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.

Dmitry Kleinbock is awarded a Simons Fellowship in Mathematics

Dmitry KleinbockProfessor of Mathematics Dmitry Kleinbock has been awarded a prestigious Simons Fellowship in Mathematics, which will support research activities during his sabbatical leave in the fall of 2022.

Kleinbock’s research deals with dynamical systems of algebraic origin and their applications to number theory. A dynamical system is simply a set of points together with an evolution law that governs the way points move over time. It turns out that many mathematical problems concerning integer solutions of some equations or inequalities can be understood in terms of the behavior of certain dynamical systems. Furthermore, systems that arise in this context are of algebraic nature (so called flows on homogeneous spaces of Lie groups), which makes it possible to use a wide variety of sophisticated tools such as representation theory, hyperbolic geometry and geometry of lattices.

During the Spring 2022 semester Kleinbock is visiting the Institute for Mathematical Research at ETH (Zürich, Switzerland), giving a lecture course on the topic of dynamics on homogeneous spaces. The plan for the spring is to finish several projects and start new collaborations. Then in the Fall 2022 semester Kleinbock will be a member of a thematic program on Applications of Dynamics in Number Theory and Algebraic Geometry at the Institute for Advanced Studies in Princeton, NJ, led by Tamar Ziegler (Hebrew University, Jerusalem). This will be an excellent opportunity, thanks to the Simons Fellowship, to explore further connections between dynamics and number theory.

Grace Han and 2 Alumni Receive 2022 Sloan Foundation Fellowships

Grace Han group photo

Grace Han (left) and her group.

The Alfred P. Sloan Foundation has announced the winners of the 2022 Sloan Research Fellowships. These fellowships are awarded to early-career scientists that represent the most promising researchers working today. Winners receive $75,000, which can be used to support their research over a two-year term. Grace Han, Assistant Professor of Chemistry and the Landsman Career Development Chair in the Sciences is one of the 2022 recipients.

The major goal of Dr. Grace Han’s research program is to develop functional organic material systems that exhibit phase transitions triggered by external stimuli, notably light. The photo-controlled phase-change materials have a game-changing potential in waste heat recycling and storage, photo-actuation, photo-lithography, and photo-regulated adhesion. In particular, the novel strategy to optically ‘fix’ a liquid phase under fluctuating temperatures allows for a long-term latent heat storage and a triggered release of energy, which is not attainable by conventional phase-change materials such as paraffins or salt hydrates. To achieve this goal, her team investigates the photo-induced structural and polarity changes of molecular switches based on azobenzene, which reversibly controls the phase of materials.
The Sloan Research Fellowship will support the new direction of Han group’s research in expanding the materials set by the rational design of photoswitches with enhanced optical and thermal properties, which will address the challenges of the current state-of-the-art switches.
Two Brandeis alumni also received 2022 fellowships: Netta Engelhardt, BS ’11 (Physics) and Dapeng Bi, PhD ’12 (Physics).

Anish Ghosh receives the 2021 Shanti Swarup Bhatnagar Prize

Anish Ghosh has received the 2021 Shanti Swarup Bhatnagar Prize in Mathematical Sciences. The Shanti Swarup Bhatnagar Prize is India’s highest science award within the country. While at Brandeis, Anish Ghosh was the student of Dmitry Kleinbock, Professor of Mathematics. He is currently a faculty member at the Tata Institute of Fundamental Research (TIFR), Mumbai where he specializes in Ergodic Theory and Number Theory.

Kleinbock wrote the following about his former student:

“It was a great pleasure to find out that Anish Ghosh, my former student here at Brandeis, has received the Shanti Swarup Bhatnagar prize. Anish is a talented mathematician working in the field of ergodic theory on homogeneous spaces. Interest in this field rose significantly during the late 1980s and early 1990s after the seminal achievements of Marina Ratner and Anish’s mathematical grandfather Gregory Margulis, whose work, in particular the proof of the Oppenheim Conjecture, has since served as a basis for numerous links between dynamics and number theory.”

“Anish has been exploring connections between the two fields throughout his mathematical career. Since his graduation in 2006 he has authored more than 40 papers, many published in top-level journals, and has become one of a few people who are shaping the subject of ergodic theory and its arithmetical applications. Among his notable achievements I can mention the work on distribution of dense lattice orbits in homogeneous spaces, on intrinsic Diophantine approximation, on applications of equidistribution to counting lattice points and – most recently – an approach to quantitative Oppenheim-type problems involving Rogers’ moment formulas.”

“Anish has also been a great mentor, who as of now has produced at least 8 PhD students and collaborated with them extensively on various problems. He has lectured extensively on the subject of connections of dynamics and number theory and edited several collections of papers. To summarize, the Bhatnagar Prize is well deserved, and I am positive that the mathematical talent of Anish Ghosh will continue to flourish.”

Divisional Prize Instructors design & teach new classes

The University Prize Instructorships have been a great opportunity for our graduate students to gain experience designing and teaching their own class, and a great opportunity for our undergraduates to engage in learning new areas with a great instructor. When the UPIs were put on hiatus during the pandemic, the Division of Science stepped in to keep this opportunity going for our community. We are really excited for the new courses that will be taught by Xin Yao Lin and Narges Iraji in the Spring 2022 semester- “Science versus Science Fiction” by Narges Iraji, and “Technology Use and Well-Being: Multidisciplinary Perspectives”.

Xin Yao Lin

Xin Yao LinI am very honored and delighted to receive the Divisional Prize Instructorship. I am currently a 5th-year psychology PhD student and I will be teaching a psychology course entitled “PSYC 55B: Technology Use and Well-Being: Multidisciplinary Perspectives” in the spring of 2022. The increase in technology use is changing how we connect, feel, and act. We are relying on technology more than ever, but whether the increased usage of technology is beneficial or detrimental to well-being has been controversial. Drawing on perspectives from psychology, neuroscience, computer-human interaction, and public health, this course explores the positive and negative impact of technology usage on our well-being across the lifespan. We will examine technology use in computer-mediated communication (e.g., smartphone, social media, internet, social apps), mHealth and telehealth, gaming, and other technology trends (e.g., Artificial intelligence, robots, virtual reality), and will explore how these technologies influence social life, adult development and aging, and health/health behavior (e.g., physical activity, diet, sleep).

I am very thankful for this opportunity provided by the Division of Science, and for my mentors and peers who have provided feedback and supported me along the way. I look forward to teaching this course and engaging students with how technology influences our social life, how we develop and age, and our health/health behavior.

Narges Iraji

Narges IrajiThe course Science and Science Fiction, designed for students with little to no science or math background, encourages conversations around science within the context of culture. Reading the works of science fiction by a diverse group of authors and discussing the science and imagination in them illuminates the inseparability of science from its human nature. I hope that this approach not only bridges the materials taught in class and the outside world but also sparks a curiosity that goes beyond the classroom.

Our inner urge to observe, decode patterns, and predict has existed well past the modern times and so has our passing of knowledge to the future in the form of storytelling. The combination of imagination and science is nothing new but the access to both, who can imagine and who can be a scientist, has changed throughout history. During the course, the students will read, discuss, and write about science fiction stories that inspire questions and problems which call for mathematical modeling. After becoming more familiar with some well-known mathematical models in areas such as population modeling and epidemiology, the students start working on a final project. They will formulate a question related to what they are passionate or curious about and pursue the answer using the tools that they have gained from the course. The goal is not to solve the problem, but to gain some insight into the steps required in doing so.

Teaching a University Prize Instructorship course has been a dream of mine since I heard about this opportunity in my first or second year. I am grateful for this, and thankful to all those who are helping me along the way. Numerous challenges follow developing a course, and while being one of the greatest projects that I have taken on, it has tested my patience a few times. I hope that after serving as a University Prize Instructorship instructor, I can help other graduate students who are interested in this opportunity by sharing some resources, such as information on inviting speakers or reserving classrooms with computers. My experience as a graduate student in physics and my research in the field of mathematical biology have truly led me to a new perspective. I now look around and find questions in all that I observe knowing someone else might have already started working on the answer. The course, Science and Science Fiction, encapsulates one of my attempts to pass this curiosity about the universe and life forward.

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