Another way that flies sense temperature

If you remember your (bio-)physical chemistry, you’ll remember that most proteins are temperature sensitive. But which ones acts as the sensors that drive behavior in higher organisms? The Garrity Lab at Brandeis has been working on thermosensation in Drosophila, and previous work has implicated the channel protein TRPA1 as a key mediator of temperature preference and thermotaxis,  In a new paper in Nature, members of the Garrity lab working in collaboration with the Griffith and Theobald have have identified another protein, GR28B(D), a member of the family of gustatory receptor proteins, as another behaviorally important temperature sensor, involved in rapid avoidance of high temperatures. Authors on the paper include postdocs Lina Ni (lead author) and Peter Bronk, grad students April Lowell (Mol. Cell Biology) and Vincent Panzano (PhD ’13, Neuroscience), undergraduate Juliette Flam ’12, and technician Elaine Chang ’08.

  • Ni L, Bronk P, Chang EC, Lowell AM, Flam JO, Panzano VC, Theobald DL, Griffith LC, Garrity PA. A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila. Nature. 2013.
  • story at BrandeisNOW

 

What a failed drug does (and is there hope for latrepirdine?)

Latrepirdine (Dimebon) was initially used as an antihistamine drug in Russia. It was later found to be neuroprotective, and entered phase II clinical trials in the US for both Alzheimer’s disease and Huntington’s disease. However, Dimebon failed in a US-based phase II replication trial of a prior successful Russian phase II trial of mild-to-moderate AD. Given the initial promise of the drug and split results,  as well as the lack of treatments for neurodegenerative diseases, there in is significant interest in understanding the underlying molecular mechanism(s) for the drug’s effects.

In a paper appearing this week in Molecular Psychiatry, Brandeis researchers in the Petsko-Ringe lab, including postdoc Shulin Ju and undergraduate Jessica Liken ’11, used yeast models of neurodegenerative disease associated proteins to show that Dimebon specifically protects yeast from the cytotoxiciy of α-synuclein, a protein involved in Parkinson’s disease. They further showed that protection is mediated through its up-regulation of autophagy pathway. In collaboration with Sam Gandy‘s group at Mount Sinai School of Medicine, these findings were further confirmed and validated in neuronal cell and animal models.

Given these observations, disparities in the contribution of α-synuclein to the neuropathology between the Russian and US Dimebon studies might also explain, at least in part, the inconsistency of the cognitive benefit in the two trials. If this speculation is correct, then it may be interesting to test for benefits of Dimebon in treating synucleinopathies such as Parkinson’s disease, Lewy body dementia, REM sleep disorder and/or multiple system atrophy.

see also: press release from Mt. Sinai Alzheimer’s Diesease Research Center

Steele JW (*), Ju S(*), Lachenmayer ML(*), Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of alpha-synuclein in cells and in mouse brain. Molecular psychiatry. 2012.

Steele JW(*), Lachenmayer ML(*), Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Molecular psychiatry. 2012.

Dynamics of double-strand break repair


In a new paper in the journal Genetics, former Brandeis postdoc Eric Coïc and undergrads Taehyun Ryu and Sue Yen Tay from Professor of Biology Jim Haber’s lab, along with grad student Joshua Martin and Professor of Physics Jané Kondev, tackle the problem of understanding the dynamics of homologous recombination after double strand breaks in yeast. According to Haber,

The accurate repair of chromosome breaks is an essential process that prevents cells from undergoing gross chromosomal rearrangements that are the hallmark of most cancer cells.  We know a lot about how such breaks are repaired.  The ends of the break are resected and provide a platform for the assembly of many copies of the key recombination protein, Rad51.  Somehow the Rad51 filament is then able to facilitate a search of the entire DNA of the nucleus to locate identical or nearly identical (homologous) sequences so that the broken end can pair up with this template and initiate local copying of this segment to patch up the chromosome break.  How this search takes place remains poorly understood.

The switching of budding yeast mating type genes has been a valuable model system in which to study the molecular events of broken chromosome repair, in real time.  It is possible to induce synchronously a site-specific double-strand break (DSB) on one chromosome, within the mating-type (MAT) locus.  At opposite ends of the same chromosome are two competing donor sequences with which the broken ends of the MAT sequence can pair up and copy new mating-type sequences into the MAT locus.

Normally one of these donors is used 9 times more often than the other.  We asked if this preference was irrevocable or if the bias could be changed by making the “wrong” donor more attractive – in this case by adding more sequences to that donor so that it shared more and more homology with the broken ends at MAT.  We found that the competition could indeed be changed and that adding more homologous sequences to the poorly-used donor increased its use.


In collaboration with Jané Kondev’s lab we devised both a “toy” model and a more rigorous thermodynamic model to explain these results.  They suggest that the Rad51 filament carrying the broken end of the MAT locus collides on average 4 times before with the preferred donor region before it actually succeeds in carrying out the next steps in the process that lead to repair and MAT switching.

Dynamics of homology searching during gene conversion in Saccharomyces cerevisiae revealed by donor competition Eric Coïc , Joshua Martin, Taehyun Ryu, Sue Yen Tay, Jané Kondev and James E. Haber. Genetics. 2011 Sep 27 2011 Sep 27

Cryo-electron tomography and the structure of doublet microtubules

In a new paper in PNAS entitled “Cryo-electron tomography reveals conserved features of doublet microtubules“, Assistant Professor of Biology Daniela Nicastro and coworkers describe in striking new detail the structure and organization of the doublet microtubules (DMTs), the most conserved feature of eukaryotic cilia and flagella.

Cilia and flagella are thin, hair-like appendages on the surface of most animal and lower plant cells, which use these organelles to move, and to sense the environment. Defects in cilia and flagella are known to cause disease and developmental disorders, including polycystic kidney disease, respiratory disease, and neurological disorders. An essential feature of these organelles is the presence of nine outer DMTs (hollow protein tubes) that form the cylindrical core of the structure known as the axoneme. The doublet microtubule is formed by tubulin protofilaments and other structural proteins, which provide a scaffold for the attachment of dynein motors (that drive ciliary and flagellar motility) and regulatory components in a highly specific and ordered manner.

To address long-standing questions and controversies about the assembly, stability, and detailed structure of DMTs , the Nicastro lab used a high-resolution imaging technique, cryo-electron microscope tomography (cryo-ET), to probe the structure of DMTs from Chlamydomonas (single-celled algae) and sea urchin sperm flagella. Cryo-ET involves:

  1. rapid freezing of the sample to cryo-immobilize the molecules without forming ice crystals,
  2. tilting the specimen in the electron microscope to collect ~70 different views from +65° to –65°,
  3. computational alignment of the views to calculate a tomogram (a three-dimensional reconstruction of the imaged sample), and
  4. computational averaging of repeating structures in the tomogram to reduce noise and increase resolution.

Cryo-ET provided the necessary resolution to show that the B-tubules of DMTs are composed of 10 protofilaments, not 11, and that the inner and outer junctions between the A- and B-tubules are fundamentally different (see figure). The outer junction, crucial for the initial formation of the DMT, appears to be formed by interactions between the tubulin subunits of three protofilaments with unusual tubulin interfaces, but one of these protofilaments does not fit with the conventionally accepted orientation for tubulin protofilaments. This outer junction is important physiologically, as shown by mutations affecting the usual pattern of posttranslational modifications of tubulin. In contrast, the inner junction is not formed by direct interactions between tubulin protofilaments. Instead, a ladder-like structure that is clearly thinner than tubulin connects protofilaments of the A- and B-tubules.

The level of detail also allowed the Nicastro lab to show that the recently discovered microtubule inner proteins (MIPs) located within the A- and B-tubules are more complex than previously thought. MIPs 1 and 2 are both composed of alternating small and large subunits recurring every 16 and/or 48 nm along the inner A-tubule wall. MIP 3 forms small protein arches connecting the two B-tubule protofilaments closest to the inner junction, but does not form the inner junction itself. MIP 4 is associated with the inner surface of the A-tubule along the partition protofilaments, i.e., the five protofilaments of the A-tubule bounded by the two junctions with the B-tubule.

The Nicastro lab plans to build on this foundation in future work on the molecular assembly and stability of the doublet microtubule and axoneme, and hope to use it to elucidate molecular mechanisms of ciliary and flagellar motility and signal transduction in normal and disease states.

Other authors on the paper include Brandeis postdocs Xiaofeng Fu and Thomas Heuser, Brandeis undergrad Alan Tso (’10), and collaborators Mary Porter and Richard Linck from the University of Minnesota.

Physics students present research at 20th Annual Berko Symposium on May 16

On Monday, May 16, the Physics Department will hold the Twentieth Annual Student Research Symposium in Memory of Professor Stephan Berko in Abelson 131. The symposium will end with talks by the two Berko Prize winning students, undergraduate Netta Engelhardt and graduate student Tim Sanchez. The whole department then gathers for a lunch of cold cuts, cookies and conversation. “It’s a great way to close out the academic year,” said Professor of Astrophysics and Department Chair John Wardle. “We come together to celebrate our students’ research and hear what the different research groups are doing.”

The undergraduate speakers will describe their senior thesis honors research. This is the final step in gaining an honors degree in physics, and most of them will also be co-authors on a paper published in a mainline science journal. The graduate student speakers are in the middle of their PhD research, and will disucss their progress and their goals.

The prize winners are nominated and chosen by the faculty for making particularly noteworthy progress in their research. Graduate student winner Sanchez’ talk is titled “Reconstructing cilia beating from the ground up.” He works in Professor Zvonimir Dogic’s lab studying soft condensed matter. Undergraduate winner Engelhardt’s talk is titled “A New Approach to Solving the Hermitian Yang-Mills Equations”. She works with Professors Matt Headrick and Bong Lian (Math) on problems in theoretical physics and string theory. The schedule for Monday morning and abstracts of all the talks can be found on the Physics Department website.

Sanchez’ research very much represents the growing interdisciplinary nature of science at Brandeis. Here, a physicist’s approach is used to study a biological organism. Professor Zvonimir Dogic says of his work “He has made a whole series of important discoveries that are going to have a measurable impact on a number of diverse fields ranging from cell biology, biophysics, soft matter physics and non-equilibrium statistical mechanics.  His discoveries have fundamentally transformed the direction of my laboratory and probably of many other laboratories as well.”

Engelhardt’s research is much more abstract and mathematical, and concerns fundamental problems in string theory, not usually an area tackled by undergraduates. Professor Headrick says “Netta really, really wants to be a theoretical physicist, preferably a string theorist. She has a passion for mathematics, physics, and the connections between them.” He adds that she is utterly fearless in tackling hard problems. Netta has been awarded an NSF Graduate Research Fellowship based on her undergraduate work here.  Next year she will enter graduate school at UC Santa Barbara and will likely work with eminent string theorist Gary Horowitz, who has already supervised the PhD research of two other Brandeis physics alumni, Matthew Roberts ’05, and Benson Way ’08.

This Student Research Symposium is now in its 20th year. The “First Annual…..” (two words which are always unwise to put next to each other) was initiated in 1992 by Wardle to honor Professor Stephan Berko, who had died suddenly the previous year. Family, friends and colleagues contributed to a fund to support and celebrate student research in his memory. This provides the prize money which Netta and Tim will share.

Stephan Berko was a brilliant and volatile experimental physicist who was one of the founding members of the physics department. He was born in Romania in 1924 and was a survivor of both the Auschwitz and Dachau concentration camps. He came to the United States under a Hillel Foundation scholarship and obtained his PhD at the University of Virginia. He came to Brandeis in 1961 to establish a program in experimental physics and worked tirelessly to build up the department. Together with Professors Karl Canter (dec. 2006) and Alan Mills (now at UC Riverside) he established Brandeis as a world center for research into positrons (the anti-matter mirror image of ordinary electrons). In a series of brilliant experiments they achieved many “firsts,” culminating in election to the National Academy of Sciences for Steve, and, it has been rumored, in a Nobel Prize nomination for the three of them. Steve was as passionate about teaching as he was about research, and when he died, it seemed most appropriate to honor his memory by celebrating the research of our graduate and undergraduate students. During the coffee break on Monday, we will show a movie of Steve lecturing on “cold fusion,” a headline-grabbing but phony claim for producing cheap energy from 1989.

Detecting Mutations the Easy Way

Recent Brandeis Ph.D graduate, Tracey Seier (Molecular and Cell Biology Program), Professor Sue Lovett, Research Assistant Vincent Sutera, together with former Brandeis undergraduates Noor Toha, Dana Padgett and Gal Zilberberg have developed a set of bacterial strains that can be used as “mutational reporters”.  Students in the Fall 2009 BIOL155a, Project Laboratory in Genetics and Genomics, course also assisted in the development of this resource. This work has recently been published in the journal Genetics.

These Escherichia coli strains carry mutations in the lacZ (β-galactosidase) gene that regain the ability to metabolize lactose by one, and only one, specific type of mutation. This set allows environmental compounds to be screened for effects on a broad set of potential mutations, establishing mutagen status and the mutational specificity in one easy step.

This strain set is improved over previous ones in the inclusion of reporters that are specific for certain types of mutations associated with mutational hotspots in gene. Mutations at these sites occur much more frequently than average and involve DNA strand misalignments at repeated DNA sequences rather than DNA polymerase errors. Such mutations are associated with human diseases, including cancer progression, and have been under-investigated because of the lack of specific assays. Using this strain set, Seier et al. also identified a mutagen, hydroxyurea, used in the treatment of leukemia and sickle cell disease, which affects only the “hotspot” class of mutations. This strain set, which will be deposited in the E. coli Genetic Stock Center,  will facilitate the screening of potential mutagens, environmental conditions or genetic loci for effects on a wide spectrum of mutational events.

 

 

Left: E. coli colonies showing lacZ mutant revertants (blue pimples) arising on a white colony on growth medium containing the beta-galactosidase indicator dye,  X-gal

 

Older Adults are Better at Spotting Fake Smiles

Studies of aging and the ability to recognize others’ emotional states tend to show that older adults are worse than younger adults at recognizing facial expressions of emotion, a pattern that parallels findings on non-social types of perception. Most of the previous research focused on the recognition of negative emotions such as anger and fear. In a study “Recognition of Posed and Spontaneous Dynamic Smiles in Young and Older Adults” recently published in Psychology and Aging, Derek Isaacowitz’s Emotion Laboratory set out to investigate possible aging effects in recognizing positive emotions; specifically, the ability to discriminate between posed or “fake” smiles and genuine smiles. They video-recorded different types of smiles (posed and genuine) from younger adults (mean age = 22) and older adults (mean age = 70). Then we showed those smiles to participants who judged whether the smiles were posed or genuine.

Across two studies, older adults were actually better at discriminating between posed and genuine smiles compared to younger adults. This is one of the only findings in the social perception literature suggesting an age difference favoring older individuals. One plausible reason why older adults may be better at distinguishing posed and spontaneous smiles is due to their greater experience in making these nuanced social judgments across the life span; this may then be a case where life experience can offset the effects of negative age-related change in cognition and perception.

This was the first known study to present younger and older adult videotaped smiles to both younger and older adult participants; using dynamic stimuli provides a more ecologically valid method of assessing social perception than using static pictures of faces. The findings are exciting because they suggest that while older adults may lose some ability to recognize the negative emotions of others, their ability to discriminate posed and genuine positive emotions may remain intact, or even improve.

The Emotion Laboratory is located in the Volen Center at Brandeis. First author Dr. Nora Murphy (now Assistant Professor of Psychology at Loyola Marymount University) conducted the research as a postdoctoral research fellow, under the supervision of Dr. Isaacowitz, and second author Jonathan Lehrfeld (Brandeis class of 2008) completed his Psychology senior honors thesis as part of the project. The research was funded by the National Institute of Aging.

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