Publications - 2025
Sleep Reactivity Amplifies the Impact of Pre-Sleep Cognitive Arousal on Sleep Disturbances |
| Shaif, N. A. S., Lim, J., Reffi, A. N., Chee, M. W. L., Massar, S. A. A., & Ong, J. L. |
| Journal of sleep research, e70220 |
| Abstract |
| Sleep reactivity-an individual's susceptibility to sleep disruptions due to stress-has been linked to increased insomnia risk. Investigating how sleep reactivity moderates the 'stress → pre-sleep arousal → sleep' pathway may help mitigate sleep disturbances and enhance treatment outcomes. In the present study, full-time university students without sleep disorders completed the Ford Insomnia Response to Stress Test (FIRST), which assesses sleep reactivity. From 264 students, 30 students with the lowest and 30 with the highest FIRST scores were selected for further study. They provided daily actigraphy, Pre-sleep Arousal Scale ratings, pre-sleep heart rate (via an ŌURA ring), and perceived stress scores over 2 weeks. Multilevel moderated mediation analyses were conducted using 800 nights of data to examine within- and between-individual associations. At the within-individual level, days with higher-than-usual perceived stress were associated with reduced total sleep time and increased sleep onset latency (p's < 0.05). These effects were mediated by heightened pre-sleep cognitive arousal (p's < 0.05) but not moderated by the FIRST group. In contrast, between-individual analyses revealed a significant moderation by the FIRST group (p < 0.05). High sleep-reactive individuals reported significantly greater average levels of perceived stress and pre-sleep cognitive arousal, leading to prolonged wakefulness after sleep onset (b = 0.123, Monte Carlo confidence interval [MCCI] = 0.006-0.292), compared to low-reactive sleepers. Overall, on a day-to-day basis, both groups showed increased pre-sleep cognitive arousal and sleep disruptions in response to elevated daily stress. However, between individuals, high sleep reactivity significantly amplified the effect of pre-sleep cognitive (but not physiological) arousal, leading to more pronounced sleep disturbances compared to low-reactive sleepers. |
Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q+ |
| Romanos Sklavenitis-Pistofidis, Elizabeth D. Lightbody, Mairead Reidy, Junko Tsuji, Jean-Baptiste Alberge, Michelle P. Aranha, Daniel Heilpern-Mallory, Harvey G. Roweth, Daisy Huynh, Stephen J. F. Chong, Anna Y. Chung, Jeremy Zhang, Liam Hackett, Nicholas J. Haradhvala, Ting Wu, Nang K. Su, Brianna Berrios, Saveliy Belkin, Ankit K. Dutta, Ryan A. Knudson, Carolyn Brandt, Patricia T. Greipp, Matthew S. Davids, Maria Papaioannou, Gad Getz, Irene M. Ghobrial, Salomon Manier |
| Blood |
| Abstract |
| The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+. |
Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies |
| Stephen J. F. Chong, Jolin X. H. Lai, Kartini Iskandar, Benedict J. Leong, Chuqi Wang, Yuhan Wang, Romain Guièze, Deepika Raman, Rachel H. F. Lim, Catherine J. Wu, Wee Joo Chng, Alice M. S. Cheung, Charles Chuah, Matthew S. Davids & Shazib Pervaiz |
| Leukemia |
| Abstract |
| Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O2.−) levels. Validating that, augmenting intracellular O2.− in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT/PKB is implicated in O2.−-induced T163pMcl-1, as reducing intracellular O2.− or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies. |
LEADS - A comprehensible human liver-on-a-chip for non-alcoholic steatohepatitis (NASH) drug testing |
| Balachander, G.M., Ng, I.C., Pai, R.R., Mitra, K., Tasnim, F., Lim, Y.S., Kwok, R., Song, Y., Yaw, L.P., Quah, C.B., Zhao, J., Septiana, W.L., Kota, V.G., Teng, Y., Zheng, K., Xu, Y., Lim, S.H., Ng, H.H., and Yu, H. |
| Lab on a Chip |
| Abstract |
| Metabolic dysfunction associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), is a progressive form of steatotic liver disease (SLD). It is an emerging healthcare threat due its high prevalence, accelerated and non-linear progression, and final culmination as decompensated liver failure and/or hepatocellular carcinoma (HCC). The pathogenesis of NASH is complex with strong ethnic influences and genetic predispositions, underscoring the need for preclinical models that utilize patient-derived cells to enhance our understanding of the disease. Current models face three major limitations: (i) reliance on primary cells with limited reproducibility, high cost, short culture duration and ethical considerations, (ii) failure to recapitulate all key features of NASH, and (iii) inadequate drug testing data and/or data did not correlate with clinical responses. Therefore, there is a pressing need for robust and relevant preclinical models that faithfully recapitulate human NASH, allow generation of patient-specific models and provide quantitative responses for mechanistic studies and drug testing. We have developed a functional liver tissue-on-a-chip by co-culturing human adult liver stem cell (haLSC)-derived hepatobiliary organoids, induced pluripotent stem cell (iPSC)-derived Kupffer cells (iKCs) and iPSC-derived hepatic stellate cells (iHSCs). We simulated the metabolic microenvironment of hyper nutrition and leaky gut by treating the cells with a concoction of free fatty acids (FFAs), fructose, gut-derived lipopolysaccharides (LPS) and a gut-derived metabolite, phenyl acetic acid (PAA). Through optimization of co-culture media and induction regimens, we were able to stably induce steatosis, hepatocellular ballooning, inflammation, and activation of iHSC and fibrosis—all key hallmarks of NASH. Our LEADS (liver-on-a-chip for NASH drug testing) model also recapitulated the pathological types of steatosis and allowed for quantification of the key features via microscopic evaluation and secretome profiling to score for disease severity. Notably, treatment with saroglitazar, pioglitazone, cenicriviroc (CVC), obeticholic acid (OCA) and resmetirom produced responses similar to those observed in clinical trials. Taken together, our LEADS model is the first model developed using patient-derived hepatic stem cells which recapitulated all key features used for comprehensive drug testing, with results matching to clinical responses. |
HIVIL: A Human In vitro Inflammatory Liver Model Recapitulates Immune-associated Drug effects with High Predictivity |
| Huang, X., Soong, Y.T., Wang, J., Ng, C.J.Y., Mitra, K., Tasnim, F., and Yu, H. |
| NAM Journal |
| Abstract |
| DILI (Drug Induced Liver Injury) is one of leading cause of failure in drug development due to adverse reaction outcomes and health hazards. Besides, understanding DILI is challenging due to lack of relevant in vitro models] that recapitulate human in vivo physiological responses. Current in vitro models employing primary human Kupffer cells (PHKCs) or alternative cells such as THP-1 derived macrophages are either complex or do not recapitulate physiological drug-induced cytokine responses. We leveraged on human iPSC derived Kupffer cells (iKCs) that functionally resemble PHKCs to establish a human in vitro inflammatory liver model (HIVIL) that is complex enough to be physiological and simple enough to be robust. HIVIL, comprising of iKCs co-cultured with iPSCs derived hepatocytes can recapitulate physiological levels of DILI associated inflammatory response of known DILI drugs in vitro. Out of 18 drug candidates tested, the cytokine responses of 16 drugs correlated (88.9 %) well with the reported serum cytokine profiles of DILI patients implying a closer-to-physiological relevant immune responses and cytochrome P450 expression . Moreover, HIVIL model was able to mechanistically distinguish the TNF⍺ mediated hepatotoxic effect of Trovafloxacin over Levofloxacin. RNA-Seq analysis provided further insight into the interactions between the cytokines and drug-induced liver injury. In contrast, HIVIL using THP-1 derived macrophages instead of iKCs did not recapitulate the cytokine responses upon treatment with paradigm compounds, demonstrating the importance of KCs-produced cytokines on hepatocyte xenobiotic metabolism. In summary, our study demonstrates for the first time, the use of iKCs and iHeps as a simple, robust and physiologically relevant in vitro drug testing model for DILI candidates. |
Metabolome-wide association identifies ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations |
| Sadhu, N., Dalan. R., Jain, P.R., Lee, C.J.M., Pakkiri, L.S., Tay, K.Y., Mina, T.H., Low, D., Min, Y., Ackers-Johnson, M., Thi, T.T., Kota, V.G., Shi, Y., Liu, Y., Yu, H., Lai, V., Yang, Y., Tay, D., Ng, H.K., Wang, X., Wong, K.E., Lam, M., Guan, X.L., Bertin, N., Wong, E., Best, J., Sarangarajan, R., Elliott, P., Riboli, E., Lee, J., Lee, E.S., Ngeow, J., Tan, P., Cheung, C., Drum, C.L., Foo, R.S.Y., Michelotti, G.A., Yu, H., Sheridan, P.A., Loh, M., Chambers, J.C. |
| Nature Cardiovascular Research |
| Abstract |
| The burden of cardiovascular disease is rising in the Asia-Pacific region, in contrast to falling cardiovascular disease mortality rates in Europe and North America. Here we perform quantification of 883 metabolites by untargeted mass spectroscopy in 8,124 Asian adults and investigate their relationships with carotid intima media thickness, a marker of atherosclerosis. Plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, were inversely associated with carotid intima media thickness, and Mendelian randomization studies supported a causal relationship between 3BH5C and coronary artery disease. The observed effect size was 5- to 6-fold higher in Asians than Europeans. Colocalization analyses indicated the presence of a shared causal variant between 3BH5C plasma levels and messenger RNA and protein expression of ferredoxin-1 (FDX1), a protein that is essential for sterol and bile acid synthesis. We validated FDX1 as a regulator of 3BH5C synthesis in hepatocytes and macrophages and demonstrated its role in cholesterol efflux in macrophages and aortic smooth muscle cells, using knockout and overexpression models. |
Effect of preoperative rapamycin supplementation on perioperative clinical frailty and cognitive performance in a murine model undergoing anesthesia and surgery |
| Sim MA, Goh J, Lee J, Tay JH, Tan FCK, Li C, Wong ESP, Loh WNH, Chew STH, Maier AB, Kennedy BK, Ti LK. |
| Sci Rep. 2025 Jun 5;15(1):19741 |
| Abstract |
| The geroprotective effects of rapamycin in mitigating frailty and cognitive complications in the perioperative period remains unknown. Of 39 C57BL/6 mice tested, 19 were young (16 weeks), and 20 were old (80 weeks). The interventional group (10 old, 10 young) received daily oral rapamycin for 8 weeks pre-op compared to controls (10 old, 9 young). Sham laparotomy was performed at week 9. Perioperative frailty was assessed using a murine clinical frailty scale, preoperatively and at 1, 4 and 8 weeks postoperatively. Spatial memory was assessed using the Barnes maze preoperatively, and at weeks 1 and 4 post-op. Rapamycin treatment is associated with significantly less decline in postoperative clinical frailty(p < 0.05). Subgroup analysis revealed similar findings for old and young mice. The rapamycin group demonstrated improved cognitive performance at 1-week postoperatively (β 40.18, 95%C.I. 8.70–71.67, p = 0.012), but only in older mice (β 54.51, 95%C.I. 6.77–102.25, p = 0.025). In a pre-clinical animal model of anesthesia and surgery, rapamycin supplementation protected against surgery-induced frailty and short-term postoperative cognitive dysfunction. |
From Inquiry to Insight: Unlocking the Potential of Students’ Questions in Medical Education in Singapore |
| Wong, A. H. P., Wong, L. W., Hooi, S. C., & Lee, S. S. |
| Teaching and Learning in Medicine, 1–10 |
| Abstract |
| Background: Question-asking serves as a fundamental tool for active learning, allowing students to articulate uncertainties, link concepts, and refine their understanding. Despite its recognized value, the potential of student-generated questions in medical education remains underexplored, particularly in Asian academic settings where sociocultural norms may discourage students from speaking up in classroom discussions. Research on students’ questions has overlooked their application as a resource for understanding cognitive engagement and identifying problem areas in student learning. This study, conducted at the National University of Singapore, addresses this gap by exploring student-generated questions as a lens into cognitive engagement with course content. Methods: A content analysis approach was used to classify questions submitted anonymously by first-year medical students via a shared question-and-answer document embedded in the self-directed learning segment of a cardiovascular physiology course. Questions were categorized by cognitive levels using the revised Bloom’s taxonomy, which provides a structured framework for assessing cognitive complexity. A chapter-based analysis examined question distribution across content areas to identify patterns in topic-specific inquiry. Two independent raters performed the classification, reaching an inter-rater agreement of 83.2%. Results: Two-hundred ninety-eight (298) questions were analyzed, with most categorized at the ‘Understand’ (56%) and ‘Apply’ (29%) levels. This distribution closely aligns with the educational objectives of the self-directed learning segment and foundational medical curriculum, which prioritize comprehension and practical application. Slight variations across cognitive levels, particularly in higher-order categories, suggest that the nature of certain topics or instructional activities may promote deeper engagement. Question frequency was not uniformly distributed across topics, with electrocardiogram and clinical examination topics eliciting the most questions, likely due to the foundational relevance and integration with subsequent teaching activities. Discussion: Incorporating opportunities for question-asking within the curriculum is a promising strategy for examining students’ cognitive engagement in medical education. The prevalence of ‘Understand’ and ‘Apply’ questions highlights a strong engagement pattern aligned with early-stage medical education, while chapter-based trends suggest topic complexity or instructional activities may influence question-asking patterns. By systematically analyzing student-generated questions, this study provides a structured means of assessing how students engage with course content at different cognitive levels. These insights can be used to inform instructional strategies that better support student engagement, allowing educators to refine teaching approaches according to learners’ needs. |
A risk-based approach can guide safe cell line development and cell banking for scaled-up cultivated meat production |
| Bennie, R.Z., Ogilvie, O.J., Loo, L.S.W., Zhou, H., Ng, S.K., Jin, A., Trlin, H.J.F., Wan, A., Yu, H., Domigan, L.J., and Dobson, R.C.J |
| Nature Food, 3 January 2025; 6: 25-30 |
| Abstract |
| For commercial viability, cultivated meats require scientifically informed approaches to identify and manage hazards and risks. Here we discuss food safety in the rapidly developing field of cultivated meat as it shifts from lab-based to commercial scales. We focus on what science-informed risk mitigation processes can be implemented from neighbouring fields. We case-study pre-market safety assessments from UPSIDE Foods, GOOD Meat and Vow Group using publicly available dossiers. Quality control and safety assurance practices need to be established and standardized for cell lines and food-grade cell banks. |
Cost-effective Production of Meaty Aroma from Porcine Cells for Hybrid Cultivated Meat |
| Zhou, H., Loo, L.S.W., Ong, F.Y.T., Lou, X., Wang, J., Myint, M.K., Thong, A., Seow, D.C.S., Wibowo, M., Ng, S., Lv, Y., Kwang, L.G., Bennie, R.Z., Pang, K.T., Dobson, R.C.J., Domigan, L.J., Kanagasundaram, Y., and Yu, H. (2025) |
| Food Chemistry, 1 May 2025 |
| Abstract |
| Cultivated meats are typically hybrids of animal cells and plant proteins, but their high production costs limit their scalability. This study explores a cost-effective alternative by hypothesizing that controlling the Maillard and lipid thermal degradation reactions in pure cells can create a meaty aroma that could be extracted from minimal cell quantities. Using spontaneously immortalized porcine myoblasts and fibroblasts adapted to suspension culture with a 1 % serum concentration, we developed a method to isolate flavor precursors via freeze-thawing. Thermal reaction conditions were optimized to enhance aroma compound production. Chemical profiling demonstrates that myoblasts produce an aroma profile closer to pork meat than fibroblasts, although serum reduction decreased aroma yield. Sensory analysis supported these findings. Incorporating the optimized aroma extract - derived from just 1.2 % (w/w) cells - into plant proteins resulted in a hybrid cultivated meat with 78.5 % sensory similarity to pork meat, but with a significant 80 % reduction in production costs. |
Rapid Universal Detection of High-Risk and Low-Abundance Microbial Contaminations in CAR-T Cell Therapy |
| Wu, X., Raymond, J.J., Liu, Y., Odermatt, A.J., Sin, W.-X., Teo, D.B.T., Natarajan, M., Ng, I.C., Birnbaum, M.E., Lu, T.K., Han, J, Springs, S.L., and Yu, H. (2025) |
| Small Methods, 30 March 2025 |
| Abstract |
| Live microbial contamination poses high risks to cell and gene therapies, threatening manufacturing processes and patient safety. Rapid, sensitive detection of live microbes in complex environments, such as CAR-T cell cultures, remains an urgent need. Here, an innovative sample-to-result workflow is introduced using digital loop-mediated isothermal amplification (dLAMP), enhanced by Electrostatic Microfiltration (EM)-based enrichment, for rapid sterility testing. By rationally designing primers targeting 16S and 18S rRNA, dLAMP assay enables both universal detection (covering >80% of known species) and strain-specific identification of bacterial and fungal contaminants in CAR-T cell spent medium and final products, directly from microorganism lysates. Enhanced by EM-based enrichment of low-abundance live microbes, the workflow achieves unparalleled sensitivity and speed, detecting contamination levels as low as 1 CFU/mL in complex CAR-T cell cultures within 6 h. Compared to qPCR and 14-day compendial methods, the approach demonstrates superior accuracy and significantly faster turnaround times. This workflow holds transformative potential for real-time monitoring in cell therapy manufacturing and rapid safety assessments of CAR-T cell products prior to patient infusion. Beyond cell therapy, the method is broadly applicable to infectious disease diagnostics, biomanufacturing monitoring, food safety, and environmental surveillance. |
Interplay Between the Cytoskeleton and DNA Damage Response in Cancer Progression |
| Halim CE, Deng S, Crasta KC, Yap CT |
| Cancers (Basel) |
| Abstract |
| DNA damage has emerged as a critical factor in fuelling the development and progression of cancer. DNA damage response (DDR) pathways lie at the crux of cell fate decisions following DNA damage induction, which can either trigger the repair of detrimental DNA lesions to protect cancer cells or induce the cell death machinery to eliminate damaged cells. Cytoskeletal dynamics have a critical role to play and influence the proper function of DDR pathways. Microfilaments, intermediate filaments, microtubules, and their associated proteins are well involved in the DDR. For instance, they are not only implicated in the recruitment of specific DDR molecules to the sites of DNA damage but also in the regulation of the mobility of the damaged DNA to repair sites in the periphery of the nucleus. The exquisite roles that these cytoskeletal proteins play in different DDR pathways, such as non-homologous end joining (NHEJ), homologous recombination (HR), base excision repair (BER), and nucleotide excision repair (NER), in cancer cells are extensively discussed in this review. Many cancer treatments are reliant upon inducing DNA damage in cancer cells to eliminate them; thus, it is important to shed light on factors that could affect their efficacy. Although the cytoskeleton is intricately involved in the DDR process, this has often been overlooked in cancer research and has not been exploited in developing DDR-targeting cancer therapy. Understanding the interplay between the cytoskeleton and the DDR in cancer will then provide insights into improving the development of cancer therapies that can leverage the synergistic action of DDR inhibitors and cytoskeleton-targeting agents. |
Exercise-induced neurogenesis through BDNF-TrkB pathway: implications for neurodegenerative disorders |
| Lee JJ, Sitjar PHS, Ang ET, Goh J |
| Transl Exerc Biomed 2025 |
| Abstract |
| Current scientific endeavours in the field of geroscience have begun to reveal how factors such as exercise could modulate the brain aging process. In this review, we ask how exercise could potentially modulate aging, and by extension, the development of Alzheimer’s Disease (AD). Furthermore, we discuss how exercise could mitigate the cascade of debilitating manifestations in AD. Mechanistically, we discuss how biomolecules such as brain-derived neurotrophic factor (BDNF) and its cognate receptor, tropomyosin receptor kinase B (TrkB) could change during the life course and how its signalling pathways could be altered with exercise (acute sessions or chronic training). Tackling these questions could help the scientific and medical community mitigate age-related decline in terms of neurological functions. |
Is it time for exercise-conditioned plasma to enter human trials? |
| Sitjar PH, Goh J |
| Int J Biol Sci 2025 |
| Abstract |
Frequency, Intensity and Duration of Physical Activity is Associated with Frailty in Older Adults with Cardiac Aging |
| Wang LYT, Lim WS, Tan RS, Teo L, Tan SY, Ooi CH, Ong A, Kovalik JP, Goh J, Koh WP, Gao F, Koh A |
| Sci Rep 2025 15, 15679 |
| Abstract |
|
While cardiovascular aging and frailty are strongly associated in older adults, their mechanistic relationship and how physical activity, through its frequency, intensity, and duration, may influence their association remains unclear. A prospective community cohort of older adults without cardiovascular disease were studied cross-sectionally for cardiac structure and function via echocardiogram, dynamometer-derived handgrip strength, skeletal muscle measurements and physical activity questionnaires. Based on handgrip strength and cardiac aging, we derived four phenotypic groups:1 Normal2, Physical frailty without cardiac aging3, Cardiac aging without physical frailty, and4 Physical frailty and cardiac aging. Multinomial logistic regression was used to examine factors associated with cardiac frailty phenotypes, adjusting for physical activity characteristics, physical measurements, demographics, and cardiovascular risk factors. Amongst 592 participants, the prevalence in the four groups were 44.9%, 20.6%, 18.8%, and 15.7% respectively. Participants in group 1 were the youngest (64, IQR 22), while those in group 4 were the oldest (75, IQR 4.7). Higher frequencies of physical activity (once a week: RRR = 8.922, 95%CI 1.799, 44.250, p = 0.007; and 2–3 times a week: RRR = 3.873, 95%CI 1.036, 14.478, p = 0.044) were associated with Group 4 category. Higher intensity of physical activity indicated by heavy breath and sweat or near exhaustion (RRR = 0.081, 95%CI 0.017, 0.380, p = 0.001), and longer duration (> 1 h: RRR = 0.261, 95%CI 0.079, 0.869, p = 0.029) were associated with Group 4 category as well. More than half of community older adults had physical frailty with or without cardiac aging. Higher intensity and longer physical activity duration were associated with lower risks of cardiac aging in the presence of physical frailty, although frequency of once and two to three times a week was associated with higher odds. Physical activity frequency showed no significant association with risks of isolated cardiac aging or physical frailty. These results highlight the importance of tailoring physical activity characteristics based on cardiac frailty phenotypes for developing individualized preventive interventions. Trial registration: ClinicalTrials.gov Identifier: NCT02791139 (06/06/2016). |
A compendium of human gene functions derived from evolutionary modelling |
| Feuermann, M., Mi, H., Gaudet, P., Muruganujan, A., Lewis, S.E., Ebert, D., Mushayahama, T., Gene Ontology, C., and Thomas, P.D |
| Nature 640, 146–154 (2025) |
| Abstract |
|
A comprehensive, computable representation of the functional repertoire of all macromolecules encoded within the human genome is a foundational resource for biology and biomedical research. The Gene Ontology Consortium has been working towards this goal by generating a structured body of information about gene functions, which now includes experimental findings reported in more than 175,000 publications for human genes and genes in experimentally tractable model organisms1,2. Here, we describe the results of a large, international effort to integrate all of these findings to create a representation of human gene functions that is as complete and accurate as possible. Specifically, we apply an expert-curated, explicit evolutionary modelling approach to all human protein-coding genes. This approach integrates available experimental information across families of related genes into models that reconstruct the gain and loss of functional characteristics over evolutionary time. The models and the resulting set of 68,667 integrated gene functions cover approximately 82% of human protein-coding genes. The functional repertoire reveals a marked preponderance of molecular regulatory functions, and the models provide insights into the evolutionary origins of human gene functions. We show that our set of descriptions of functions can improve the widely used genomic technique of Gene Ontology enrichment analysis. The experimental evidence for each functional characteristic is recorded, thereby enabling the scientific community to help review and improve the resource, which we have made publicly available. |
Schizophrenia: Genetics, neurological mechanisms, and therapeutic approaches |
| Lim, D.X.E., Yeo, S.Y., Chia, Z.Y.A., Fernandis, A.Z., Lee, J., and Chua, J.J.E. |
| Neural Regeneration Research ():10.4103/NRR.NRR-D-24-01375, May 06, 2025 |
| Abstract |
|
Schizophrenia is a complex psychiatric disorder marked by positive and negative symptoms, leading to mood disturbances, cognitive impairments, and social withdrawal. While anti-psychotic medications remain the cornerstone of treatment, they often fail to fully address certain symptoms. Additionally, treatment-resistant schizophrenia, affecting 30%-40% of patients, remains a substantial clinical challenge. Positive, negative symptoms and cognitive impairments have been linked to disruptions in the glutamatergic, serotonin, GABAergic, and muscarinic pathways in the brain. Recent advances using genome-wide association study and other approaches have uncovered a significant number of new schizophrenia risk genes that uncovered new, and reinforced prior, concepts on the genetic and neurological underpinnings of schizophrenia, including abnormalities in synaptic function, immune processes, and lipid metabolism. Concurrently, new therapeutics targeting different modalities, which are expected to address some of the limitations of anti-psychotic drugs currently being offered to patients, are currently being evaluated. Collectively, these efforts provide new momentum for the next phase of schizophrenia research and treatment. |
CD137-expressing Regulatory T Cells in Cancer and Autoimmune Diseases |
| Lee Kang Yi, Yu Mei, Haiyan Liu, Herbert Schwarz |
| Molecular Therapy, 33(1):51-70, 2025 |
| Abstract |
|
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, with critical roles in preventing aberrant immune responses that occur in autoimmune diseases and chronic inflammation. Conversely, the abundance of Tregs in cancer is associated with impaired anti-tumor immunity, and tumor immune evasion. Recent work demonstrates that CD137, a well-known costimulatory molecule for T cells, is highly expressed on Tregs in pathological conditions, while its expression is minimal or negligible on peripheral Tregs. The expression of CD137 marks Tregs with potent immunosuppressive phenotype that foster cancer progression and are protective against certain autoimmune diseases. Hence CD137 has emerged as a marker for Tregs. However, several important questions still remain regarding the expression and function of CD137 in Tregs. Here, we provide an overview of our current knowledge of Treg mechanisms of action, with a focus on the role of CD137 in modulating Treg activity. We also explore the implications of CD137+ Tregs in both cancer and autoimmune diseases, emphasizing the significance of targeting these cells for therapeutic intervention in these conditions. |
Induction of cell death in malignant cells and regulatory T cells in the tumour microenvironment by targeting CD137 |
| Sun Rui, Kang Yi Lee, Yu Mei, Emily Nickles, Jia Le Lin, Runze Xia, Haiyan Liu, Herbert Schwarz. |
| OncoImmunology, 14(1):2443265, 2025 |
| Abstract |
|
Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cell-mediated cytotoxicity (ADCC) in CD137+ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137+ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137+ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy. |
Efficacy of Rituximab on Antibody-Positive Small Fiber Neuropathy: A series of 5 cases |
| Chan Amanda C.Y., Shahana R, Kewin TH Siah, Nicholas Foo, Yee-Cheun Chan, Kay WP Ng, Amy ML Quek, Rahul Rathakrishnan, Shi-Yang Ng, Herbert Schwarz, Anselm Mak, Vijay Kumar Sharma |
| J. Neuroimmunol. 401 (2025) 578559 February 17, 2025 |
| Abstract |
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Background & aims: We evaluated the efficacy of rituximab in patients with anti-TS-HDS, anti-FGFR3 and anti-plexin D1 small fiber neuropathy (SFN) who failed to respond to conventional treatments and immunotherapy. Methods: We reviewed 111 patients diagnosed with SFN - 83 definite SFN, 9 had positive antibody titers towards TS-HDS, FGFR3 or plexin-D1 and received symptomatic treatment, in addition to trials of intravenous immunoglobulin (IVIg) and/or corticosteroids. Five patients who failed to respond were offered rituximab (two intravenous 1 g infusions, two weeks apart). Clinical parameters and questionnaires were compared. Results: Two patients were positive for anti-TS-HDS, one for anti-plexin D1 and two for anti-FGFR3 antibodies. Therapeutic efficacy was assessed by circulating CD19+ B cell levels with flow cytometry. Clinical questionnaires, including Visual Analogue Scale (VAS), Rasch Transformed 13-item SFN Symptom Inventory Quotient (RT-SFN-SIQ), Small Fiber Neuropathy-specific Rasch-built overall disability scale (SFN-RODS) and the Composite Autonomic Symptom Scale (COMPASS-31) were obtained prior to rituximab infusion, and at 4 weeks and 4 months post-infusion. Significantly improved VAS was seen at 4 months after rituximab, while a trend towards improvement was seen in RT-SFN-SIQ, and SFN-RODS. COMPASS-31 score remained static. Interpretation: This study illustrates the efficacy and potential role of anti-CD20 monoclonal antibody in antibody-associated immune SFN, especially in those who fail to respond to IVIg or corticosteroid. Further randomized controlled trials and larger prospective studies are needed to determine the effectiveness and safety of Rituximab in seropositive patients with SFN. Keywords: Anti-CD20 monoclonal antibody; Anti-FGFR3 antibody; Anti-TS-HDS antibody; Anti-plexin D1 antibody; Small fiber neuropathy. |
EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression |
| Bajaj U, Das D, Leung JY, Rashi NFB, and Taneja R |
| Br J Cancer (2025) |
| Abstract |
| Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. When metastatic, survival of children with RMS is less than 20% and has remained unchanged over two decades. No targeted drug therapy is available for these cancers. Genomic analysis has revealed a low incidence of somatic mutations in RMS. Epigenetic modifiers thus play important roles in driving oncogenesis. In this study, we examined the role of EHMT1 in fusion- negative embryonal rhabdomyosarcoma (ERMS), the most frequent subtype of RMS. |
Rewiring of SINE-MIR enhancer topology and Esrrb modulation in expanded and naive pluripotency. |
| Cipta NO, Zeng Y, Wong KW, Zheng ZH, Yi Y, Warrier T, Teo JZ, Teo JHJ, Kok YJ, Bi X, Taneja R, Ong DST, Xu J, Ginhoux F, Li H, Liou YC, Loh YH |
| Genome Biol. 2025 Apr 28;26(1):107 |
| Abstract |
| The interplay between 3D genomic structure and transposable elements (TE) in regulating cell state-specific gene expression program is largely unknown. Here, we explore the utilization of TE-derived enhancers in naïve and expanded pluripotent states by integrative analysis of genome-wide Hi-C-defined enhancer interactions, H3K27ac HiChIP profiling and CRISPR-guided TE proteomics landscape. |
Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression |
| Cobo I, Murillo-Saich J, Alishala M, Calderon S, Coras R, Hemming B, Inkum F, Rosas F, Takei R, Spann N, Prohaska TA, Alabarse PVG, Jeong SJ, Nickl CK, Cheng A, Li B, Vogel A, Weichhart T, Fuster JJ, Le T, Bradstreet TR, Webber AM, Edelson BT, Razani B, Ebert BL, Taneja R, Terkeltaub R, Bryan RL, Guma M, Glass CK |
| Immunity. 2025 Apr 8;58(4):826-842.e8 |
| Abstract |
| Exposure to particles is a driver of several inflammatory diseases. Here, we investigated macrophage responses to monosodium urate crystals, calcium pyrophosphate crystals, aluminum salts, and silica nanoparticles. While each particle induced a distinct gene expression pattern, we identified a common inflammatory signature and acute activation of lysosomal acidification genes. Using monosodium urate crystals as a model, we demonstrated that this lysosomal gene program is regulated by a 5'-prime-AMP-activated protein kinase (AMPK)-dependent transcriptional network, including TFEB, TFE3, and the epigenetic regulators DNA methyl transferase 3a (DNMT3A) and DOT1L. This lysosomal acidification program operates in parallel with, but largely independently of, a JNK-AP-1-dependent network driving crystal-induced chemokine and cytokine expression. These findings reveal a bifurcation in pathways governing inflammatory and lysosomal responses, offering insights for treating particle-associated diseases. |
Role of epigenetics in paediatric cancer pathogenesis & drug resistance |
| Leung JY, Chiu HY, Taneja R |
| Br J Cancer 132, 757–769 (2025) |
| Abstract |
| Paediatric oncogenesis is tightly intertwined with errors in developmental processes involving cell specification and differentiation, which are governed by intricate temporal epigenetic signals. As paediatric cancers are characterised by a low number of somatic mutations, dysregulated chromatin landscapes are believed to be key drivers of oncogenesis. Epigenetic dysregulation is induced by mutations and aberrant expression of histones and epigenetic regulatory genes, to altered DNA methylation patterns and dysregulated noncoding RNA expression. In this review, we discuss epigenetic alterations in paediatric cancer oncogenesis and recurrence, and their potential as diagnostic biomarkers. We also discuss various epigenetic drugs that have entered clinical trials for aggressive paediatric cancers. Targeting paediatric-specific epigenetic vulnerabilities may improve recurrence-free survival in high-risk cancers. |
BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia |
| Stephen Jun Fei Chong, Junyan Lu, Rebecca Valentin, Timothy Z. Lehmberg, Jie Qing Eu, Jing Wang, Fen Zhu, Li Ren Kong, Stacey M. Fernandes, Jeremy Zhang, Charles Herbaux, Boon Cher Goh, Jennifer R. Brown, Carsten U. Niemann, Wolfgang Huber, Thorsten Zenz & Matthew S. Davids |
| Mol Cancer 24, 62 (2025) |
| Abstract |
| Established genetic biomarkers in chronic lymphocytic leukemia (CLL) have been useful in predicting response to chemoimmunotherapy but are less predictive of response to targeted therapies. With several such targeted therapies now approved for CLL, identifying novel, non-genetic predictive biomarkers of response may help to select the optimal therapy for individual patients. |