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Proteins — and labs — coming together to prevent Rett syndrome

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New discoveries about the disruption of condensates in the neurodevelopmental disorder Rett syndrome provide insights into how cells compartmentalize chromosomes, as well as new potential paths for therapies.

Scientists have, for many years, conceptualized the cell as a relatively free-flowing space, where — apart from the organization provided by specific cellular structures — molecules float freely, somehow ultimately ending up in the right place at the right time. In recent years, however, scientists have discovered that cells have much more spatial organization than previously thought, thanks to a mechanism called phase separation, which occurs in cells when certain molecules form large droplet-like structures that separate what’s inside of the droplet from the rest of the cell. The droplets, called condensates, help sequester and concentrate molecules in specific locations, and appear to increase the efficiency of certain cellular functions.

Whitehead Institute member and MIT professor of biology Richard Young has been exploring the previously unknown role that condensates play in gathering the molecules needed for gene transcription — the process by which DNA is read into RNA. In order to better understand when and how cells use phase separation, Charles Li, a graduate student in Young’s lab, set out to identify more proteins that can form condensates. That search led him to MeCP2, a protein associated with the severe neurodevelopmental disorder Rett syndrome, studied by Young’s colleague, Whitehead Institute founding member Rudolf Jaenisch, who is also a professor of biology at MIT. No cure for Rett syndrome currently exists, and Jaenisch’s lab has been investigating the biology of the disorder in the hopes of discovering a medical therapy that can rescue neurons affected by Rett syndrome.

With the discovery of MeCP2’s condensate-forming ability, Young and Jaenisch saw the opportunity for a promising collaboration between their labs. Led by co-first authors Li and Eliot Coffey, another graduate student in Young’s lab, the two labs investigated MeCP2 and whether the disruption of its condensate-forming ability contributes to Rett syndrome. During these investigations, the researchers also uncovered how cells may use condensates to help organize the active and inactive parts of chromosomes. Their findings, published in the journal Nature on June 22, report on these insights and suggest new paths for developing therapies for Rett syndrome.

Phase separation and Rett syndrome

Proteins that form condensates often contain intrinsically disordered regions (IDRs), long spaghetti-like strands that transiently stick together to form a dynamic mesh. Research has historically focused on the structured regions of proteins, which bind very specifically to other molecules, while IDRs have largely been overlooked. In this case, MeCP2’s large IDRs were exactly what drew Li to it.

“What was striking to me was that this protein has been studied for decades, and so much function has been ascribed to the protein as a whole, yet it only has one structured domain with a recognized function, the DNA binding domain. Beyond that, the entire protein is disordered, and how its parts function was largely unknown,” Li says.

The researchers found that MeCP2 used its IDRs to glom together and form condensates. Then they tested many of the mutations in the MECP2 gene that are associated with Rett syndrome and found that they all disrupt MeCP2’s ability to form condensates. Their findings suggest that therapies targeting condensates associated with the protein, rather than the protein itself, may be promising in the hunt for a Rett syndrome treatment.

“MeCP2 and Rett syndrome have been studied intensely for many years in many labs, and yet not a single therapy has been developed. When the project began, I was immediately fascinated by the idea that we might find a new disease mechanism that could help us finally understand how Rett syndrome arises and how it could be treated,” Coffey says.

“Rick [Young] has shown that condensates play key roles in maintaining normal cellular function, and our latest collaboration illuminates how their disruption may drive diseases such as Rett syndrome,” Jaenisch says. “I hope the insights we have gained will prove useful both in our continued search for a treatment for Rett syndrome and, more broadly, in research on condensates and disease.”

Compartmentalizing chromosomes

The researchers’ investigation into MeCP2’s condensate-forming behavior also shed light on how chromosomes are organized into regions of active and inactive genes. When MeCP2 is functioning normally, it helps to maintain heterochromatin, the roughly half of our chromosomes where genes are “turned off,” unable to be read into RNA or further processed to make proteins. MeCP2 binds to sequences of DNA marked with a certain type of regulatory tag that is typically found in heterochromatin. This helps crowd MeCP2 to the threshold concentration needed to form heterochromatin condensates. These condensates, in turn, help to sequester the molecules needed to maintain it apart from euchromatin, the half of our chromosomes filled with active genes. Different proteins form condensates near euchromatin, concentrating the molecular machinery needed to transcribe active genes there.

Since condensates form when proteins with large spaghetti-like IDRs stick together, one might expect that any protein containing IDRs could interact with any other IDR-containing protein to form droplets, and that is what the researchers have often seen. However, what they observed with MeCP2, which is associated with heterochromatin, is that key condensate-forming proteins associated with euchromatin refused to mix.

It’s important for the health of the cell that the genes in heterochromatin not be inadvertently turned on. The researchers reason that discrete euchromatin and heterochromatin condensates may play a key role in ensuring that transcriptional machinery localizes to euchromatin only, while repressive machinery — like MeCP2 — localizes to heterochromatin. The researchers are excited to turn their attention to how proteins are able to join condensates selectively, and when and where else in the cell they do so.

“There’s a chemical grammar waiting to be deciphered that explains this difference in the ability of some proteins to move into one condensate versus another,” Young says. “Discovering that grammar can help us understand how cells maintain the crucial balance between the active and silent halves of our genome, and it could help us understand how to treat disorders such as Rett syndrome.”


Source: http://news.mit.edu/2020/proteins-and-labs-coming-together-prevent-rett-syndrome-0729

Biotechnology

Forging ahead with care and compassion

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Amidst the uncertainty and stressors of the dual scourges of Covid-19 and structural racism, a number of MIT professors are forging thoughtful ways to support students’ well-being and scholarly development. Several Committed to Caring honorees shared their approaches for being proactive and including their research groups in decision-making, including Associate Professor Gene-Wei Li, Professor Paola Cappellaro, Professor Cathy Drennan, Professor Colette Heald, Professor Warren Seering, Associate Professor Anna Mikusheva, and Associate Professor Kerri Cahoy.

Transparency and collaborative approaches — at every level — are deeply beneficial in empowering students and building resilience in the face of considerable challenges.

Providing a roadmap

Weeks before shutdown orders in Massachusetts, Professor Gene-Wei Li emailed his lab, outlining the likely course of the coming weeks, both in terms of infectious disease progression and public health efforts. On March 1, Li encouraged students to begin gathering the supplies they needed to work from home.

Attending to the financial precarity of some graduate students, Li offered to help students who could not afford to stockpile a month’s worth of groceries and household supplies. Vitally, Li notes, “acting early is important to ensure research continuity and reduce emotional impact when an avalanche of restrictions are implemented.”

Professor Paola Cappellaro reached out to students in her classes and laboratory to offer support and advice as local Covid-19 cases emerged in March. She helped students weigh their options and access financial support as they made hurried decisions about their living situations. Cappellaro’s laboratory had transitioned to Zoom group meetings prior to MIT’s ramping down of research, which enabled them to be intentional with their discussions of research continuity.

Participatory decision-making guided by principles

Collaborative decision-making is helping Li’s lab weather the crisis. The group was among the first laboratories to begin to return to campus in June. In talking with his advisees, Li provided two principles to guide their decision-making: “safety cannot be sacrificed,” and “your careers must advance.”

He then sought their input on what a research ramp-up should look like for their lab. Providing clear structures for student involvement in decision-making was very helpful in ameliorating the high level of uncertainty and lack of control the disruptions engendered.

Li also paid attention to the little things, inviting his students to help build a “system (and not Poisson statistics) to ensure that there [was] at most one person per room at any given time.” Based on these conversations, he installed convex mirrors in shared spaces so students would know if someone else was already in a room they were about to enter. Li also installed iPads: the first few students who returned to lab are now recording and streaming their experiments, providing a resource to students who are at an earlier point in their graduate careers.

Creating deliberate interactions

Unplanned meetings are lost with remote work. Li observes, “the very nature of scheduled meetings makes them more formalized and less personal.” He has sought to address this by offering regular open Zoom hours. Being responsive and adapting communication patterns to students’ needs has been very effective in building a cohesive remote lab group.

With the loss of spontaneity, Professor Cathy Drennan is finding that problems often escalate before students raise them with her. In the past, a simple hallway interaction or tagging along on a dog walk offered informal mechanisms for students to express challenges to her before they had worsened.

Drennan is reflecting on past instances where she was annoyed with herself for working on a time-sensitive project in her office, where she could be easily interrupted. Now, she realizes that the informal lab interactions were a critical piece of her role as a principal investigator, ensuring stability and well-being within the lab group. Presently, she works to build in more availability to lower the threshold for students to raise obstacles.

Reaching out

For many, advising has turned in a more personal direction. Professor Warren Seering writes that “our students are facing unusual difficulties … We need to be on call for our students, and conversations need to include wellness check-ins to give students the chance to ask for help or guidance.”

Professor Colette Heald has made more time available for meeting with students and has introduced Zoom tea and coffee breaks, for unstructured conversation. She is very intentional about fostering the human side of mentorship. Heald finds it effective to spend “much more time sharing stories about how we are all adapting to this new normal and discussing issues in the news.”

Concurring, Professor Anna Mikusheva empathizes with the challenges students face. She writes, “in isolation, it’s very hard to stay focused and to maintain a connection with your community, peers, and advisors.” Mikusheva urges advisors to be “proactive” in checking in on students and maintaining regular meetings.

Building connections within a research group can be pivotal in persevering amid the torrent of upsetting news. “I try to nudge people to reach out to each other even in lockdown,” Cappellaro notes, “and indeed there’s been new collaborations among the group sprouting from this situation.”

Courageous conversations

Li is catalyzing conversations in his laboratory to process the traumatic histories of structural racism and sexism in this country and renew efforts to combat them. The Li lab has introduced “critical, structured social engagement” as part of their regular interactions, focusing on topics such as “racial bias in science and higher education” and “deepened gender bias in the pandemic.”

As Li notes, such conversations have always been a part of their lab’s culture, though they have become “more structured in light of our increasingly unstructured society.” Providing a trusted and safe forum in which to discuss these topics can help students as individuals as well as help advance the reforms that are vitally needed in academia.

Modeling self care

Adaptations to advising have required concerted thinking regarding needs and limitations. Vitally, faculty members are facing unusual burdens from the public health crisis as well.

Like many faculty parents, professors Kerri Cahoy and Gene-Wei Li’s hours have stretched considerably with the need to care for their young kids as well as support their advisees. They try to make transparency and self-care a regular practice, demonstrating humility with advisees.

“I don’t try to hide that I’m a real person with conflicting priorities,” Cahoy says.

Li shared with his lab that he was feeling burnt out, and took a short break in April. Their openness normalizes struggles, which is conducive to students sharing their own difficulties, and enables conversations about accommodations.

Grappling with the uncertainty of the pandemic and the ongoing harms of structural racism is a considerable burden for many graduate students. Having the support of professors who are Committed to Caring provides students with the resources and tools to rise to the challenge.

Source: https://news.mit.edu/2020/committed-to-caring-1020

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PAOG Advances FDA Application Process For Respiratory Cannabis Drug Treatment

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Sandusky, OH – October 20, 2020 – OTC PR WIRE — PAO Group, Inc. (OTC PINK: PAOG) today announced the company plans to release a new key update this Friday, October 23, 2020, on its progress to advance an investigational New Drug application (IND) with the Food and Drug Administration (FDA).  PAOG announced last week that it anticipates soon entering into an agreement with a contract research organization (CRO) making a major breakthrough in advancing PAOG’s RespRx treatment for Chronic Obstructive Pulmonary Disease (COPD) toward FDA approval.

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On July 30, 2020, PAOG acquired RespRx from Kali-Extracts, Inc. (OTC PINK: KALY).  RespRx is a cannabis treatment under development for COPD derived from a patented cannabis extraction method – U.S. Patent No. 9,199,960 entitled “METHOD AND APPARATUS FOR PROCESSING HERBACEOUS PLANT MATERIALS INCLUDING THE CANNABIS PLANT.”

In an initial scientific evaluation as a treatment for COPD, RespRx has demonstrated effecting significant increases in respiration rate, tidal volume and inspiratory air flow rate. Overall data from the evaluation demonstrated that RespRx can significantly improve inspiratory lung functions in instances of moderate pulmonary fibrosis.

www.paogroupinc.com

Forward-Looking Statements: Certain statements in this news release may contain forward-looking information within the meaning of Rule 175 under the Securities Act of 1933 and Rule 3b-6 under the Securities Exchange Act of 1934, and are subject to the safe harbor created by those rules. All statements, other than statements of fact, included in this release, including, without limitation, statements regarding potential future plans and objectives of the company are forward-looking statements that involve risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Technical complications, which may arise, could prevent the prompt implementation of any strategically significant plan(s) outlined above. The Company undertakes no duty to revise or update any forward-looking statements to reflect events or circumstances after the date of this release.

CONTACT INFORMATION

Contact Us:
Jim DiPrima
888-272-6472
info@pao.group

Source: https://otcprwire.com/paog-advances-fda-application-process-for-respiratory-cannabis-drug-treatment/

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Learning by doing, remotely

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Experiential learning is alive and well at MIT — even when it’s remote.

Just ask Julian Zulueta, a sophomore in biological engineering. Last May, he spotted an intriguing social impact internship opportunity in the PKG Public Service Center newsletter: The CDC Foundation, a Congressionally-chartered nonprofit created to support the Centers for Disease Control and Prevention (CDC), was seeking remote students to assist with the Covid-19 response.

He applied — one of 60 candidates for two spots — and got the position. As a member of the CDC Foundation’s Workforce Strike Team, Zulueta interfaced with state and local health departments, with a particular focus on the Midwest region. Drawing on his introductory Python experience at MIT, he analyzed requisition data and created visualizations to detect trends in resources and in the effectiveness of medical interventions. He also studied correlations in universities’ response to Covid-19 and helped establish new professional growth policies within the CDC Foundation.

The internship was eye-opening, and it stoked his interest in exploring public health careers further. “To my surprise, I realized that public health was more than just the opinions of doctors and nurses. Rather, it extends to incorporate ideas related to public policy design and statistics, which can favor majority groups and lead to disparities in health outcomes,” Zulueta says.

Zulueta’s experience is heartening to Kate Trimble, senior associate dean and director of the Office of Experiential Learning (OEL). “When the pandemic first hit, we were very concerned that students were going to miss out on the hands-on experiences that are so critical to their personal and professional development,” she says.

The PKG Center newsletter that changed Zulueta’s trajectory was the result of concerted efforts by OEL and other campus partners to help students whose summer plans had fallen through or were up in the air — efforts that seem to have paid off. While data from industry partners are not available, statistics from the PKG Center and the Undergraduate Research Opportunities Program (UROP) show a marked uptick in participation this summer. A total of 213 students worked remotely in intensive social impact programs through the PKG Center (compared to 136 in 2019), and 1,523 students participated in UROP (compared to 975 last year).

And, even better, those efforts served as a roadmap for rethinking similar experiences for the mostly-remote fall academic semester. “It was really inspiring to see the MIT community spring into action to adapt in-person UROPs and internships — and even global experiences through MISTI — to a remote format,” says Trimble. “In retrospect, we shouldn’t have been surprised; the ‘magic’ of MIT lies in hands-on learning, and everyone here excels at problem-solving.”

Retooling the best laid plans

Some students were able to extend or reconfigure in-person opportunities into remote versions. When sophomore Sherry Nyeo realized that she would not be able to intern for the summer at a biotech company in Israel, she applied to continue a UROP she started in February at the Whitehead Institute for Biomedical Research, working on RNA secondary structure. Nyeo, who is majoring in electrical engineering and computer science and biology, remotely analyzed the lab’s data and ran the data pipeline.

“I do appreciate that I got a firsthand experience of what goes behind research, and I had a lot of opportunities to present papers to my lab during journal club,” Nyeo says. Her computational data analysis, along with figures she generated, have been incorporated into a paper on the SARS CoV-2 genome, on which she is listed as a co-author.

Marisa Gaetz, a 2020 MIT graduate who is staying on to pursue a PhD in mathematics, managed to tweak her ESG-PKG Fellowship for The Educational Justice Institute (TEJI) at MIT, a nonprofit that leverages education and technology to address mass incarceration.

Before the pandemic, she was planning to help facilitate a summer program for Boston-area youth who have been drawn into the criminal justice system. Instead, she adapted the in-person elements of the program into engaging online activities that encourage discussions about wrongdoing, ethical dilemmas, and moral worth. In addition, Gaetz researched interactive boards with Zoom capabilities and secured funding to install the technology in correctional facilities in Suffolk County, Massachusetts, and Maine, ensuring that TEJI can continue to offer its signature classes in these facilities.

“Even though many experiences have to be remote right now, Covid has also exposed a lot of different needs, and so there’s a lot of new opportunities to do impactful work as well,” Gaetz says.

Sophomore Catherine Lu is one of many participants in MIT International Science and Technology Initiatives (MISTI) who were able to convert their global education experiences into remote versions. Originally, the civil and environmental major was slated to travel to Tulum, Mexico, to help restore a lighthouse into a coral education center. Instead, Lu designed and created a virtual reality experience of the lighthouse, which allows users to visualize and interact with the physical space and, by extension, promotes awareness of coral restoration efforts.

“Through this virtual reality world, we are able to expand even more on the idea of coral education, since much of the audience we’re targeting are people who might not live near coral or are not able to physically travel there,” Lu says.

Seizing a singular opportunity

For juniors Carlos Mercado-Lara and Evan Gwozdz, shifting gears to a remote summer opened up unique opportunities they could not have anticipated.

Once Mercado-Lara found out that his MISTI-France program was cancelled, he channeled his time and efforts into SciTeens, as a PKG Center IDEAS grantee. SciTeens, a nonprofit he co-founded in high school, connects underrepresented high school students from underserved communities with online mentors in STEM. This summer, Mercado-Lara and the SciTeens team collaborated with an organization in Zimbabwe to mentor local teens working on science projects.

“That was great, because it was our first time working internationally with students and establishing trust with another organization,” says Mercado-Lara, who is majoring in biological engineering. The experience also helped him shift his focus for the future. “If I had done an internship, it would have helped my career and allowed me to explore a career path, but over the summer I was able to realign some of the things that I want to continue doing for the next few years while I’m at MIT, and hopefully grad school.”

Gwozdz ditched his plans to find an internship in March, since many of them were being cancelled. He reached out to faculty doing interesting research in his major, chemical engineering, and landed a remote UROP in the Zack Smith lab, which investigates polymer membranes for gas separations.

Since he couldn’t physically be in the lab, he focused on learning about molecular simulations, using software to model experimental polymer systems. “Simulations are heavily used in the field, but they haven’t been explored thoroughly in the Smith lab,” Gwozdz explains. By delving into simulations, he created a niche for himself and has become a valuable member of the team. “With this remote project, I think I was able to contribute as much to them as I received myself,” he says.

Expanding ELOs to all undergraduates

The experiences that Zulueta, Nyeo, Gaetz, Lu, Mercado-Lara, and Gwozdz had are indicative of the diversity and range of opportunities available to students, Trimble says.

“The all-remote summer allowed some students to think outside the box and explore amazing experiences — like social impact internships or work in their own communities — that they might not have considered before. And many students used their positions to make a difference on urgent issues like the pandemic, climate change, and racial justice.”

At the same time, Trimble notes, OEL and other offices learned a great deal over the spring and summer about how to support virtual experiential learning. “We’re putting all of that into practice this academic year,” she says.

To that end, MIT is guaranteeing all undergraduates a paid experiential learning opportunity (ELO) this year. Students who are on campus or at home can earn up to $1,900 while working in a wide variety of remote or on-campus ELOs. The OEL’s new website serves as a guidepost, with resources organized into six tracks: research; public service and social impact; innovation and entrepreneurship; global opportunities; teaching and learning; and opportunities for first-year students.

Source: https://news.mit.edu/2020/learning-by-doing-remotely-1019

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