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Tag: National University of Singapore (NUS)

  • The Complete Library of Charles Darwin revealed for the first time

    The Complete Library of Charles Darwin revealed for the first time


    Newswise — Charles Darwin – arguably the most influential man of science in history, accumulated a vast personal library throughout his working life. Until now, 85 per cent of its contents were unknown or unpublished. 

    This year, coinciding with Darwin’s 215th birthday, The Complete Work of Charles Darwin Online, the scholarly project helmed by Dr John van Wyhe at the National University of Singapore (NUS) Department of Biological Sciences, has released an online 300-page catalogue detailing Darwin’s complete personal library, with 7,400 titles across 13,000 volumes and items including books, pamphlets and journals. Previous lists only had 15 per cent of his whole collection. Darwin’s library has also been virtually re-assembled with 9,300 links to copies of the works freely available online.

    “This unprecedentedly detailed view of Darwin’s complete library allows one to appreciate more than ever that he was not an isolated figure working alone but an expert of his time building on the sophisticated science and studies and other knowledge of thousands of people. Indeed, the size and range of works in the library makes manifest the extraordinary extent of Darwin’s research into the work of others,” said Dr van Wyhe.

    Discovering Darwin’s complete library

    After his death in 1882, much of Darwin’s library was preserved and catalogued, but many other items were dispersed or lost, and details of the vast majority of the contents have never been published until now. For many years, scholars have referred to Darwin’s library as containing 1,480 books, based on those that survive in the two main collections, the University of Cambridge and Down House.

    Over 18 years the Darwin Online project has identified thousands of Darwin’s obscure references in his own catalogues and lists of items such as pamphlets and journals that were originally in his library. Each reference required its own detective story to discover the publications that Darwin had hurriedly recorded. In addition, missing details such as author, date or the source of clippings in thousands of records from older catalogues have been identified for the first time.

    A major source of information that helped to reveal the original contents is the 426-page handwritten “Catalogue of the Library of Charles Darwin”, compiled from 1875. Painstaking comparison of its abbreviated entries revealed 440 unknown titles that were originally in the library. An inventory of his home made after his death recorded 2,065 bound books and an unknown number of unbound volumes and pamphlets. In the drawing room, 133 titles and 289 volumes of mostly unscientific literature were recorded. Amazingly, the legacy duty valuer estimated that the “Scientific Library that is books relating to Science” was worth only 30 pounds and 12 shillings [about £2,000 today] Indeed, all the books were valued at only66 pounds and 10 shillings [about £4,400 today]. Today any book that belonged to Darwin is worth a great deal to collectors.

    Other sources of information that helped to build Darwin’s complete library were lists of pamphlets, Darwin’s reading notebooks, Emma Darwin’s diaries, the Catalogue of books given to the Cambridge Botany School in 1908 and the 30 volumes of the Darwin Correspondence. Items that still exist but were never included in the lists of Darwin’s library include his unbound materials at Cambridge University Library, books now in other institutional collections, private collections and books sold at auctions over the past 130 years. Combining these and many other sources of evidence allowed Darwin’s library to be reconstructed.

    For example, Darwin’s copy of an 1826 article by the ornithologist John James Audubon: ‘Account of the habits of the Turkey Buzzard (Vultura aura), particularly with the view of exploding the opinion generally entertained of its extraordinary power of smelling’ was sold in 1975. Darwin had investigated this point during the voyage of the Beagle and recorded reading a critic of Audubon in the lost Galapagos notebook. In 2019, a copy of Elizabeth Gaskell’s 1880 novel Wives and daughters appeared at auction. A note in it records: “This book was a great favourite of Charles Darwin’s and the last book to be read aloud to him.”

    Understanding Darwin’s library

    Most of the works in Darwin’s library are, unsurprisingly, on scientific subjects, especially biology and geology. Yet, the library also included works on farming, animal breeding and behaviour, geographical distribution, philosophy, psychology, religion, and other topics that interested Darwin, such as art, history, travel and language. Most of the works are in English, but almost half are in other languages, especially German, French and Italian as well as Dutch, Danish, Spanish, Swedish and Latin.

    Some of the hundreds of books not previously known to be in Darwin’s library include Sun Pictures, a 1872 coffee table book showcasing photographs of artworks. Another book that the we did not know that the Darwins purchased was a copy of the popular science book on gorillas that was all the rage just after Origin of species was published: Paul Du Chaillu’s Explorations and adventures in equatorial Africa. Of the thousands of shorter items were also found in Darwin’s library, such as an issue of a German scientific periodical sent to him in 1877 that contained the first published photographs of bacteria and another article amusingly entitled The hateful or Colorado grasshopper. In his complete library, Darwin’s eclectic sources are there for all to see.

    Click to view The Complete Library of Charles Darwin

    Click to view Introduction to the Library by John van Wyhe





    National University of Singapore (NUS)

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  • NUS team discovers new method of cultivating human norovirus using zebrafish embryo

    NUS team discovers new method of cultivating human norovirus using zebrafish embryo

    Food virologists from the National University of Singapore (NUS) have successfully propagated the human norovirus using zebrafish embryos, providing a valuable platform to assess the effectiveness of virus inactivation for the water treatment and food industries.

    Human norovirus (HuNoV) is currently the predominant cause of acute gastroenteritis worldwide, contributing to an estimated 684 million diarrhoea cases, resulting in 212,000 annual fatalities. For a substantial period, the absence of an in vitro culture system has been a major hurdle in norovirus research. The most recently optimised human intestinal enteroid model, designed to support HuNoV replication, relies on human biopsy specimens obtained from surgical or endoscopic procedures, which are typically scarce. Moreover, the maintenance of these cells is both labour and resource intensive.

    A research team led by Assistant Professor Li Dan from the NUS Department of Food Science and Technology, in collaboration with Professor Gong Zhiyuan from the NUS Department of Biological Sciences, serendipitously discovered that zebrafish embryo can be used as a host for cultivating HuNoV. The zebrafish embryo model is easy to handle, robust and has a capacity to efficiently replicate HuNoVs. This study, to the best of their knowledge, represents an inaugural demonstration of the highest fold-increase over the baseline. Most notably, this model enables the continuous passaging of HuNoV within a laboratory setting. With this model, researchers can effectively propagate and sustain the presence of HuNoV over time, enabling them to study in more depth its behaviour, replication, and other properties.

    Asst Prof Li said, “The zebrafish embryo model represents an essential improvement in the HuNoV cultivation method. With its high efficiency and robustness, this tool is able to enhance both the breadth and depth of HuNoV-related research. It is expected that this tool will not only benefit the advancement of epidemiological research on HuNoV but will also be invaluable in establishing HuNoV inactivation parameters. These parameters are highly needed by the water treatment and food industries to develop more effective methods for preventing the spread of the virus.”

    This research was published in the journal Applied and Environmental Microbiology on 21 March 2023.

    In the future, the research team plans to utilise the zebrafish embryo model to investigate inactivation methods for HuNoVs in food products. To date, the successful detection of infectious HuNoV in food products remains an elusive goal. While further refinement and optimisation efforts are still required, the research team’s ongoing work holds great promise in tackling this challenging task.

    National University of Singapore (NUS)

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  • Novel AI-based approach for more accurate RNA 3D structure prediction

    Novel AI-based approach for more accurate RNA 3D structure prediction

    Newswise — A research team from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has successfully harnessed artificial intelligence (AI) and deep-learning techniques to model atomic-level RNA 3D structures from primary RNA sequences. Called DRfold, this novel AI-based method improves the accuracy of RNA models by more than 70 percent, compared to traditional approaches.

    The team, which is led by Professor ZHANG Yang from CSI Singapore and NUS School of Computing, published their findings in the scientific journal Nature Communications on 16 September 2023.

    RNAs are large biomolecules consisting of a single chain of nucleotides, which derive their sequence order from double-stranded DNA molecules during transcription. RNAs are widely known for their role in transcription and translation processes, which facilitates the transfer of gene information embodied in DNA sequences into protein amino acid sequences. In recent years, RNAs have been found to play important roles in regulating various biological processes, hence positioning them as novel drug targets.

    It has been estimated that targeting RNAs with small molecules will expand the drug design landscape exponentially, compared to traditional protein-targeted drug discovery. Accordingly, RNA biology and its applications in developing new therapeutics represent a critical emerging field, garnering significant academic and industry investment worldwide.

    Predicting RNA structures

    Compared to well-folded protein structures, RNA structures and their folds are generally considered less stable due to the relatively shallow energy landscape. Therefore, traditional physics- and statistics-based force fields, which are often error-prone, cannot accurately describe the elegant and intricate folding interactions of RNAs. Meanwhile, the limited availability of experimental RNA structures in the Protein Data Bank (PDB) further constrains the accuracy of these traditional knowledge-based force fields, which are derived from the statistics of the PDB structures.

    To address these challenges, DRfold created two complementary deep-learning network pipelines – one focused on end-to-end learning, and the other on geometrical restraint learning. This innovative approach significantly improved the accuracy of the AI-based force field. The synergistic coupling of these two networks also further enhanced the accuracy of the single neural network-based AI potentials.

    The key innovation lies in introducing a deep learning approach for predicting RNA tertiary structure. While traditional methods relied on homologous modelling or physics-based folding simulations, which suffer from the limitation of the force field accuracy, DRfold uses self-attention transformer networks to predict 3D structures from RNA sequences, marking a revolutionary shift in addressing this crucial challenge. DRfold’s new strategy of integrating two parallel and complementary networks built on end-to-end and geometry learnings helps to enhance the accuracy of the potential function and RNA model prediction, making it light, highly flexible, scalable, and hence, the preferred prediction method.

    Dr LI Yang, a Research Scientist at CSI Singapore and first author of this study, said, “Since the biological functions of RNAs depend on the specific tertiary structures, it becomes increasingly important and necessary to determine the 3D structures of RNAs in order to facilitate RNA-based function annotation and drug discovery.”

    He added, “The golden standard in structural biology, such as using biophysical experiments — X-ray crystallography, Cryogenic Electron Microscopy (Cryo-EM), and Nuclear Magnetic Resonance (NMR) Spectroscopy — to determine RNA structures, are often cost- and labour-intensive, limiting their application to a tiny portion of known RNAs. Currently, there are more than 30 million known RNA sequences in the RNA central database, but only less than 500 (or 0.0017 per cent) have experimentally solved structures. This frustratingly leaves more than 99 per cent of RNA targets with no structural information. Hence, our study’s core aim is to develop new computational methods capable of predicting high-quality RNA structure models, filling this substantial information gap.”

    Potential applications in drug design and virtual screening

    Commenting on the significance of their research, Prof Zhang, Senior Principal Investigator at CSI Singapore and corresponding author of the study, highlighted, “Our primary goal for this study is to bridge the gap between the scarcity of experimental RNA structures and the increasing demand of the RNA biology field and drug industry. In this regard, high-confident DRfold models can be used as a starting point to guide the RNA drug design and virtual screening, or to help elucidate the biological functions of the RNA molecules in cells.”

    “Considering the potency and effectiveness of mRNA vaccines in combating pandemics, tools such as DRfold play a crucial role in predicting and optimising RNA structures and the stability of vaccines. Furthermore, these tools can be used to study the biological functions of RNAs, particularly non-coding RNAs, and design novel RNA experiments using predicted models which follow the sequence-to-structure-to-function paradigm,” Prof Zhang added.

    The group has opened the source codes of DRfold to the public community via their webpage: https://zhanggroup.org/DRfold. Its high scalability and open-source framework render it incredibly flexible and applicable for solving other related problems, such as RNA-protein interaction modelling.

    Next steps

    Moving forward, the team envisions extending their AI strategy to encompass protein-RNA interactions, an area where reliable AI approaches for high-quality protein-RNA complex structure prediction are currently absent. Such tools are highly relevant for RNA function annotation and RNA drug discovery.

    In addition, the team hopes to further improve DRfold’s accuracy in single-chain RNA structure prediction. One of the inherent barriers stems from the limited availability of experimental RNA structures, which impacts the accuracy of the deep learning models, especially for large-sized RNAs (approximately more than 200 nucleotides). Novel strategies and ideas are needed to break through the bottleneck of high-accuracy RNA structure predictions, and the researchers are currently working on it with encouraging progress.

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  • Rough draft of Darwin’s Origin of species goes online

    Rough draft of Darwin’s Origin of species goes online

    Newswise — On the 164th anniversary of Charles Darwin’s Origin of species, the Darwin Online project at the National University of Singapore (NUS) will launch all the surviving draft pages of one of the most influential scientific books in history. After his book was published, the unsentimental Darwin discarded the hundreds of pages of the original handwritten draft of his epoch-making book into the Darwin family’s scrap paper pile. His children used some sheets for drawings and others were torn in half by one of Darwin’s son who used the blank back sides for mathematical exercises.

    In the end, almost all of the draft pages were destroyed. Towards the end of Darwin’s life, his theory of evolution was more widely accepted and there was intense interest in the original draft of Origin of Species. Some were rescued from the piles of scrap paper and old notes and, over decades, many were given away as gifts especially by his children after his death. These draft pages are now dispersed around the world and some have probably been lost forever.

    Discovering Darwin’s manuscripts

    Today, the rough drafts of Darwin’s Origin of species are some of the most precious and valuable pieces of paper in the history of science worth almost a million dollars each. The last one to sell at auction, in 2018, went for £490,000 (approximately USD$ 600,000). The United Kingdom’s Minister for Arts, Heritage and Tourism placed an export bar on Darwin’s manuscript, due to its cultural and national significance, in hopes of keeping it in the country.

    So far, about 50 sheets were known to survive. This launch of the drafts by Darwin scholar, Dr John van Wyhe from the NUS Department of Biological Sciences, includes seven draft pages not found in previous lists with three draft pages recently rediscovered – bringing the total to 59. This collection of draft pages includes unprecedented details about each sheet and its history. For example, one was donated by Darwin’s daughter Henrietta Litchfield to a Red Cross auction during WWI for the war wounded. It was purchased anonymously by cotton merchant and aviation pioneer Sir Alfred Paton who donated it to his old school, Clifton College. It was later sold at auction in 1999 for £39,500 to an anonymous buyer “in the Americas” and has never been seen again. Fortunately, it was photocopied by Clifton College and a photograph was printed in the auction catalogue.

    Uncovering the mysteries behind Darwin’s drafts

    Darwin’s handwriting is notoriously difficult to read. All of the drafts have been transcribed and edited showing where the text appears in the published book so they may be compared. The drafts make it possible to see in detail how Darwin originally composed and revised many of his arguments. The drafts total 11,700 words (7.7% of Origin of species) and contain many sentences that were never published, offering fascinating insights into Darwin’s thinking as he composed the book that changed the world. What would have happened if he had published the original version of some of his arguments? In one crossed out sentence, Darwin wrote that “An instinct may almost be called an empty trick.”

    In a famous passage of the Origin of species, Darwin argued that natural selection could gradually transform an animal like a bear into something like a whale. He was mocked and criticised by reviewers so severely that he deleted the passage from all later editions. What would have happened if he had published the passage as originally written?

    In one of the drafts, this never-printed paragraph was revealed as follows:

    “In N. America a bear has been seen swimming for hours with widely open mouth, thus catching the minute crustaceans swimming on the surface. Even in so extreme a case as this, if the supply of minute crustaceans were constant, & there did not in the region exist better adapted competitors, I can see no difficulty in a race of Bears being rendered by natural selection more & more aquatic in habits & structure, with larger & larger mouth, till a creature was produced as monstrous in size & structure as a whale though feeding on prey so minute.”

    Darwin later made very extensive corrections to the first and second proofs which makes the text of the first draft differ even more from the published book. His son Francis recalled that “my mother looked over the proofs of the ‘Origin.’”

    The drafts can be viewed for free via a detailed illustrated introduction here. The link will be made live after the embargo is lifted.

    The drafts join the world’s largest collection of Darwin’s writings, both publications and handwritten manuscripts, Darwin Online.

    National University of Singapore (NUS)

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  • NUS pharmacists develop a “cheeky” and pain-free solution for drug delivery

    NUS pharmacists develop a “cheeky” and pain-free solution for drug delivery

    Newswise — Singapore, 4 July 2023 – Conventional ways of administering medication – by swallowing tablets, consuming bitter syrups, injections or rectal insertions – could be distressing and unpleasant for some patients, especially young children or the elderly. A team of researchers led by Associate Professor Chan Sui Yung, Honorary Fellow at the Department of Pharmacy under the Faculty of Science at the National University of Singapore (NUS), has recently developed easy-to-use oral films that enable painless, efficient, and discreet drug administration.

    This patient-friendly drug delivery method is now being commercialised through an NUS start-up PharLyfe+ founded by Assoc Prof Chan and her students, Dr Tan Poh Leng and Ms Chua Qi Shan, who are the Business Lead and Clinical Lead of PharLyfe+ respectively. The start-up is supported by NUS Graduate Research Innovation Programme (GRIP), a venture creation programme which encourages NUS researchers and postgraduate students to start their own deep-tech companies.

    The novel oral film releases drugs into the bloodstream via the mucosal membrane – the moist, inner lining of the mouth. Each oral film can be easily placed onto the inner cheek of the patient’s mouth, and medication will be released into the bloodstream over pre-determined period of time.

    This method of medication administration reduces the risk of choking, aspiration, and rejection. Moreover, the manufacturing method of the films eliminates dosing errors commonly associated with multi-dose bottles of liquid medicine.

    Patient-centric, personalised drug delivery

    Assoc Prof Chan said, “Our oral film marks a significant milestone in patient-centric and personalised medicine, offering a safer and eco-friendly alternative to traditional drug delivery methods. The film is very easy to use, so patients are empowered with dignity and independence in managing their treatment from the comfort of their homes. We look forward to collaborating with healthcare providers to develop and apply the oral films to improve patient care and treatment outcomes.”

    Each oral film is very thin and round, and it comes in two sizes – 10- and 20-cent coin sizes – making it convenient to be carried around, distributed, or stored in larger quantities at healthcare institutions. Additionally, the films have a low water content, so they have a longer shelf life compared to compounded liquid medicines, hence they could be a reliable option for patients and healthcare providers.

    The oral film developed by NUS researchers is convenient to use, and enables painless, efficient, and discreet drug administration.

    The team’s first oral film product will focus on administering medications for patients suffering from end-of-life delirium and anxiety. The process of treating end-of-life symptoms can be painful as injections are often administered, when comfort care should be the top priority. “We hope that our solution can help improve the quality of care for these patients,” said Ms Chua. The film may also benefit epileptic patients, with more studies underway.

    A sustainable and cost-effective solution

    The oral films are easy to produce. Each film comprises a customised premix of ingredients formulated for a specific medication. These ingredients are added to the drug solution, and an accurate volume of the required drug dosage is pipetted onto a mould. The resulting mixture is dried using a light-duty oven. This method of production uses fewer ingredients and smaller quantities of materials compared to traditional drug-delivery methods, particularly those that require costly, single-use applicators and devices such as syringes, needles, inhalers, and auto-injectors.

    Without the need for bulky packaging, or the use of dosage-measuring devices such as syringes and spoons, which are made of plastic and supplied with each treatment course, the oral film is therefore more environmentally friendly and cost-effective.

    Dr Tan, whose PhD work focused on oral films, explained, “Our films are compounded on-demand to ensure that they contain the precise dosage and strength for each patient, and then sealed in minimal packaging. This streamlined approach to drug delivery not only saves time and money, but also reduces the environmental impact.”

    Associate Professor Lita Chew, President of the Singapore Pharmacy Council, and a clinical faculty member at NUS Pharmacy who is not involved in the start-up, said, “The innovative approach to compound prescribed drug into oral film is a game-changer for delivery of medication, especially to segment of populations that have difficulty taking traditional dosage forms such as tablets, capsules, syrups and injections. I look forward to the day when the oral film premix kits can be extended to home use, like the many self-test kits on pharmacy shelves.”

    After drying the films using a light-duty oven, the research team seals them in compact packaging so that they can be carried around conveniently.

    Future plans

    The NUS team has filed a provisional patent for this innovative approach. Currently, the researchers are developing and evaluating their film products for different medications, such as for antidotes, general medication, and medication for pets, to prepare for regulatory filing in Singapore and the United States of America.

    They plan to supply the premix of the oral film to healthcare institutions for pharmacists and clinic staff to prepare oral film medications when doctors prescribe them to patients. HCA Hospice Care is one of the healthcare institutions whom they partnered for the initial launch of their ready-to-market package comprising facilities set-up and staff training for preparing film medicines using PharLyfe+ premix.

    The team also aims to work with investors, regulatory experts, contract manufacturers, and pharmaceutical marketers to commercialise their technology.

    National University of Singapore (NUS)

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  • CSI Singapore researchers uncover potential novel therapeutic targets against natural killer/T-cell lymphoma

    CSI Singapore researchers uncover potential novel therapeutic targets against natural killer/T-cell lymphoma

    Newswise — Singapore, 29 May 2023 – A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has discovered that a transcription factor, TOX2, was aberrantly increased in patients with Natural killer/T-cell lymphoma (NKTL). The increased TOX2 level leads to the growth and spread of NKTL, as well as the overproduction of PRL-3 – an oncogenic phosphatase that is a known key player in the survival and metastasis of several other types of cancers. This breakthrough discovery presents a potential novel therapeutic target to treat NKTL.

    NKTL is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) with very poor treatment outcomes in the advanced stages. It is prevalent in Asia and Latin America but rare in Europe and North America. Combined radiation therapy and chemotherapy is the consensus standard therapy for NKTL patients, however, they are also often associated with high relapse rate and serious side effects. Thus, improved knowledge of the molecular mechanism leading to NKTL progression, as well as the development of novel targeted therapy strategies, has to be addressed urgently.

    Professor Chng Wee Joo and Associate Professor Takaomi Sanda from CSI Singapore, along with Dr Ong Choon Kiat from Duke-NUS Medical School, reported their ground-breaking findings in a paper published in scientific journal Molecular Cancer on 10 April 2023. Collective efforts from Dr Jianbiao Zhou, Dr Tze-King Tan, Ms Sabrina Hui-Min Toh, Miss Sinan Xiong, and the rest of the team, have contributed to these pioneering revelations.

    Their findings are also the first to show the involvement of TOX2 and PRL-3 in NKTL. These findings were validated in both cell lines and in a large set of patient tumour samples. In addition, the team analysed the clinical features of 42 NKTL cases in an independent cohort and found that TOX2 was not only overexpressed in NKTL primary tumours, but also negatively associated with patient survival.

    Currently, there are no TOX2-specific inhibitors. As such, targeting TOX2, or its downstream PRL-3, could be a valuable therapeutic intervention for NKTL patients and warrants further study in the clinic.

    Prof Chng, who is the co-lead author of the study, said, “We have now identified novel treatment targets, TOX2 and the downstream PRL3, in NKTL, where new treatment is greatly needed. We can use different strategies to target these. Proteolysis-targeting chimera (PROTAC) targeting TOX2 to degrade TOX2 protein may be a viable NKTL therapy option. A humanised antibody, PRL3-zumab, has been approved for Phase 2 clinical trials in Singapore, US, and China to treat all solid tumours. With our findings from this study, it is definitely timely to evaluate PRL3-zumab’s effect in patient with NKTL.”

    “Overall, treatment for NKTL patients remains a challenge in the clinic. Novel insight into the molecular mechanisms of this disease would guide the development of effective targeted therapies to improve the survival of NKTL patients, especially for those refractory or relapsed cases,” said Dr Jianbiao Zhou from CSI Singapore, the first author of this study.

    Moving forward, the group is currently testing novel agents for targeting TOX2 and PRL-3 in NKTL. The long-term goal is to bring these novel agents into clinical trials.

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