Publications - 2024
Redox changes and cellular senescence in Alzheimer's disease |
| Yu, N., Pasha, M., and Chua, J.J.E. (2024) |
| Redox Biol 70, 103048 |
| Abstract |
| The redox process and cellular senescence are involved in a range of essential physiological functions. However, they are also implicated in pathological processes underlying age-related neurodegenerative disorders, including Alzheimer's disease (AD). Elevated levels of reactive oxygen species (ROS) are generated as a result of abnormal accumulation of beta-amyloid peptide (Aβ), tau protein, and heme dyshomeostasis and is further aggravated by mitochondria dysfunction and endoplasmic reticulum (ER) stress. Excessive ROS damages vital cellular components such as proteins, DNA and lipids. Such damage eventually leads to impaired neuronal function and cell death. Heightened oxidative stress can also induce cellular senescence via activation of the senescence-associated secretory phenotype to further exacerbate inflammation and tissue dysfunction. In this review, we focus on how changes in the redox system and cellular senescence contribute to AD and how they are affected by perturbations in heme metabolism and mitochondrial function. While potential therapeutic strategies targeting such changes have received some attention, more research is necessary to bring them into clinical application. |
External auricle temperature enhances ear-based wearable accuracy during physiological strain monitoring in the heat |
| Tan SCC, Tran TCK, Chiang CYN, Pan J, Low ICC |
| Sci Rep 14, 12418 (2024) |
| Abstract |
| Body core temperature (Tc) monitoring is crucial for minimizing heat injury risk. However, validated strategies are invasive and expensive. Although promising, aural canal temperature (Tac) is susceptible to environmental influences. This study investigated whether incorporation of external auricle temperature (Tea) into an ear-based Tc algorithm enhances its accuracy during multiple heat stress conditions. Twenty males (mean ± SD; age = 25 ± 3 years, BMI = 21.7 ± 1.8, body fat = 12 ± 3%, maximal aerobic capacity (VO2max) = 64 ± 7 ml/kg/min) donned an ear-based wearable and performed a passive heating (PAH), running (RUN) and brisk walking trial (WALK). PAH comprised of immersion in hot water (42.0 ± 0.3 °C). RUN (70 ± 3%VO2max) and WALK (50 ± 10%VO2max) were conducted in an environmental chamber (Tdb = 30.0 ± 0.2 °C, RH = 71 ± 2%). Several Tc models, developed using Tac, Tea and heart rate, were validated against gastrointestinal temperature. Inclusion of Tea as a model input improved the accuracy of the ear-based Tc algorithm. Our best performing model (Trf3) displayed good group prediction errors (mean bias error = − 0.02 ± 0.26 °C) but exhibited individual prediction errors (percentage target attainment ± 0.40 °C = 88%) that marginally exceeded our validity criterion. Therefore, Trf3 demonstrates potential utility for group-based Tc monitoring, with additional refinement needed to extend its applicability to personalized heat strain monitoring. |
Effects of Heat Exposure and Ice Slurry Ingestion on Risk-Taking Behavior in Healthcare Workers |
| Alhadad, Sharifah Badriyah; Ponampalam, R; Louisa Si Xian; Low, Ivan Cherh Chiet; Kshitij, Rahalkar; Abdul Karim, Aziz Bin; Salamoon, Zamshek Bin; Marimuthu, Yogarajah S/O; Lee, Jason Kai Wei |
| Medicine & Science in Sports & Exercise 56(10):p 2016-2025, October 2024. |
| Abstract |
| Purpose: Healthcare workers (HCWs) wearing personal protective equipment (PPE) experience physiological strain that can impair motor and psychological functions, potentially affecting patient care. We assessed the effects of heat exposure on maximal strength and risk-taking behavior among PPE-wearing HCWs and the efficacy of ice slurry to alleviate adverse effects.
Methods: Seventeen HCWS completed two experimental trials in a crossover design, consuming 5 g·kg -1 of body mass of ambient drink (AMB) or ice slurry (ICE) before donning PPE and undergoing 2 h of simulated decontamination exercise (wet-bulb globe temperature (WBGT): 25.9°C ± 0.8°C, PPE microenvironment WBGT: 29.1°C ± 2.1°C). Body core temperature ( Tc ), heart rate (HR), chest skin temperature ( Tsk ), ratings of perceived exertion (RPE), thermal sensation (RTS), maximal voluntary contraction (MVC), risk-taking behavior (balloon analogue risk-taking task (BART)), and salivary cortisol were assessed. Results: Predrinking to postdrinking ∆ Tc was greater in ICE (-0.2°C ± 0.1°C) than AMB (-0.0°C ± 0.1°C, P = 0.003). Post-drinking RTS was lower in ICE (2.7 ± 1.2) than AMB (4.1 ± 0.4, P < 0.001). ICE and AMB had similar Tc and HR (both P > 0.05), but Tsk was lower in ICE than AMB ( P = 0.049). A lower MVC (30.3 ± 6.7 vs 27.4 ± 4.9 kg, P = 0.001) and higher BART-adjusted total pump count (472 ± 170 vs 615 ± 174 pumps, P = 0.017) was observed pretrial to posttrial in AMB but absent in ICE (both P > 0.05). Salivary cortisol was similar between trials ( P = 0.42). Conclusions: Heat-exposed PPE-wearing HCWs had impaired maximal strength and elevated risk-taking behavior. This may increase the risk of avoidable workplace accidents that can jeopardize HCWs and patient care. Ice slurry ingestion alleviated these heat-related impairments, suggesting its potential as an ergogenic aid. |
Elevated brain temperature under severe heat exposure impairs cortical motor activity and executive function |
| Xiang Ren Tan, Mary C. Stephenson, Sharifah Badriyah Alhadad, Kelvin W.Z. Loh, Tuck Wah Soong, Jason K.W. Lee, Ivan C.C. Low, |
| Journal of Sport and Health Science, Volume 13, Issue 2, 2024, Pages 233-244 |
| Abstract |
| Excessive heat exposure can lead to hyperthermia in humans, which impairs physical performance and disrupts cognitive function. While heat is a known physiological stressor, it is unclear how severe heat stress affects brain physiology and function. |
Accuracy and reliability of large language models in assessing learning outcomes achievement across cognitive domains |
| Swapna Haresh Teckwani, Amanda Huee-Ping Wong, Nathasha Vihangi Luke, Ivan Cherh Chiet Low |
| Advances in Physiology Education Volume 48 Issue 4 |
| Abstract |
| The advent of artificial intelligence (AI), particularly large language models (LLMs) like ChatGPT and Gemini, has significantly impacted the educational landscape, offering unique opportunities for learning and assessment. In the realm of written assessment grading, traditionally viewed as a laborious and subjective process, this study sought to evaluate the accuracy and reliability of these LLMs in evaluating the achievement of learning outcomes across different cognitive domains in a scientific inquiry course on sports physiology. Human graders and three LLMs, GPT-3.5, GPT-4o, and Gemini, were tasked with scoring submitted student assignments according to a set of rubrics aligned with various cognitive domains, namely “Understand,” “Analyze,” and “Evaluate” from the revised Bloom’s taxonomy and “Scientific Inquiry Competency.” Our findings revealed that while LLMs demonstrated some level of competency, they do not yet meet the assessment standards of human graders. Specifically, interrater reliability (percentage agreement and correlation analysis) between human graders was superior as compared to between two grading rounds for each LLM, respectively. Furthermore, concordance and correlation between human and LLM graders were mostly moderate to poor in terms of overall scores and across the pre-specified cognitive domains. The results suggest a future where AI could complement human expertise in educational assessment but underscore the importance of adaptive learning by educators and continuous improvement in current AI technologies to fully realize this potential. |
Pre-exercise hot water immersion increased circulatory heat shock proteins but did not alter muscle damage markers or endurance capacity after eccentric exercise |
| Tan, X. R., Low, I. C. C., Soong, T. W., & Lee, J. K. W. |
| Temperature, 11(2), 157–169 |
| Abstract |
| Pre-exercise passive heating attenuates muscle damage caused by eccentric exercise in rats where the induction of heat shock proteins (HSPs) confers a myoprotective effect. We investigated whether pre-exercise hot water immersion (HWI) confers similar benefits in humans. Eleven recreational male athletes were immersed in 41°C water up to 60 min or until rectal temperatures reached 39.5°C. After a 6 h rest, the participants performed an eccentric downhill run for 1 h at −4% gradient to induce muscle damage. An endurance capacity test at 75% VO2max was conducted 18 h later. The control trial was similar except that participants were immersed at 34°C. Blood samples were collected to assess HSPs levels, creatine kinase, and lactate dehydrogenase activities. Plasma eHSP70 was higher post-immersion in HWI trials (1.3 ± 0.4 vs 1.1 ± 0.4; p = 0.005). Plasma eHSP27 was higher before (p = 0.049) and after (p = 0.015) endurance test in HWI. Leukocytic p-HSP27 was increased 18 h after HWI (0.97 ± 0.14 vs 0.67 ± 0.11; p = 0.04). Creatine kinase and lactate dehydrogenase activities were increased by 3-fold and 1.5-fold, respectively, after endurance test in HWI but did not differ across trials (p > 0.05). Mean heart rates were higher during eccentric run and endurance test in HWI as compared to control (p < 0.05). Endurance capacity was similar between trials (57.3 ± 11.5 min vs 55.0 ± 13.5 min; p = 0.564). Pre-exercise heating increased the expression of plasma eHSPs and leukocytic p-HSP27 but did not reduce muscle damage nor enhance endurance capacity. |
BRD4 isoforms have distinct roles in tumour progression and metastasis in rhabdomyosarcoma |
| Das D, Leung JY, Balamurugan S, Tergaonkar V, Loh AHP, Chiang CM, Taneja R |
| EMBO Rep. 2024 Feb;25(2):832-852. |
| Abstract |
| BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analysed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in fusion negative embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumour progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumour growth, but strikingly promotes metastasis in vivo. Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. In fusion positive alveolar rhabdomyosarcoma, BRD4-L is unrestricted in its oncogenic role, with no evident involvement of BRD4-S. Our work unveils isoform-specific functions of BRD4 in rhabdomyosarcoma. |
Is ChatGPT 'ready' to be a learning tool for medical undergraduates and will it perform equally in different subjects? Comparative study of ChatGPT performance in tutorial and case-based learning questions in physiology and biochemistry. |
| Luke WANV, Seow Chong L, Ban KH, Wong AH, Zhi Xiong C, Shuh Shing L, Taneja R, Samarasekera DD, Yap CT |
| Med Teach. 2024 Nov;46(11):1441-1447 |
| Abstract |
| Purpose: Generative AI will become an integral part of education in future. The potential of this technology in different disciplines should be identified to promote effective adoption. This study evaluated the performance of ChatGPT in tutorial and case-based learning questions in physiology and biochemistry for medical undergraduates. Our study mainly focused on the performance of GPT-3.5 version while a subgroup was comparatively assessed on GPT-3.5 and GPT-4 performances.
Materials and methods: Answers were generated in GPT-3.5 for 44 modified essay questions (MEQs) in physiology and 43 MEQs in biochemistry. Each answer was graded by two independent examiners. Subsequently, a subset of 15 questions from each subject were selected to represent different score categories of the GPT-3.5 answers; responses were generated in GPT-4, and graded. Results: The mean score for physiology answers was 74.7 (SD 25.96). GPT-3.5 demonstrated a statistically significant (p = .009) superior performance in lower-order questions of Bloom's taxonomy in comparison to higher-order questions. Deficiencies in the application of physiological principles in clinical context were noted as a drawback. Scores in biochemistry were relatively lower with a mean score of 59.3 (SD 26.9) for GPT-3.5. There was no statistically significant difference in the scores for higher and lower-order questions of Bloom's taxonomy. The deficiencies highlighted were lack of in-depth explanations and precision. The subset of questions where the GPT-4 and GPT-3.5 were compared demonstrated a better overall performance in GPT-4 responses in both subjects. This difference between the GPT-3.5 and GPT-4 performance was statistically significant in biochemistry but not in physiology. Conclusions: The differences in performance across the two versions, GPT-3.5 and GPT-4 across the disciplines are noteworthy. Educators and students should understand the strengths and limitations of this technology in different fields to effectively integrate this technology into teaching and learning. |
Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors |
| Gupta A, Das D, Taneja R |
| Cancers (Basel). 2024 Mar 28;16(7):1313 |
| Abstract |
| Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics. |
BHLHE40 Regulates Myeloid Cell Polarization through IL-10-Dependent and -Independent Mechanisms |
| Hendrix SV, Mreyoud Y, McNehlan ME, Smirnov A, Chavez SM, Hie B, Chamberland MM, Bradstreet TR, Webber AM, Kreamalmeyer D, Taneja R, Bryson BD, Edelson BT, Stallings CL |
| J Immunol. 2024 Jun 1;212(11):1766-1781 |
| Abstract |
| Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to M. tuberculosis infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to M. tuberculosis infection, but how BHLHE40 impacts macrophage and dendritic cell responses to M. tuberculosis is unknown. In this study, we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a proinflammatory state and better control of M. tuberculosis infection. Loss of Bhlhe40 expression in murine bone marrow-derived myeloid cells cultured in the presence of GM-CSF results in lower levels of proinflammatory associated signaling molecules IL-1β, IL-6, IL-12, TNF-α, inducible NO synthase, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory-associated molecules MCP-1 and IL-10 following exposure to heat-killed M. tuberculosis. Deletion of Il10 in Bhlhe40-/- myeloid cells restored some, but not all, proinflammatory signals, demonstrating that BHLHE40 promotes proinflammatory responses via both IL-10-dependent and -independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of M. tuberculosis-infected Bhlhe40-/- mice exhibit defects in inducible NO synthase production compared with infected wild-type mice, supporting that BHLHE40 promotes proinflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during M. tuberculosis infection in vivo. |
PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin |
| Feng J, Chuah YH, Liang Y, Cipta NO, Zeng Y, Warrier T, Elfar GARE, Yoon J, Grinchuk OV, Tay EXY, Lok KZ, Zheng ZQ, Khong ZJ, Chong ZS, Teo J, Sanford EM, Neo CJY, Chiu HY, Leung JY, Wang LC, Lim YT, Zhao T, Sobota RM, Crasta KC, Tergaonkar V, Taneja R, Ng SY, Cheok CF, Ling SC, Loh YH, Ong DST |
| Nucleic Acids Res. 2024 Jul 8;52(12):7063-7080 |
| Abstract |
| Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural stem cells (NSC). PHF2 loss impairs DNA replication due to the activation of dormant replication origins in NSC. Notably, the PHF2/RAD21 co-bound genomic regions are characterized by CTCF enrichment and epigenomic features that resemble efficient, active replication origins, and can act as boundaries to separate adjacent domains. Accordingly, PHF2 loss weakens TADs and chromatin loops at the co-bound loci due to reduced RAD21 occupancy. The observed topological and DNA replication defects in PHF2 KO NSC support a cohesin-dependent mechanism. Furthermore, we demonstrate that the PHF2/RAD21 complex exerts little effect on gene regulation, and that PHF2's histone-demethylase activity is dispensable for normal DNA replication and proliferation of NSC. We propose that PHF2 may serve as a topological accessory to cohesin for cohesin localization to TADs and chromatin loops, where cohesin represses dormant replication origins directly or indirectly, to sustain DNA replication in NSC. |
Shifting Trend of Protein Consumption in Southeast Asia: Toward Health, Innovation, and Sustainability |
| Tjahyo AS, Wu JY, Smith G, Acuin C, Maier AB, Sim SYJ, Taneja R, Haldar S, Henry CJ |
| Curr Dev Nutr. 2024 Aug 18;8(10):104443 |
| Abstract |
| Complementing discourse following a February 2023 event on dietary protein needs in Southeast Asia (SEA), this symposium report summarizes the region’s protein intake, while simultaneously examining the impact of dietary shift toward complementary and alternative proteins and their health implications. It highlights the importance of protein quality in dietary evaluations, optimal intake, and sustainability, advocating for environmentally conscious protein production and innovation in future foods. Discussion points, expert opinions, national nutrition data, and relevant literature, addressing protein intake and quality, their impact on human health, and various technologies for future foods production, have been included. Despite increased protein supply in SEA, protein requirements, particularly during crucial life stages, are often unmet owing to insufficient focus on protein quality. Factoring in amino acids content and bioaccessibility are crucial for assessing nutritional requirement and sustainability evaluations, rather than solely relying on protein quantity alone. Different food sources of protein also have different key conutrients for health relevance such as vitamin B-12 and ω-3 fatty acids. Innovations in food structure, processing, and technology are key to developing nutritious, sustainable, and appealing future foods, including from complementary and alternative protein sources, while considering safety aspects, especially allergenicity. Addressing protein needs in SEA requires a dual focus on protein quantity and quality, underlining the role of public health policies and guidelines that consider key nutritional differences of animal-source and plant-based proteins. To address regional demands, future food innovations should aim at creating unique yet needful food categories or supplementing current existing sources, rather than mimicking current products. |
Lost in translation: challenges of current pharmacotherapy for sarcopenia |
| Tsai Shih-Yin |
| Trends in Molecular Medicine, Volume 30, Issue 11 |
| Abstract |
| A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy. |
The role of artificial intelligence in knowledge management for medical students and doctors |
| Medical Teacher |
| Abstract |
| The skill of knowledge management empowers practitioners to efficiently integrate and apply knowledge in the clinical context. Current medical knowledge is vast which is beyond the human capacity to retain. Hence, modern-day learning is not just knowledge acquisition, but the organization of knowledge in a retrievable manner. Advancing technology in digital learning spaces and artificial intelligence enables the development of personalized knowledge platforms. Clinicians should find their own ideal spaces for knowledge management from the early stages of their careers, and develop it into a lifelong learning platform, which will eventually lead to better patient care. |
Neurokinin1 − cholinergic receptor mechanisms in the medial Septum-Dorsal hippocampus axis mediates experimental neuropathic pain |
| Mohammed Zacky Ariffin, Si Yun Ng, Hamzah Nadia, Darrel Koh, Natasha Loh, Naomi Michiko, Sanjay Khanna |
| Neurobiology of Pain, Volume 16, 2024, 100162, ISSN 2452-073X. |
| Abstract |
| The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs. |
Synapses tagged, memories kept: synaptic tagging and capture hypothesis in brain health and disease |
| Mohammad Zaki Bin Ibrahim, Zijun Wang and Sreedharan Sajikumar |
| Phil. Trans. R. Soc. B 379:20230237. |
| Abstract |
| The synaptic tagging and capture (STC) hypothesis lays the framework on the synapse-specific mechanism of protein synthesis-dependent long-term plasticity upon synaptic induction. Activated synapses will display a transient tag that will capture plasticity-related products (PRPs). These two events, tag setting and PRP synthesis, can be teased apart and have been studied extensively—from their electrophysiological and pharmacological properties to the molecular events involved. Consequently, the hypothesis also permits interactions of synaptic populations that encode different memories within the same neuronal population—hence, it gives rise to the associativity of plasticity. In this review, the recent advances and progress since the experimental debut of the STC hypothesis will be shared. This includes the role of neuromodulation in PRP synthesis and tag integrity, behavioural correlates of the hypothesis and modelling in silico. STC, as a more sensitive assay for synaptic health, can also assess neuronal aberrations. We will also expound how synaptic plasticity and associativity are altered in ageing-related decline and pathological conditions such as juvenile stress, cancer, sleep deprivation and Alzheimer’s disease.
This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’. |
PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin |
| Jia Feng, You Heng Chuah, Yajing Liang, Nadia Omega Cipta, Yingying Zeng, Tushar Warrier, Gamal Ahmed Rashed Elsayed Elfar, Jeehyun Yoon, Oleg V Grinchuk, Emmy Xue Yun Tay, Ker-Zhing Lok, Zong-Qing Zheng, Zi Jian Khong, Zheng-Shan Chong, Jackie Teo, Emma May Sanford, Cheryl Jia Yi Neo, Hsin Yao Chiu, Jia Yu Leung, Loo Chien Wang, Yan Ting Lim, Tianyun Zhao, Radoslaw M Sobota, Karen Carmelina Crasta, Vinay Tergaonkar, Reshma Taneja, Shi-Yan Ng, Chit Fang Cheok, Shuo-Chien Ling, Yuin-Han Loh, Derrick Sek Tong Ong |
| Nucleic Acids Research, Volume 52, Issue 12, 8 July 2024, Pages 7063–7080 |
| Abstract |
| Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural stem cells (NSC). PHF2 loss impairs DNA replication due to the activation of dormant replication origins in NSC. Notably, the PHF2/RAD21 co-bound genomic regions are characterized by CTCF enrichment and epigenomic features that resemble efficient, active replication origins, and can act as boundaries to separate adjacent domains. Accordingly, PHF2 loss weakens TADs and chromatin loops at the co-bound loci due to reduced RAD21 occupancy. The observed topological and DNA replication defects in PHF2 KO NSC support a cohesin-dependent mechanism. Furthermore, we demonstrate that the PHF2/RAD21 complex exerts little effect on gene regulation, and that PHF2’s histone-demethylase activity is dispensable for normal DNA replication and proliferation of NSC. We propose that PHF2 may serve as a topological accessory to cohesin for cohesin localization to TADs and chromatin loops, where cohesin represses dormant replication origins directly or indirectly, to sustain DNA replication in NSC. |
A novel MTORC2-AKT-ROS axis triggers mitofission and mitophagy-associated execution of colorectal cancer cells upon drug-induced activation of mutant KRAS |
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Kartini Iskandar, Jonathan Foo, Angeline Qiu Xia Liew, Haiyuxin Zhu, Deepika Raman, Jayshree L. Hirpara, Yan Yi Leong, Maria V. Babak, Anna A. Kirsanova, Anne-Sophie Armand, Franck Oury, Gregory Bellot & Shazib Pervaiz
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| Autophagy 2024, Vol. 20, No. 6, 1418–1441 |
| Abstract |
| RAS is one of the most commonly mutated oncogenes associated with multiple cancer hallmarks. Notably, RAS activation induces intracellular reactive oxygen species (ROS) generation, which we previously demonstrated as a trigger for autophagy-associated execution of mutant KRAS-expressing cancer cells. Here we report that drug (merodantoin; C1)-induced activation of mutant KRAS promotes phospho-AKT S473-dependent ROS-mediated S616 phosphorylation and mitochondrial localization of DNM1L/DRP1 (dynamin 1 like) and cleavage of the fusion-associated protein OPA1 (OPA1 mitochondrial dynamin like GTPase). Interestingly, accumulation of the outer mitochondrial membrane protein VDAC1 (voltage dependent anion channel 1) is observed in mutant KRAS-expressing cells upon exposure to C1. Conversely, silencing VDAC1 abolishes C1-induced mitophagy, and gene knockdown of either KRAS, AKT or DNM1L rescues ROS-dependent VDAC1 accumulation and stability, thus suggesting an axis of mutant active KRAS-phospho-AKT S473-ROS-DNM1L-VDAC1 in mitochondrial morphology change and cancer cell execution. Importantly, we identified MTOR (mechanistic target of rapamycin kinsase) complex 2 (MTORC2) as the upstream mediator of AKT phosphorylation at S473 in our model. Pharmacological or genetic inhibition of MTORC2 abrogated C1-induced phosphorylation of AKT S473, ROS generation and mitophagy induction, as well as rescued tumor colony forming ability and migratory capacity. Finally, increase in thermal stability of KRAS, AKT and DNM1L were observed upon exposure to C1 only in mutant KRAS-expressing cells. Taken together, our work has unraveled a novel mechanism of selective targeting of mutant KRAS-expressing cancers via MTORC2-mediated AKT activation and ROS-dependent mitofission, which could have potential therapeutic implications given the relative lack of direct RAS-targeting strategies in cancer. |
Is ChatGPT ‘ready’ to be a learning tool for medical undergraduates and will it perform equally in different subjects? Comparative study of ChatGPT performance in tutorial and case-based learning questions in physiology and biochemistry |
| W. A. Nathasha V. Luke, Lee Seow Chong, Kenneth H. Ban, Amanda H. Wong, Chen Zhi Xiong, Lee Shuh Shing, Reshma Taneja, Dujeepa D. Samarasekera and Celestial T. Yap |
| Medical Teacher, 1–7. |
| Abstract |
| Generative AI will become an integral part of education in future. The potential of this technology in different disciplines should be identified to promote effective adoption. This study evaluated the performance of ChatGPT in tutorial and case-based learning questions in physiology and biochemistry for medical undergraduates. Our study mainly focused on the performance of GPT-3.5 version while a subgroup was comparatively assessed on GPT-3.5 and GPT-4 performances. |
BRD4 isoforms have distinct roles in tumour progression and metastasis in rhabdomyosarcoma |
| Dipanwita Das, Jia Yu Leung, Shivaranjani Balamurugan, Vinay Tergaonkar, Amos Hong Pheng Loh, Cheng-Ming Chiang and Reshma Taneja |
| Abstract |
| BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analysed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in fusion negative embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumour progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumour growth, but strikingly promotes metastasis in vivo. Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. In fusion positive alveolar rhabdomyosarcoma, BRD4-L is unrestricted in its oncogenic role, with no evident involvement of BRD4-S. Our work unveils isoform-specific functions of BRD4 in rhabdomyosarcoma. |
Secretome from Magnetically Stimulated Muscle Exhibits Anticancer Potency: Novel Preconditioning Methodology Highlighting HTRA1 Action |
| Alfredo Franco-Obregón |
| Bioengineering 2024, 11(7), 637; |
| Abstract |
| Briefly (10 min) exposing C2C12 myotubes to low amplitude (1.5 mT) pulsed electromagnetic fields (PEMFs) generated a conditioned media (pCM) that was capable of mitigating breast cancer cell growth, migration, and invasiveness in vitro, whereas the conditioned media harvested from unexposed myotubes, representing constitutively released secretome (cCM), was less effective. Administering pCM to breast cancer microtumors engrafted onto the chorioallantoic membrane of chicken eggs reduced tumor volume and vascularity. Blood serum collected from PEMF-exposed or exercised mice allayed breast cancer cell growth, migration, and invasiveness. A secretome preconditioning methodology is presented that accentuates the graded anticancer potencies of both the cCM and pCM harvested from myotubes, demonstrating an adaptive response to pCM administered during early myogenesis that emulated secretome-based exercise adaptations observed in vivo. HTRA1 was shown to be upregulated in pCM and was demonstrated to be necessary and sufficient for the anticancer potency of the pCM; recombinant HTRA1 added to basal media recapitulated the anticancer effects of pCM and antibody-based absorption of HTRA1 from pCM precluded its anticancer effects. Brief and non-invasive PEMF stimulation may represent a method to commandeer the secretome response of muscle, both in vitro and in vivo, for clinical exploitation in breast and other cancers. |
Synergistic Cellular Responses Conferred by Concurrent Optical and Magnetic Stimulation Are Attenuated by Simultaneous Exposure to Streptomycin: An Antibiotic Dilemma |
| Alfredo Franco-Obregón |
| Bioengineering 2024, 11(7), 637; |
| Abstract |
| Concurrent optical and magnetic stimulation (COMS) combines extremely low-frequency electromagnetic and light exposure for enhanced wound healing. We investigated the potential mechanistic synergism between the magnetic and light components of COMS by comparing their individual and combined cellular responses. Lone magnetic field exposure produced greater enhancements in cell proliferation than light alone, yet the combined effects of magnetic fields and light were supra-additive of the individual responses. Reactive oxygen species were incrementally reduced by exposure to light, magnetics fields, and their combination, wherein statistical significance was only achieved by the combined COMS modality. By contrast, ATP production was most greatly enhanced by magnetic exposure in combination with light, indicating that mitochondrial respiratory efficiency was improved by the combination of magnetic fields plus light. Protein expression pertaining to cell proliferation was preferentially enhanced by the COMS modality, as were the protein levels of the TRPC1 cation channel that had been previously implicated as part of a calcium–mitochondrial signaling axis invoked by electromagnetic exposure and necessary for proliferation. These results indicate that light facilitates functional synergism with magnetic fields that ultimately impinge on mitochondria-dependent developmental responses. Aminoglycoside antibiotics (AGAs) have been previously shown to inhibit TRPC1-mediated magnetotransduction, whereas their influence over photomodulation has not been explored. Streptomycin applied during exposure to light, magnetic fields, or COMS reduced their respective proliferation enhancements, whereas streptomycin added after the exposure did not. Magnetic field exposure and the COMS modality were capable of partially overcoming the antagonism of proliferation produced by streptomycin treatment, whereas light alone was not. The antagonism of photon-electromagnetic effects by streptomycin implicates TRPC1-mediated calcium entry in both magnetotransduction and photomodulation. Avoiding the prophylactic use of AGAs during COMS therapy will be crucial for maintaining clinical efficacy and is a common concern in most other electromagnetic regenerative paradigms. |
Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes |
| Derrick Sek Tong Ong |
| Biogerontology. 2024 Apr;25(2):341-360. doi: 10.1007/s10522-023-10076-5. Epub 2023 Nov 21. |
| Abstract |
| Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases. |
Are Aminoglycoside Antibiotics TRPing Your Metabolic Switches? |
| Alfredo Franco-Obregón |
| Cells 2024, 13(15), 1273; |
| Abstract |
| Transient receptor potential (TRP) channels are broadly implicated in the developmental programs of most tissues. Amongst these tissues, skeletal muscle and adipose are noteworthy for being essential in establishing systemic metabolic balance. TRP channels respond to environmental stimuli by supplying intracellular calcium that instigates enzymatic cascades of developmental consequence and often impinge on mitochondrial function and biogenesis. Critically, aminoglycoside antibiotics (AGAs) have been shown to block the capacity of TRP channels to conduct calcium entry into the cell in response to a wide range of developmental stimuli of a biophysical nature, including mechanical, electromagnetic, thermal, and chemical. Paradoxically, in vitro paradigms commonly used to understand organismal muscle and adipose development may have been led astray by the conventional use of streptomycin, an AGA, to help prevent bacterial contamination. Accordingly, streptomycin has been shown to disrupt both in vitro and in vivo myogenesis, as well as the phenotypic switch of white adipose into beige thermogenic status. In vivo, streptomycin has been shown to disrupt TRP-mediated calcium-dependent exercise adaptations of importance to systemic metabolism. Alternatively, streptomycin has also been used to curb detrimental levels of calcium leakage into dystrophic skeletal muscle through aberrantly gated TRPC1 channels that have been shown to be involved in the etiology of X-linked muscular dystrophies. TRP channels susceptible to AGA antagonism are critically involved in modulating the development of muscle and adipose tissues that, if administered to behaving animals, may translate to systemwide metabolic disruption. Regenerative medicine and clinical communities need to be made aware of this caveat of AGA usage and seek viable alternatives, to prevent contamination or infection in in vitro and in vivo paradigms, respectively. |