Ho Woon Fei

Blood-based biomarkers of cerebral small vessel disease

Blood-based biomarkers of cerebral small vessel disease
Liu-Yun Wu, Yuek Ling Chai, Irwin K. Cheah, Rachel S.L. Chia Saima Hilal, Thiruma V. Arumugam, Christopher P. Chen, Mitchell K.P. Lai

Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry a substantial risk of subsequent stroke and vascular cognitive impairment in aging populations. Owing to advances in neu-roimaging, in vivo visualization of cerebral vasculature abnormities and detection of CSVD, including lacunes, microinfarcts, microbleeds and white matter lesions, is now possible, but remains a resource-, skills- and time- intensive approach. As a result, there has been a recent proliferation of blood-based biomarker studies for CSVD aimed at developing accessible screening tools for early detection and risk stratification. However, a good understanding of the pathophysiological processes underpinning CSVD is needed to identify and assess clinically useful biomarkers. Here, we provide an overview of processes associated with CSVD pathogenesis, including endothelial injury and dysfunction, neuroinflammation, oxidative stress, perivascular neuronal damage as well as cardiovascular dysfunction. Then, we review clinical studies of the key biomolecules involved in the afore-mentioned processes. Lastly, we outline future trends and directions for CSVD biomarker discovery and clinical validation.

Link to full article: https://pubmed.ncbi.nlm.nih.gov/38417710/

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Winners of Student Presentations in Graduate’s Academic Progress in Pharmacology (GAPP) Meeting

The three winners of Student Presentations in GAPP Meeting and Dr LE.

From right:

Winner 1 – Phyllis GAN Xiu Li (Supervisor: Prof Fred WONG), Title: Corticosteroids Reverse Severe Eosinophilic Asthma by Reprogramming Lung Metabolism

Winner 2 – LE Hong Anh (Supervisor: Dr LE Thi Nguyet Minh), Title: Novel insights in the intracellular mechanism of drug delivery

Winner 3 – Migara Kavishka JAYASINGHE (Supervisor: Dr LE Thi Nguyet Minh), Title: Serum Brevican as a Biomarker of Cerebrovascular Disease in an Elderly Cognitively Impaired Cohort

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Congratulations to Dr LE, MA Yuanhe and Brendon YEO on success of Graduate’s Academic Progress in Pharmacology (GAPP) Meeting!

From left: Yuanhe (emcee), Dr LE, Edwin WONG, Dr KONG (panellists)

Congratulations to Dr LE, MA Yuanhe and Brendon YEO on success of Graduate’s Academic Progress in Pharmacology (GAPP) Meeting!

The objective of GAPP Meeting is for research fellows and student representatives to share the research highlights and experiences at Department of Pharmacology.

GAPP 2024 Organizing Committee: Dr LE Thi Nguyet Minh, Bredon YEO and MA Yuanhe.

Keynote Speaker: Dr KONG Li Ren

Panellists: Dr LE Thi Nguyet Minh, Dr KONG Li Ren and Edwin WONG

Host and Support: Department of Pharmacology and Pharmacological Society of Singapore

Congratulations to Dr LE, MA Yuanhe and Brendon YEO on success of Graduate’s Academic Progress in Pharmacology (GAPP) Meeting! Read More »

Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor

 

Tharindunee Jayakody, Asuka Inoue, Srinivasaraghavan Kannan, Gaku Nakamura, Kouki Kawakami, Krishan Mendis, Thanh-Binh Nguyen, Jianguo Li, Deron R. Herr, Chandra S. Verma, Gavin S. Dawe

The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modu- lates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the

activation of G proteins and β-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gαi/o-biased agonists of RXFP3. These peptides did not induce recruitment of β-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of β-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the

binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.

Image credit: Office of the Deputy President (Research and Technology)

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Modifying brain molecule relaxin-3 can potentially reduce side effects in treating anxiety, depression and more

Drugs that treat conditions like depression and anxiety often come with varying side effects, as they regulate various functions within the human body at the same time. What if these drugs  could activate only the functions that target the specific conditions that they are designed to treat?

A team of researchers has found a potential way to treat these conditions with fewer side effects. Led by Professor Gavin Dawe, Head of the Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), the team conducted modifications of relaxin-3—a neuropeptide, or molecule, found mainly in the human brain and nervous system—which regulates a wide range of physiological functions, including stress responses, appetite, mood and pain perception. When relaxin-3 is released in the brain, it binds to a target receptor RXFP3—to trigger a variety of signalling responses among the cells, which affect the body’s physiological processes.

For more details: https://medicine.nus.edu.sg/wp-content/uploads/2024/02/2024-02-19-Press-Release-Modifying-Relaxin-3-can-potentially-reduce-side-effects_final.pdf

Image credit: Office of the Deputy President (Research and Technology)

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While Pursuing PhD, Edwin WONG Founds Psyrin as CEO to Innovate in Mental Health with AI

Founding a startup alongside your PhD: a Q&A with Edwin Wong

Edwin (left of the photo) is a final-year PhD candidate at the NUS Department of Pharmacology and King’s College London (co-supervisors Prof Allan Young and A/Prof Gavin Dawe). He’s also co-founder and CEO at Psyrin, a venture-backed startup developing objective biomarkers for serious mental illness. Here, he offers some reflections on his journey to date.

Q: Can you share with us a little about your journey founding Psyrin?

A: It was really a string of good fortune – I started going to a bunch of startup events and met some great founders. I was inspired enough to host an event, where my eventual co-founders showed up! We were all working in mental health, so there was an easy ‘click’. On a whim, we pitched an idea at a university “idea competition” and ended up winning! From there, we just started having a ton of conversations. It took a lot of active seeking of opportunity but just as much luck.

Q: When and how did you realize that founding a startup was possible? Where did you learn the fundamental tools?

A: It was a leap of faith. There’s no threshold where you’re suddenly ready. Getting some external validation of our core principles helped, but by then, we’d already committed to building a startup. People often wait for an idea, but a startup is far more about execution and iterative thinking, so there’s no point obsessing over the “right” idea. Ultimately, founding a startup is always a possibility; it just takes some faith and determination to commit.

Q: Academia and entrepreneurship seem vastly different – how did you adapt to this transition?

A: I approached it by immersing myself in the world of startups (it’s smaller than you think!) There are tons of online resources – Y Combinator lectures, blogs by legends like Paul Graham, industry pieces by investors, etc. Pair that with non-stop interaction with other founders (especially academic founders), and the transition becomes quite natural. It helps that the two worlds are not actually that different – it’s a different mentality, but the skill overlap is strong.

Q: Balancing the demands of a PhD program with a startup sounds challenging – how did you manage this effectively?

A: Sadly, I don’t have a clear, step-by-step answer to this, but I want to emphasize that it is absolutely possible! It’s been helpful to set clear milestones, both with the PhD and the startup. I also rely heavily on Google Calendar, blocking out time and recording this explicitly. I’m also lucky to have supportive supervisors who trust me to get my work done; it’s so important to have them on board!

Q: What were some of the key challenges you encountered while building your startup?

A: The first thing that comes to mind is all the rejection. I expected some rejection – but the sheer volume was shocking. It’s why I’m so grateful for a great support system that keeps me optimistic. It’s also challenging to balance idealism and pragmatism. A lot of what we do is aspirational and disruptive, but it’s so important to keep your user (and customer) in mind, a process that’s not necessarily intuitive.

Q: Did you find your PhD training helpful while building Psyrin?

A: There is certainly overlap, it’s why academics often make great founders! This is a bit cliche, but a PhD really does foster soft skills – resilience, persistence, critical thinking – that translate to a startup. Plus, the actual work overlaps. At Psyrin, I’ve written grants, coordinated partnerships, and made tons of presentations, just like academics do!

Q: And finally, what advice would you have for a new PhD student thinking about founding a startup?

A: Go for it! Nothing is stopping you. There are a million reasons not to start a startup – but most either don’t matter or aren’t worth worrying about. If you want to start smaller, I’d encourage talking to founders. It costs nothing to approach people, whether that’s at one of many events (there are several in Singapore!) or over a cold LinkedIn message.

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Twelve tips to leverage AI for efficient and effective medical question generation: A guide for educators using Chat GPT

Twelve tips to leverage AI for efficient and effective medical question generation: A guide for educators using Chat GPT

Inthrani Raja Indran , Priya Paramanathan, Neelima Gupta and Nurulhuda Mustafa

Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, Singapore

Abstract

Background: Crafting quality assessment questions in medical education is a crucial yet time-consuming, expertise-driven undertaking that calls for innovative solutions. Large language models (LLMs), such as ChatGPT (Chat Generative Pre-Trained Transformer), present a promising yet underexplored avenue for such innovations.

Aims: This study explores the utility of ChatGPT to generate diverse, high-quality medical questions, focusing on multiple-choice questions (MCQs) as an illustrative example, to increase educator’s productivity and enable self-directed learning for students.

Description: Leveraging 12 strategies, we demonstrate how ChatGPT can be effectively used to generate assessment questions aligned with Bloom’s taxonomy and core knowledge domains while promoting best practices in assessment design.

Conclusion: Integrating LLM tools like ChatGPT into generating medical assessment questions like MCQs augments but does not replace human expertise. With continual instruction refinement, AI can produce high-standard questions. Yet, the onus of ensuring ultimate quality and accuracy remains with subject matter experts, affirming the irreplaceable value of human involvement in the artificial intelligence-driven education paradigm.

MEDICAL TEACHER
https://doi.org/10.1080/0142159X.2023.2294703

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SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition

SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition

Xianning Lai, Sarah Kit Leng Lui, Hiu Yan Lam, Yuta Adachi, Wen Jing Sim, Natali Vasilevski, Nicola J. Armstrong, Stephanie Claire Bridgeman,

Nathan Michael Main, Tuan Zea Tan, Janina E. E. Tirnitz-Parker, Jean Paul Thiery, Hiromichi Ebi, Alan Prem Kumar, and Pieter Johan Adam Eichhorn

Abstract

Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by
their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation
mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits
TGFβ activity by ubiquitinating and targeting the TGFβ receptor for proteosome degradation. Using a functional RNAi screen
targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFβ activity. Specifically,
SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains
SMURF2 in an inactive state, resulting in the maintenance of TGFβ activity. Furthermore, we demonstrate that depleting SHP2 has
significant implications on TGFβ-mediated migration, senescence, and cell survival. These effects can be overcome through the use
of TGFβ-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFβ inhibitors to enhance
tumour responses leading to improved patient outcomes.


npj Precision Oncology (2023)7:136 ; https://doi.org/10.1038/s41698-023-00486-6

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Nano-sized Cell Particles are Promising Intervention Tools in Treating Infectious Diseases

 

Authors of the study, from NUS Medicine: (Back row, from left) Assoc Prof Justin Chu, Dr. Kai Sen Tan, Migara Jayasinghe (Pharmacology), Dr. Dai Cao Phung (Pharmacology), Brendon Zhi Jie Yeo (Pharmacology); (Front row, from left) Asst Prof Minh Le (Pharmacology), Gao Chang (Pharmacology), Rebecca Carissa Prajogo (Pharmacology).

The COVID-19 pandemic demonstrated the importance of being prepared with drug interventions to contain viral outbreaks that can otherwise have devastating consequences. In preparing for the next pandemic—or Disease X, there is an urgent need for versatile platform technologies that could be repurposed upon short notice, to combat infectious outbreaks.

A team of researchers, led by Assistant Professor Minh Le from the Institute for Digital Medicine (WisDM) and Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), discovered that nano-sized particles released by cells, termed “extracellular vesicles” (EVs), can curb the viral infectivity of SARS-CoV-2—its wild type and variant strains—and potentially other infectious diseases. Asst Prof Le said, “Our study showed that these cell-derived nanoparticles are effective carriers of drugs that target viral genes precisely. These EVs are therefore an efficient tool for therapeutic intervention in patients who are infected with COVID-19 or other infectious diseases.”

The study, conducted in collaboration with NUS Medicine’s Biosafety Level 3 (BSL3) Core Facility, the Cancer Science Institute of Singapore, and the School of Physical and Mathematical Sciences at Nanyang Technological University (NTU), demonstrated potent inhibition of COVID-19 infection in laboratory models using a combination of EV-based inhibition and anti-sense RNA therapy mediated by antisense oligonucleotides (ASOs).

Read more: https://medicine.nus.edu.sg/news/nano-sized-cell-particles-are-promising-intervention-tool-in-treating-infectious-diseases/

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IES and ASEAN Outstanding Engineering Achievement Award

A team led by Professor Dean HO, Director of the Institute for Digital Medicine (WisDM) at the NUS Yong Loo Lin School of Medicine, Director of the N.1 Institute for Health, and Joint Professor at Department of Pharmacology, was awarded the Prestigious Engineering Achievement Award from the Institution of Engineers, Singapore (IES) as well as the ASEAN Outstanding Engineering Achievement Award.

The team includes a few other members from Department of Pharmacology: A/Prof Edward CHOW Kai-Hua, Dr Agata BIASIAK (Joint Staff) and Lissa HOOI.

The IES Prestigious Engineering Achievement Award and the ASEAN Outstanding Engineering Achievement Award were created to recognise outstanding engineering achievements that have made significant contributions to engineering progress and quality of life in Singapore and ASEAN.

Read full news here: https://medicine.nus.edu.sg/news/ies-and-asean-engineering-achievement-awards/

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