons that receive, analyze, and store information about internal and external conditions, and are highly interconnected. To prevent either hyperexcitability (epilepsy) or hyopexcitability (catatonia) of brain circuits, neurons possess an array of “homeostatic” plasticity mechanisms that serve to stabilize average neuronal firing.

Synaptic scaling is one such form of homeostatic plasticity that acts like a synaptic thermostat, and allows neurons to turn up or down the gain of synaptic transmission to stabilize average activity. The signaling pathways that allow neurons to perform this neat trick are incompletely understood, and it has been controversial whether neurons do this in a cell-autonomous manner, or whether synaptic scaling is induced in response to release of soluble factors such as the pro-inflammatory cytokine TNFα.

A study published this week in Journal of Neuroscience by Brandeis postdoctoral fellow Celine Steinmetz and Professor Gina Turrigiano helps to resolve this controversy by showing that TNFα is not instructive for synaptic scaling, but instead is critical for maintaining  synapses in a plastic state in which they are able to express synaptic scaling. This study suggests that glial cells serve a permissive role in maintaining synaptic plasticity through release of soluble factors such as TNFα, while neurons actively adjust their synaptic thermostat in response to cell-autonomous changes in their own activity.

Novel IMPDH inhibitors are candidates for antibacterial drugs

The rise of multiply drug resistant bacteria creates an urgent need for new antibiotics and novel antibiotic targets.  IMPDH, a key enzyme in the biosynthesis of RNA/DNA precursors, is a target for cancer therapy that has not been exploited in antibiotic development. In their recent paper in Chemistry & Biology entitled Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases, Prof. Lizbeth Hedstrom and Brandeis postdocs Deviprasad Golapalli, Iain MacPherson and Suresh Gorla show that selective inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum also exhibit antibacterial activity. This work could lead to novel treatments for a wide variety of bacterial infections, including some of the most devastating and troubling human pathogens: Mycobacterium tuberculosis, drug-resistant Staphylococcus aureus (e.g. MRSA and VRSA), drug resistant Streptococcus pneumoniae and select agents such as Bacillus anthracis, Burkholderia mallei/pseudomallei and Francisella tularensis.  Importantly, these compounds will spare some commensal bacteria, which should decrease side effects and slow the rise of resistance.  This work suggests that IMPDH-targeted inhibitors can be developed into a new class of broader spectrum antibiotics.

Connecting with underrepresented minorities in the sciences

For the past six years, Brandeis has been participating yearly at two undergraduate-oriented conferences in an effort to recruit the best minority students for the life sciences graduate programs. These two conferences are: SACNAS (Society for advancing Hispanics/chicanos and Native American in science) and ABRCMS (Annual Biomedical research conference for minority students).

This year SACNAS was held at Anaheim, CA during September 30 and October 3. Professor Jim Morris and 2 graduate students represented Brandeis and interacted with post-docs, graduate students, pre college teachers, undergrads and other 300 exhibitors. The theme of this year conference was Science, Technology & Diversity for a Sustainable Future. In addition, SACNAS combined efforts with MAES (Society for Mexican American engineers and scientists) in order to make the experience more interdisciplinary.

For the past 30 years SACNAS has been holding this conference to enforce the underrepresented minority population in science to pursue advanced degrees, careers, and positions of leadership. A Brandeis SACNAS chapter was created over a year ago, in order to provide information and give access to professional tools to all the undergrads interested in pursuing careers in science. This year, the Brandeis SACNAS chapter was recognized during the meeting as a new chapter, and 9 of our undergraduates participated in the conference; 2 of them Angel Garcia and Kerwin Vega, presented their research in the poster sessions. You can also connect with the Brandeis chapter on Facebook.

– Yaihara Fortis

Time for Worms in Circadian Biology

Almost every organism on earth, from archae to humans, exhibits circadian rhythms – periodic cycles of behavior or gene expression that repeat approximately every 24 hours. These rhythms are generated by a circadian clock – an internal time-keeping mechanism – which can be entrained and synchronized by environmental cues such as temperature or light/dark cycles. This clock may provide organisms with an adaptive advantage throughout their life, and disruption of the function of this clock can lead to severe behavioral and metabolic disorders in humans.

For more than two decades researchers have wondered whether the tiny soil-dwelling nematode worm Caenorhabditis elegans, one of the foremost model organisms, contains a circadian clock. Circadian rhythmic behaviors described previously in C. elegans are variable and hard to quantify, and no genes were known to exhibit gene expression oscillations with 24 hr cycles as shown in many other animals.

Now, in a recent study published in the open-access journal PLoS Biology, several students and postdoctoral fellows in the labs of Piali Sengupta and Michael Rosbash joined forces and took on the challenge to identify C. elegans genes under clock control.

Light and temperature cycles both drive and entrain 24 hr oscillations in gene expression in C. elegans.

They showed that indeed C. elegans contains genes whose expression cycles in a circadian manner. They found that light and temperature cycles appear to regulate different sets of genes (see above), indicating that these stimuli may entrain two distinct clocks. Moreover, the underlying clock mechanisms may not be dependent on oscillations of known clock genes. “These findings were surprising to us since Drosophila only has a single conserved clock running in multiple cells and tissues” says Alexander van der Linden – lead author and former postdoctoral fellow in the Sengupta Lab.

C. elegans has a wealth of genetic and behavioral tools. The next critical step will be to identify the mechanisms underlying the C. elegans circadian clock(s). These investigations may also provide information of how the clock evolved since nematodes and humans split about 600-1200 million years ago.

Alexander M. van der Linden is now an Assistant Professor at the University of Nevada, Reno. The work was conducted in the labs of Profs. Michael Rosbash, a member of the Howard Hughes Medical Institute and Piali Sengupta in the Department of Biology. Other authors who contributed to this work include Molecular and Cell Biology graduate students Matthew Beverly, Joseph Rodriquez and Sara Wasserman (now a postdoctoral fellow at UCLA), and Sebastian Kadener, a former postdoctoral fellow who is now an Assistant Professor at the Silberman Institute of Life Science, The Hebrew University of Jerusalem, Israel.

Life is a Ponzi Scheme (and more)

Greg Petsko, Gyula and Katica Tauber Professor of Biochemistry & Chemistry, has been writing a monthly column in the journal Genome Biology since its inception 10 years ago. To honor the journal’s 10th anniversary, these columns have now been released as an e-book.

These columns are wide-ranging and rarely fail to amuse and inform. Some examples:

The Contribution of Childhood Trauma to the Neurobiology of Depression

On Thursday, Oct 28th at 3:30, Christine Heim, PhD, will speak in the Martin Weiner Lecture Series on the Psychology of Aging and the Brain, Body & Behavior program. Her presentation The Contribution of Childhood Trauma to the Neurobiology of Depression will take place in Levine Ross, Hassenfeld.
She will talk about how early life experiences, in particular childhood trauma, can have a long-lasting impact on human biology and psychology. Her research shows for example that childhood trauma can lead to specific neuroendocrine changes and contribute to the development of depression with a specific, biologically distinguishable profile, that is responsive to different types of treatment than other subtypes of depression.
Christine Heim is Associate Professor in the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA.
There are still some time slots available for meeting with Christine on Thurday (between 1pm and 3pm). Please contact Nicolas Rohleder if you’re interested!

The Changing Face of Science Reflected in Exciting New Courses

Exciting advances in science are reflected in at least 9 new courses to be offered by the Division of Science. From epigenetics to medicinal enzymology to stem cells to MATLAB, these courses will expose students to some of the frontiers of new knowledge in science.

Details of the courses offered can be found on the following pages

A Taste of Don

Even when we are trying to take a break from lab and chemosensory research on the weekends, it somehow ends up right in our laps. Riding the T we found in one of the ubiquitous discarded papers this article about the science of taste that highlights our own Don Katz, doing his part to mix business and pleasure this week at one of Boston’s premier cocktail destinations:

http://digboston.com/taste/2010/10/science-of-taste/

- Yaihara Fortis and Benjamin Rubin


(editor’s note: the fundraiser is on Wed, Oct 27, see http://lupecboston.com/2010/10/14/science-of-taste-seminar/)

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