Funded by the Provost’s Office and the Office of Technology Licensing (OTL), Sprout is designed to encourage and support translational research activity within the Brandeis community for faculty, postdocs, and student researchers (graduate and undergraduate) in the Division of Science. The awards (up to $25,000) are intended to help advance early-stage technologies to industry adoption.
Pre-applications are due by March 29. Successful pre-applicants will be invited to submit a final application, followed by a final pitch to a panel of industry judges.
The Brandeis University Postdoctoral Association (BUPA) is organizing its yearly Invited Postdoc Research Colloquium (IPRC) for the academic year 2022-2023. BUPA is inviting two senior neuroscience postdocs to Brandeis to present their research and visit the Brandeis community. Selected speakers will give an hour-long seminar, meet with faculty one-on-one, and engage in informal discussion with Brandeis postdocs over lunch and dinner. This provides a great opportunity for the speakers to receive scientific feedback and increase their visibility in the scientific community, two essential aspects for their future job search. Also, of course, this is an equally great opportunity for the Brandeis community to engage in fruitful scientific discussion and learn about exciting research performed outside of the Brandeis campus.
Interested postdocs should send an updated CV as well as an abstract of their research (maximum 250 words) to BUPA (bupa@brandeis.edu). Seminars will be organized in person and funds for travel, accommodation and food will be provided for the speakers. Virtual presentations will be organized should the need arise. Women and underrepresented minorities are strongly encouraged to apply. The application deadline is August 31, 2022.
For additional information, please contact BUPA at bupa@brandeis.edu.
Yerdos Ordabayev et al. in the Department of Biochemistry use Bayesian probabilistic programming to implement computer software “Tapqir” for analysis of colocalization single-molecule spectroscopy (CoSMoS) image data. CoSMoS is a tool widely used in vitro to study the biochemical and physical mechanisms of the protein and nucleic acid macromolecular “machines” that perform essential biological functions. In this method, formation and/or dissociation of molecular complexes is observed by single-molecule fluorescence microscopy as the colocalization of binder and target macromolecules each labeled with a different color of fluorescent dye. Despite the use of the method for over twenty years, reliable analysis of CoSMoS data remains a significant challenge to the effective and more widespread use of the technique.
This work describes a holistic causal probabilistic model of CoSMoS image data formation. This model is physics-based and includes realistic shot noise in fluorescent spots, camera noise, the size and shape of spots, and the presence of both specific and nonspecific binder molecules in the images. Most importantly, instead of yielding a binary spot-/no-spot determination, the algorithm calculates the probability of a colocalization event. Unlike alternative approaches, Tapqir does not require subjective threshold settings of parameters so they can be used effectively and accurately by non-expert analysts. The program is implemented in the state-of-the-art Python-based probabilistic programming language Pyro (open-sourced by Uber AI Labs in 2017), which enables efficient use of graphics processing unit (GPU)-based hardware for rapid parallel processing of data and facilitates future modifications to the model. Tapqir is free, open-source software. We envision that Tapqir program is likely to be adopted by researchers who use single-molecule colocalization methods to study a wide range of different biological systems.
Reference:
Yerdos A Ordabayev, Larry J Friedman, Jeff Gelles, Douglas L Theobald. Bayesian machine learning analysis of single-molecule fluorescence colocalization images. eLife 2022;11:e73860.
Michael Rosbash, the Peter Gruber Endowed Chair in Neuroscience and Professor of Biology and his wife, Nadja Abovich, established the Rosbash-Abovich Award as a way to inspire and acknowledge excellence in research by post-doctoral fellows and graduate students in the Brandeis life sciences. The Rosbash-Abovich award will be awarded annually.
The award honors the most outstanding papers published the previous year that have been authored by a Brandeis postdoctoral fellow and a Brandeis PhD student. In addition to the honor being selected, each winner is presented with a monetary award.
Future winners will present their talks at upcoming Volen Scientific Retreats, but due to COVID restrictions, the 2020 winners will be presenting their talks during the Molecular Genetics Journal Club meetings.
Mike is a remarkable scientist and mentor. He single-handedly and independently established a new research direction in my lab. He also served as an informal mentor to many graduate students and has continued to do so even after he left my lab. I greatly appreciated our long discussions and arguments, and he is very much missed.
Sengupta also noted that O’Donnell was chosen to receive this award
on the basis of the creativity and novelty of his work that was published in Nature. The committee was particularly interested in nominating a researcher who was a driving force behind the work and Mike certainly fulfilled this criteria.
O’Donnell is now an assistant professor at Yale and recently formed the O’Donnell lab. He presented his talk to the Molecular Genetics Journal Club on December 2, 2020. He spoke about his work on neuromodulators produced by different bacteria.
When asked about his former PhD student, Haber said
I was delighted to learn that Gonen was the recipient of the Rosbash/Abovich award for the best publication by a graduate student last year; but I had to ask “which paper” because Gonen made two important discoveries last year about the way cells respond to DNA damage. Gonen helped develop a highly efficient way to edit the yeast genome and to create dozens of very precise mutations in the Mec1 gene that is the master regulator of the DNA damage response. When there is a chromosome break, the Mec1 protein phosphorylates a number of proteins that creates a cascade of signaling to prevent cells from progressing through mitosis until damage is repaired. Gonen discovered that the extinction of the this signal depended on Mec1’s autophosphorylation of one specific target and that changing that specific amino acid to one that could not be phosphorylated was enough to cause cells to remain arrested. She also identified several alterations of the Ddc2 protein that associates with Mec1 that were also critical for its normal activation.
During her time in my lab Gonen was a super hard-working and exceptionally insightful grad student, but also incredibly generous with her time, helping others in the lab
The central nervous system has the most cellular diversity of any organ in the body, but how does this diversity arise?
While the presumption is that genetic programs specify each neuron type, our understanding of these programs is in its infancy. To begin uncovering the underlying design principles of neuronal architecture in the brain, scientists from the Nelson Lab at Brandeis University and the HHMI Janelia Research Campus jointly formed the NeuroSeq project to profile genetic programs in a monumental number of neurons throughout the nervous system. Selected neurons were from transgenic animals to facilitate access among the scientific community for future functional studies. While single cell sequencing is the most popular method for transcriptome profiling, its technical limitations only provide a shallow view of molecular profiles. To go deeper, the NeuroSeq program assessed transcription in pools of nearly 200 genetically identified mouse cell types. NeuroSeq captured 80% of single gene copies and could even assess splice isoforms.
What did the NeuroSeq effort find?
Interestingly, two unique classes of genes lie at the heart of adult neuronal identity. Homeobox transcription factors and long genes explain a great deal of the neuronal diversity in the central nervous system. This extends the role of homeobox genes well beyond development and into neuronal identity maintenance. It also highlights long genes as an important class of neuronal identity effectors. Long genes are long due to insertion of foreign elements, and they come with costs, namely increased energy consumption and risk of mutations. These costs seem to be overcome by the benefits of neuronal diversification. We are excited to spotlight the NeuroSeq project in providing a unique resource for future discoveries concerning neuronal diversity and function.
The data resource is available at neuroseq.janelia.org, and the findings are described in a recent paper in eLife. Brandeis-affiliated authors on the paper include Professor Sacha Nelson, former postdoc Ken Sugino PhD ’05 (now at HHMI Janelia), current postdoc Erin Clark, and former research scientist Yasuyuki Shima.
By Craig W. Stropkay, (PhD ’13, Molecular and Cell Biology, Ren lab)
Reach for the stars, they said. You should definitely go get your PhD, you’d be great for it, they said. Well, I guess they did have a point. Pursuing my doctorate degree in Molecular Biology at Brandeis was definitely one of the most challenging things that I have ever had to do in my life. I could spend hours telling you about the long hours I spent trying to construct my dissertation or the countless nights that I had to wake up and drive into the lab from Medford just to “feed” my cells — but that’s not the point of this article. I want to talk about something that I wish was more openly discussed when I first started my journey towards pursuing a PhD. Something that I believe is important to anyone who is currently working their way towards earning their doctoral degree: a job.
Now I know what you may be thinking: why would I need to worry about a job when I know I will continue onto a postdoc and then a tenure-track academic post? Isn’t that what everyone does? That is precisely my point. Don’t get me wrong: there is absolutely nothing wrong with continuing a career in academia upon completion of your doctorate. It takes a lot of patience, skill, and dedication to remain in the field after you have literally spent years becoming an expert in everything dealing with Life Science. Maybe you’ve considered going that route, feeling that your choices are limited. Many people believe that apart from academia, their only “alternative” option is to go into industry and work in biotech or pharma.
Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.
Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.
Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.
They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!
Why humans and other animals sleep is one of the remaining deep mysteries of physiology. One prominent theory in neuroscience is that sleep is when the brain replays memories “offline” to better encode them (“memory consolidation”). A prominent and competing theory is that sleep is important for re-balancing activity in brain networks that have been perturbed during learning while awake. Such “rebalancing” of brain activity involves homeostatic plasticity mechanisms that were first discovered at Brandeis University, and have been thoroughly studied by a number of Brandeis labs including the Turrigiano lab. Now, a study from the Turrigiano lab just published in the journal Cell shows that these homeostatic mechanisms are indeed gated by sleep and wake, but in the opposite direction from that theorized previously: homeostatic brain rebalancing occurs exclusively when animals are awake, and is suppressed by sleep. These findings raise the intriguing possibility that different forms of brain plasticity – for example those involved in memory consolidation and those involved in homeostatic rebalancing – must be temporally segregated from each other to prevent interference.
The requirement that neurons carefully maintain an average firing rate, much like the thermostat in a house senses and maintains temperature, has long been suggested by computational work. Without homeostatic (“thermostat-like”) control of firing rates, models of neural networks cannot learn and drift into states of epilepsy-like saturation or complete quiescence. Much of the work in discovering and describing candidate mechanisms continues to be conducted at Brandeis. In 2013, the Turrigiano Lab provided the first in vivo evidence for firing rate homeostasis in the mammalian brain: lab members recorded the activity of individual neurons in the visual cortex of freely behaving rat pups for 8h per day across a nine-day period during which vision through one eye was occluded. The activity of neurons initially dropped, but over the next 4 days, firing rates came back to basal levels despite the visual occlusion. In essence, these experiments confirmed what had long been suspected – the activity of neurons in intact brains is indeed homeostatically governed.
Due to the unique opportunity to study a fundamental mechanism of brain plasticity in an unrestrained animal, the lab has been probing the possibility of an intersection between an animal’s behavior and homeostatic plasticity. In order to truly evaluate possible circadian and behavioral influences on neuronal homeostasis, it was necessary to capture the entire 9-day experiment, rather than evaluate snapshots of each day. For this work, the Turrigiano Lab had to find creative computational solutions to recording many terabytes of data necessary to follow the activity of single neurons without interruption for more than 200 hours. Ultimately, these data revealed that the homeostatic regulation of neuronal activity in the cortex is gated by sleep and wake states. In a surprising and unpredicted twist, the homeostatic recovery of activity occurred almost exclusively during periods of activity and was inhibited during sleep. Prior predictions either assumed no role for behavioral state, or that sleeping would account for homeostasis. Finally, the lab established evidence for a causal role for active waking by artificially enhancing natural waking periods during the homeostatic rebound. When animals were kept awake, homeostatic plasticity was further enhanced.
This finding opens doors onto a new field of understanding the behavioral, environmental, and circadian influences on homeostatic plasticity mechanisms in the brain. Some of the key questions that immediately beg to be answered include:
What it is about sleep that precludes the expression of homeostatic plasticity?
How is it possible that mechanisms requiring complex patterns of transcription, translation, trafficking, and modification can be modulated on the short timescales of behavioral state-transitions in rodents?
And finally, how generalizable is this finding? As homeostasis is bidirectional, does a shift in the opposite direction similarly require wake or does the change in sign allow for new rules in expression?
Authors on the paper include postdoctoral fellow Keith Hengen, Neuroscience grad student Alejandro Torrado Pachedo, and Neuroscience undergraduate James McGregor ’14 (now in grad school at Emory).
Hengen KB, Torrado Pacheco A, McGregor JN, Van Hooser SD, Turrigiano GG. Neuronal Firing Rate Homeostasis is Inhibited by Sleep and Promoted by Wake. Cell. 2016.
Registration for our annual, one-week summer course, “Introduction to Microfluidics Technology” at Brandeis University, near Boston, MA, is now open. The application deadline is March 31, 2016.
Introduction to Microfluidics Technology is a hands-on laboratory course sponsored by the National Science Foundation’s Bioinspired Soft Materials Research Science and Engineering Center (MRSEC) at Brandeis. It will be offered during the week of June 13 ‐ 17, 2016. The course is intended for graduate students, post docs, faculty, and industrial scientists/engineers interested in utilizing microfluidic technology in their work, both in the physical and life sciences. The course does not assume any specific prerequisites.
“Introduction to Microfluidics Technology” (June 13 – 17, 2016) will be taught by Dr. Nathan Tompkins.
The $750 fee covers course tuition, housing in double-occupancy rooms, and breakfast/lunch/coffee from Monday through Friday. Single rooms are not available. Local students who do not need housing will pay a non-resident fee of $500 (cash and check only please).
Laboratories around the world and here at Brandeis are generating a tsunami of deep-sequencing data from organisms large and small, past and present. These sequencing data range from genomes to segments of chromatin to RNA transcripts. To explore this “big data” ocean, one can navigate the portals of the National Computational Biotechnology Institute’s (NCBI’s) two signature repositories, the Sequencing Read Archive (SRA) and the Gene Expression Omnibus (GEO). With the right bioinformatics tools, scientists can explore and discover freely-available data that can lead to new biological insights.
In the NAR study, postdoctoral fellow Reazur Rahman and the Lau team devised a program called TIDAL (Transposon Insertion and Depletion AnaLyzer) that scoured over 360 fly genome sequences publicly accessible in the SRA portal. Their study discovered that transposons (jumping genetic parasites) formed different genome patterns in every fly strain. Common fly strains with the same name but living in different laboratories turn out to have very different patterns of transposons. Simply noting “Canton-S” or “Oregon-R” strains are used may not be enough to fully characterize a strain. The Lau lab hopes to utilize the TIDAL tool to study how expanding transposon patterns might alter genomes in aging fly brains.
The piRNAs from these animals were compared in the PLoS Genetics story
In the PLoSGen study, visiting scientist Gung-wei Chirn and the Lau team developed a novel small RNA tracking program that discovered Piwi-interacting RNA loci expression patterns from many mammalian datasets extracted from the GEO portal. Coupling these datasets with other small RNA datasets created in the Lau lab at Brandeis, the Lau group discovered a remarkable diversity of these RNA loci for each species. For example, the piRNA genomic loci made in humans were quite distinct from other primates like the macaque monkey and the marmoset. However, a special set of these genomic loci have been conserved in their piRNA expression patterns, extending across humans, through primates, to rodents, and even to dogs, horses and pigs.
These conserved piRNA expression patterns span nearly 100 million years of evolution, which is quite a long time for these types of loci to be maintained for some likely important function in mammals. To test this hypothesis that evolution preserved these piRNAs for their utility, the Lau lab analyzed two existing mouse mutations in these loci. They showed that the mutations indeed affected the generation of the piRNAs, and these mice were less fertile because sperm count was reduced. The future studies from the Lau lab will explore how infertility diseases may be linked to these specific piRNA loci.
Science at Brandeis 
