SciFest XI to be held on Thursday, 8/11/22

Save the Date for SciFest!

SciFest, the Division of Science’s annual celebration of undergraduate research, is a poster session featuring work done by undergraduates in Brandeis laboratories each summer. This is a capstone event for the undergraduate researchers where they can present the results of their research to peers, grad students, and faculty.

Join us for the SciFest XI which will be held on Thursday, August 11, 2022 in the Shapiro Science Center.

Christine Grienberger Receives 2022 Smith Family Award

Grienberger Smith Family AwardChristine Grienberger, Assistant Professor of Biology, has received the 2022 Smith Family Awards Program for Excellence in Biomedical Research. This award is given to new faculty working in the field of biomedical research.

The following is a summary of Professor Grienberger’s research:

The brain has an extraordinary capacity to learn and to use past experiences to guide future behavior. When individuals learn, they create connections among features, e.g., the location of a restaurant and the food quality, to predict a future outcome. The hippocampal formation, a network of synaptically connected areas in the mammalian brain, is crucial for rapidly forming these associations and relaying them to the rest of the brain to drive learning. Our goal is to understand how the output region of the hippocampal formation, the subiculum, promotes this function. To this end, we will combine for the first time subicular whole-cell recordings, optogenetic perturbation of neural activity, and a spatial learning task. Our findings will provide novel insights into how basic cellular properties endow neurons in the currently poorly understood subiculum with the ability to affect learning. This work will also provide a starting point for investigating functional disruptions in neuropsychiatric disorders, in which the patients’ ability to learn is impaired, e.g., Alzheimer’s disease.

Congratulations!

 

Virtual Conference: Climate & Math to be held 5/26/22

As part of the Brandeis’ Year of Climate ActionThomas Fai, Assistant Professor of Mathematics and Jonathan Touboul, Associate Professor or Mathematics (with Denis Patterson from Princeton University) have organized a Climate and Math Conference for Thursday, May 26th (10:00 AM to 5:00 PM). This will be a virtual one-day conference offered as part of the Brandeis Mathematical Biology Seminar.

This conference will bring together leading researchers in mathematical modeling related to climate change. It will cover techniques from mathematical modeling, data analysis and climate policy, and topics including impact of climate change on vegetation, animal populations, water/ice, carbon, and human health.

This virtual conference is part of the Brandeis Year of Climate Action program that will be occurring throughout 2022 and 2023. The Office of Sustainability is responsible for this program.

 

Blanchette and Scalera et al., discover new insights into an intercellular communication method in neurons

Fruit fly neuron (magenta) with extracellular vesicle cargoes (green). Cargoes are packaged inside the neuron and, then released outside of the neuron in extracellular vesicles.

Research scientist Cassie Blanchette and Neuroscience Ph.D. student Amy Scalera, working in the Rodal lab, discovered a new mechanism of regulation of extracellular vesicles (EVs). EVs are small, membrane-bound compartments that can transfer cargoes such as DNA and proteins between cells for communication. EVs are important for normal cell-cell signaling, but they are also hijacked in neurodegenerative disease to spread toxic disease proteins to other cells. Therefore, it is crucial to understand how and where EVs are formed. Blanchette and Scalera discovered a novel method of regulation of EVs specifically at the synapses (the region of the neuron that contacts adjacent cells), using the fruit fly nervous system as an experimental model.

EVs are derived from endosomes, a network of intracellular sorting compartments that cells use to separate cargoes into different ‘packages’ with distinct inter and intracellular destinations. Blanchette and Scalera found a surprising function for the proteins that regulate endocytosis, a process in which the cell membrane buds inward, thus forming a compartment to bring cargoes to endosomes. The authors found that mutants lacking endocytic proteins lose the local pool of EV cargoes that are available for release from synapses, and instead send these cargoes for disposal elsewhere in the neuron. They hypothesized that the normal function of endocytosis  is akin to a plane circling in a holding pattern at an airport – while it waits for its time to land, it is better for the passengers to circle (between the cell membrane and endosomes), nearby their destination (release in EVs), rather than being sent to an entirely different city (a different region of the neuron). They also found that disrupting this holding pattern had consequences for the physiological functions of EV cargoes; in endocytic mutants, loss of Synaptotagmin-4, an EV cargo important for neuronal adaptability, was associated with failure of the neuron to grow in response to firing. Endocytic mutants also caused synaptic depletion of the Alzheimer’s disease associated EV cargo Amyloid Precursor Protein (APP), thus suppressing its toxicity and increasing the survival of APP-expressing flies. These discoveries raise the possibility that proteins regulating EV traffic may be targets for neurodegenerative disease therapies.

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

SARS-CoV-2 is the pathogen causing the COVID-19 pandemic, that as of early February 2022 has caused 5.7 million deaths worldwide.

When a virus infects a cell, it transforms it, so it can become a “virus factory”. To do so, it needs to suspend it from doing the normal functions, but not to a point that the immune system will detect those changes and “decide” to kill the infected cell. Understanding how viruses accomplish that is very important for virology and medicine as, for example, it could be used to help the immune system identify these cells and stop the virus from spreading through the body.

Graphical abstract for Zaffagni post

To tackle this issue, researchers identify genes that get activated or repressed when a virus infects a cell. One way to monitor the genes that are “on” or “off” during the infection is to measure RNAs abundance by RNA sequencing (RNA-seq). Through this approach, recent studies showed that SARS-CoV-2 infection induces big changes on the cells that it infects. Generally, scientists believe changes induced by viral infection are the consequence of the concerned action of the virus proteins acting within the host cell. For example, the SARS-CoV-2 genome encodes 29 proteins. The effect of the virus is so strong that it changes more than 5000 genes in just 48hs, this is almost ¼ of our genes.

How do individual viral proteins contribute to these changes? To answer this question, the Kadener lab in the Department of Biology introduced singular viral SARS-CoV-2 proteins into human cells and monitored gene expression changes through RNA-seq. Between the 26 tested proteins, non-structural protein 14 (Nsp14) was the one inducing the most dramatic effect, altering the expression of ≈4000 genes. Importantly, these changes overlap well with previously published RNA-seq data from human cells infected with SARS-CoV-2. This suggests that transient expression of Nsp14 partially recapitulates the molecular events downstream to SARS-CoV-2 infection. They also showed that a cellular enzyme (IMPDH2) mediates these changes, and that treatment with IMPDH2 inhibitors partially rescues the changes induced by Nsp14.

This research contributes to understanding the function of viral proteins on the host cell and on the molecular mechanisms that control the progression of viral infection. The Kadener lab showed that Nsp14 also modulates gene expression of the host cell by activating a cellular enzyme. These events may be conserved in other coronaviruses infections and the discovery of these molecular mechanisms may be important for designing new therapeutic approaches.

Publication:

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Michela Zaffagni, Jenna M Harris, Ines L Patop, Nagarjuna Reddy Pamudurti, Sinead Nguyen, Sebastian Kadener.  eLife 2022;11:e71945 DOI: 10.7554/eLife.71945.

Ordabayev et al. developed an open-source analysis software for colocalization single-molecule fluorescence experiments

Tapqir analysis

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.
Publication Date: March 23, 2022.

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