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HKU biologists designed and developed novel anti-allergic drugs by targeting Mas-related G protein-coupled receptor (GPCR) X2 (MRGPRX2)

Allergic diseases are increasing at an alarming rate across the world. Despite available treatments, several cases of allergies are untreated and cause a huge disease burden. Moreover, allergies cause discomfort and life-threatening threats and can deprive one of taking life-saving vaccines. A research team led by Professor Billy K C CHOW from the School of Biological Sciences, Faculty of Science, the University of Hong Kong (HKU), have designed and developed novel small molecule MRGPRX2 antagonists which can be developed as novel anti-allergic drugs. This study has recently been published in The Journal of Allergy and Clinical Immunology (JACI). Research background In the area of allergy, previously, research on both mast cell degranulation and host response mechanism was focused on the IgE receptors (FcεRI)-mediated immune response. However, investigating the alternative non-IgE mechanisms of mast cell degranulation and allergic reactions has gained immense interest recently. Accumulating evidence on MRGPRX2 has shown its critical role in drug-induced allergic reactions, hypersensitivity reactions, and inflammatory diseases. Mast cells are tissue-resident innate immune cells, present predominately at exterior environment barriers, such as the skin and the respiratory tract. Mast cells are known for their densely packed secretory granules. On activation via activators (allergens, infectious agents, toxins, and drugs), mast cells can rapidly release these inflammatory mediators- this process is known as mas cell degranulation. This lead to allergies and inflammation of surrounding tissues or the whole body (See the diagram).   We have recently published a comprehensive review on the emerging role of Mas-related G protein-coupled receptor (GPCR) X2 (MRGPRX2) as a novel GPCR responsible for non-IgE mediated allergies and other inflammatory reactions. Several FDA-approved drugs, such as fluoroquinolone antibiotics, neuromuscular blockers, Icatibant, opioids, and diagnostic agents, have been reported to cause allergic and inflammatory reactions via MRGPRX2 activation.  Also, recently we have reported the mechanism of allergic reactions induced by a peptide P17 isolated from ant venom and the anti-allergic activity of the flavonoid compound genistein. In the current research, based on the lead structure (genistein), we have designed potent novel small molecule MRGPRX2 antagonists. These novel small molecule antagonists bind with MRGPRX2 (like a lock and key) and inhibit mast cell degranulation and release of inflammatory mediators; thus can be developed as novel ant-allergic drugs. Key findings We used a combined approach of structure-aided drug designing, virtual screening, medicinal chemistry, and experimental pharmacology, often used in big pharma for drug development. After screening thousands of molecules, we shortlisted six potent novel small molecules, designed the synthetic schemes and successfully synthesized and characterized them. These molecules are novel in structure and, to our best knowledge, have never been reported. Furthermore, we have screened these novel molecules via our well-established human mast cell model and mice models of acute and systemic allergies. Also, we have tested the anti-allergic potential of small molecules against FDA-approved drugs such as Fluoroquinolone antibiotic ciprofloxacin. The novel small molecule has shown a potent anti-allergic activity.  The societal impact of the findings The current state of research implies the crucial role of MRGPRX2 in non-IgE mediated allergic reactions, drug-induced allergies, pruritis, and inflammatory skin diseases. The current treatment strategies encompass mainly the symptomatic use of medications like anti-histaminic, corticosteroids, and monoclonal antibodies against IgE receptors. However, several cases of allergies are refractive to currently available treatments and fail to treat acute to severe cases. Moreover, no MRGPRX2-specific and effective drug is available in the market, indicating an unmet demand for drug development.  The research outcome from our project holds promising potential in the domain of mast cell biology and drug discovery and development as it has a direct pharmacological implication. The novel small molecule MRGPRX2 antagonist can be used as the experimental antagonist to understand the mast cells -MRGPRX2 mediated pathways and pathophysiology and can further be developed as a therapeutic drug molecule for the treatment of non-IgE mediated allergic reactions, itch, and inflammatory disorders. Based on the novelty and commercial impact of these small molecules, we have filed a US patent and a Chinese patent with the help of the technology transfer office of the University of Hong Kong. It is anticipated that our findings possess tremendous therapeutic and social impact. "Our translational research has opened a novel therapeutic area for treating chronic allergies," said Professor Chow. "I hope our efforts and others in this field will bring therapeutic solutions for chronic allergies in the coming years," said Dr Kumar. The research was conducted by the team led by Professor Billy K. C. CHOW(On the right). Postdoctoral fellow Dr Mukesh Kumar (on the left) from Professor Chow's group is the paper's first author.  Research Team The research was conducted by the team led by Professor Billy K. C. CHOW. Dr Mukesh Kumar (Postdoctoral fellow) from Professor Chow's group is the paper's first author. Dr Karthi Duraisamy from Prof Chow's group, Dr Rajasekar Reddy Annapureddy from Ludwig-Maximilians-Universität München, Germany and Dr Chi Bun Chan from the School of Biological Sciences, HKU are the other collaborator and contributed to the research. This research has been supported by the Hong Kong government RGC GRF 1711320, NSFC/RGC 17111421 and HKU seed fund for basic research 201910159222 and 104006152 to Prof Billy K. C. Chow.  About Professor Chow Professor Billy K. C. Chow is a Chair of Endocrinology at the School of Biological Sciences, HKU. His expertise lies in GPCR and ligand interactions, eventually leading to deciphering the physiologic actions of GPCRs and identifying novel GPCR agonists/antagonists as therapeutic solutions. He is the founder of an HKU spin-off company PhrmaSec Ltd, which aims to translate basic research into societal impact by targeting GPCRs.  The Journal can be accessed here. Click here for further reading.

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Catching the wrongdoers in the act: HKU chemists develop a novel tool to decipher bacterial infections in real time

A research team led by Professor Xiang David LI from the Department of Chemistry at The University of Hong Kong (HKU) has developed a novel chemical tool to reveal how bacteria adapt to the host environment and control host cells. This tool can be used to investigate bacterial interactions with the host in real-time during an infection, which cannot be easily achieved by other methods. The findings were recently published in a top-class international scientific journal — Nature Chemical Biology. Pathogenic bacteria, while only numbering fewer than a hundred, heavily threaten human health all over the world. For example, Mycobacterium tuberculosis infection causes tuberculosis, which leads to more than one million deaths each year. It was the world’s deadliest infectious disease until it was overtaken by COVID-19. Despite effective antibiotic treatments, multiple drug-resistant tuberculosis has become a growing problem worldwide. Therefore, a more comprehensive understanding of how bacteria infect their human host is key to developing new drugs and therapies. When bacteria meet their host (e.g., human cells), they send out ‘assassins’ (virulence factor proteins) that ‘hijack’ important protein players of the host to sow chaos during an invasion. Therefore, investigating which virulence factors bacteria secrete and which host proteins are targeted is crucial for the understanding of bacterial infections. However, it can be extremely challenging to identify these key players among the ‘crowded streets’ (excessive host cellular matrix). To tackle this challenge, Professor Li’s group designed a multifunctional unnatural amino acid called photo-ANA that only labels proteins of the engineered bacteria but not the host during infection. With the help of its alkyne handle, photo-ANA can conjugate with fluorescence or biotin via a Nobel prize-winning chemical reaction (‘click’ chemistry), which enables the visualisation and enrichment of the labelled bacterial proteins from the complex host environment. Thus, Photo-ANA serves as an ‘undercover agent’ to gather intelligence and tag all the ‘assassins’ sent by the bacteria. More importantly, photo-ANA also carries a diazirine group that can ‘handcuff’ the bacterial virulence proteins to their host target proteins upon exposure to ultraviolet (UV) light — cathing them in the act. Using photo-ANA, Professor Li’s group comprehensively profiled the adaptation of Salmonella, bacteria that can cause severe diarrhoea, to the host environment and revealed the extensive interplay between Salmonella and the host during different infection stages, which identified known interactions and some newly discovered interactions. Moreover, the photo-ANA-based approach can be easily applied to other pathogenic bacteria and even other pathogens such as fungi. With this new chemical tool, scientists can now investigate the activity of bacteria inside the host in real-time. In the future, this tool may help us decipher the hidden interactions of deadly bacteria with the host and the mechanisms of multidrug-resistant superbugs, which will further our understanding of infectious diseases and inspire new treatments. Link of journal paper can be accessed from here. 

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HKU Chemist and collaborators engineered an effective and stable singe-atom catalyst which is a hundred times more effective than the commercial catalyst

Developing a cost-effective electrocatalyst for green hydrogen generation from water is crucial for the development of renewable energy technologies to resolve the current energy and environmental crisis. In a concerted research effort, Professor Zhengxiao GUO from the Department of Chemistry at The University of Hong Kong (HKU) and his long-term collaborators in mainland China, have engineered an effective and stable ‘single-atom catalyst’ (SAC), with Pt single atoms supported on a vacancy-enriched dual metal hydroxide, (Co,Ni)(OH)2. This catalyst exhibits a far superior hydrogen evolution reaction (HER) activity, which is 116 times higher than that of the commercial 20 wt% Pt/C catalyst, even with a small fraction of the Pt loading. There is also negligible attenuation or degradation after the electrochemical test at 100 mAcm−2 for 24 hours or cyclic voltammetry for 20000 cycles, indicating the high stability of the catalyst, even at a relatively high current density for potential practical applications. The findings have just been published in Energy and Environmental Science. A sustainable clean energy supply is one of the foremost challenges to achieving ‘net-zero’ or carbon neutrality. Hydrogen is a promising clean energy carrier for such a purpose. However, its conventional production by methane reforming is accompanied by the generation of CO2 and also insufficient purity for the long-term operation of fuel cells. Using renewable power sources, such as solar or wind, is environmentally friendly for electrochemical water splitting to produce high-purity H2, which is increasingly important as the demand for hydrogen is likely to increase by 6-8 folds by 2050. However, this will create even more pressure on the already scarce Pt catalyst and its reserve. Moreover, the conventional cathode shows a relatively large overpotential and hence low efficiency (~60-80%) for H2 evolution, especially under alkaline conditions. Therefore, it is very desirable but challenging to develop a catalytic cathode that can efficiently evolve hydrogen at a relatively low overpotential under alkaline conditions. Despite considerable effort in the past, transition metal (TM) based catalysts usually show a relatively high overpotential and inferior catalytic performance to the commercial 20 wt% Pt/C, thus unfavourable for industrial applications. To date, Pt is still the most active candidate due to the moderate free energy for the chemisorption of atomic hydrogen, which is more advantageous than other metals for the formation of H2 via the intermediate Pt-*H (* denotes 'adsorbed'). Unfortunately, the HER efficiency depends not only on ΔGH but also on the dissociation of water to obtain *H and *OH and the subsequent transfer of the dissociated species. The direct water dissociation on Pt to form Pt-*H is usually sluggish under an alkaline condition, due to a relatively high water-dissociation barrier. Compared to the Pt nanoparticles and clusters, Pt Single-Atom Catalysts (SACs) show readily regulatable electronic properties and high atom utilisation efficiency (or atomic economy) for various reactions. Such single atoms can be stabilised and anchored on another material or substrate, such as TM oxides and hydroxides, to impart further the electronic synergy for catalytic performance. Particularly, TM hydroxides (e.g., TM = Fe, Ni, Co) are characterised by low-cost, good alkaline stability, high hydrophilicity and distinctive electronic structures with partially-filled d orbitals to facilitate interactions with charge carriers. However, the pristine TM hydroxides still exhibit low efficiency for the HER due to their relatively high adsorption energies of *H and/or *OH after water dissociation, unfavourable for *H diffusion to the Pt site and/or continued water adsorption due to *OH accumulation, respectively. In the combined electronic structural simulations and experimental analysis, the research team has identified that the bimetallic hydroxide of cobalt and nickel creates the electronic synergy for water dissociation with the 'just right' binding energies of *H and *OH to be transferred away from the hydroxide surface. Concurrently, the finely-tuned electronic microenvironment of Pt single atoms co-located over the (Ni,Co)(OH)2 substrate effectively reduced the energy barrier for hydrogen transfer on the (Ni,Co)(OH)2, to enhance hydrogen evolution. The generation of Ni-*OH and Co-*OH was directly observed by Operando Raman, indicating the enhancement of the (Co,Ni)(OH)2 for water dissociation in an alkaline electrolyte. Partial charge transfer from Pt to O atoms of (Co,Ni)(OH)2 creates an adequate local environment around the Pt, to attract the adsorbed *H species and then allow them to form hydrogen molecules with ease. In summary, this study opens up a new avenue for developing SACs via effective electronic tuning of Pt single atoms with heterogeneous atomic coordination in hydroxide substrates. More specifically, the catalyst demonstrated great potential to break the bottleneck of low efficiency for hydrogen generation in alkaline fuel cells, currently under popular consideration in large-scale electrolysis of water to produce clean fuels of the future. The journal paper can be accessed from here. 

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AFCD and SWIMS Enhance Collaboration in Managing and Disseminating Biodiversity Data

​The Agriculture, Fisheries and Conservation Department (AFCD) and The Swire Institute of Marine Science (SWIMS) of The University of Hong Kong entered into a Memorandum of Understanding (MoU) for enhanced collaboration in managing and disseminating marine biodiversity data.  The AFCD launched the HKBIH in March 2022 to provide a one-stop shop for information on local biodiversity. The forthcoming Biodiversity Geographic Information System (BGIS), which is expected to be launched in 2024 as part and parcel of the Hong Kong Biodiversity Information Hub (HKBIH), will facilitate the sharing of spatial data of local species. The AFCD and SWIMS endeavour to make the HKBIH a more comprehensive data repository to foster a better understanding and conservation of Hong Kong’s wealth of biodiversity. Information sharing is an important foundation of biodiversity conservation. Simon Chan, the Assistant Director (Conservation) at AFCD said the department will co-operate with SWIMS to share a vast amount of spatial data of local marine species with the public, via the BGIS of HKBIH. One of SWIMS’ main research directions is to continue building an up-to-date inventory of Hong Kong’s rich marine biodiversity. The Director of SWIMS, Professor Gray WILLIAMS, said he is delighted to collaborate with the AFCD to disseminate the information for public education and conservation initiatives.    Click here to learn more about HKBIH.  Click here to learn more about SWIMS. 

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Renowned Physicist Professor Shuang ZHANG was selected in Tencent’s New Cornerstone Investigator Program 2022

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HKU Marine Scientists discovered the reward and punishment system in coral-algae relationship

In human society, reward and punishment are introduced as an incentive to induce cooperation. However, some people still try to cheat to win. So, is there a system with clear rewards and punishments in the world of other organisms? The answer is ‘yes’. Corals may ‘punish’ the algae that live inside them by cutting off their food supply if such algae become selfish and renege on their part of the resource-sharing deal with the coral as part of their symbiosis – a mutually beneficial relationship. These are the findings of Dr Shelby MCILROY of the Swire Institute of Marine Science (SWIMS) and the School of Biological Sciences at The University of Hong Kong(HKU) and her collaborators.. In the coral-algae relationship, the two sides – the coral host, and the algal symbiont, share and recycle nutrients they cannot access on their own. But this relationship is open to abuse. Corals can host several species of symbiotic algae at the same time, but not all algal species are honest. Some take advantage of their host by keeping more nutrients for their own needs instead of passing them to the coral. In this way, the selfish algae gain an advantage over more beneficial species that grow slower because they share their nutrients more generously. This cheating ultimately undermines the long-term health and growth of the coral itself. In other symbiotic relationships, for example, between trees and fungi, the cheated hosts can interfere and punish their dishonest partners. However, until McIlroy’s latest research came out in the journal Microbiome, it has been difficult to determine if or how corals could do the same with their algae. Using stable isotope techniques, McIlroy was able to unravel the flow of nutrients between different species of algae in their host, a Caribbean coral species. ‘Stable isotopes combined with genetic techniques allow us to track the currency exchange between the partners. In this case, the currency is nutrients, in the form of carbon and nitrogen,’ McIlory explained. The results showed that the coral might indeed punish the cheats and reward the honest partners. ‘Our study showed that corals seem to limit the supply of nutrients to the symbiotic algae that are less beneficial to them, as a way of fostering more beneficial algal symbionts,’ McIlroy added. Understanding how corals control and manipulate their symbiotic algae is now crucially important for coral survival. Because of climate change, the seas are becoming too hot for the algae living inside the coral. When water temperatures spike, algae die, and so does the coral itself – a phenomenon known as bleaching. Episodes of bleaching are now becoming increasingly common, and most of the world’s coral reefs are now threatened by it. If scientists could get the coral to host the species of algae that can handle higher temperatures – a form of ‘coral probiotics’,  it could prevent bleaching and buy more time for corals threatened by the warming of the oceans. ‘We may have the ability to intervene and help corals resist bleaching by exposing them to more thermally tolerant partners. But we need to understand the biology of corals and how they might react to these interventions so that we can work effectively and efficiently. There’s no time to lose.’ McIlroy concluded. The journal can be accessed here. A video introduction to the research.

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Professor Billy Chow receives US National Academy of Medicine Health Longevity Catalyst Award (Hong Kong) 2022

Six research teams from The University of Hong Kong (HKU) were awarded the Healthy Longevity Catalyst Awards (Hong Kong) 2022 in the Healthy Longevity Global Competition, including the team of Professor Billy Chow from the School of Biological Sciences. The competition is held by the United States National Academy of Medicine (NAM) with the Research Grants Council as its Hong Kong sponsor. A total of ten research teams from Hong Kong were awarded this year. Launched in 2019, the Healthy Longevity Global Grand Challengeoffers opportunities for innovators, scientists, and entrepreneurs to catalyse breakthrough discoveries and innovations that could leapfrog existing barriers and jumpstart new solutions, thereby propelling the field of ageing research and improving the health of persons as they age. The competition composed three phases of Awards- Catalyst Award, Accelerator Award and the Grand Prize. The Catalyst Awards reward bold, new, potentially transformative ideas from fields such as biomedicine, behavioural science, sociology, engineering and infrastructure, technology, policy, to improve the physical, mental, or social well-being for people as they age, and in a measurable and equitable way. In particular, NAM seeks ideas that will extend the human health span through innovations in disease prevention, biology, mobility and function, social connectedness, productive longevity and more. Ideas could focus on early-, mid-, or late-life, as long as it ultimately promotes health as people age. Of the ten Catalyst Awards in Hong Kong this year, each includes a US$50,000 (approx. HK$389,000) cash prize at a maximum for a period of 12 months and travel subsidies (HK$30,000 per person; max. 6 persons per team) for awarded teams to attend an Innovator Summit in 2023. Project from the Faculty of Science: Development of Small-Molecule Modulators of the Secretin Receptor as Novel Anti-Hypertensive Agents Project leader: Professor Billy CHOW, Chair of Endocrinology, School of Biological Sciences, Faculty of Science About the project: Large segments of ageing hypertensive patients are resistant to a wide range of conventional drugs and hence there is an urgent need for new initiatives to develop alternative treatments. The research team developed the first small molecule-based Secretin receptor modulator (KSD179019), which not only has a similar blood pressure lowering effect as SCT peptide but, more importantly, has a much longer half-life (~8 hours). The development of KSD179019 as a novel class of oral anti-hypertensive drug can be of critical importance, as it could tackle resistant hypertension. This project could potentially provide an important advancement in finding novel small molecule drugs for resistant hypertension by targeting Secretin receptor. The Healthy Longevity Catalyst Awards (Hong Kong) 2022 Research Grants Council webpage The US NAM Healthy Longevity Challenge

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HKU biologists and collaborators reveal how DNA unzipping machine works, shedding lights on cancer therapy

A research team led by Dr Yuanliang ZHAI from the School of Biological Sciences, The University of Hong Kong (HKU), and his collaborators from The Hong Kong University of Science and Technology (HKUST) and Institut Curie, France, has uncovered a new mechanism of the human MCM2-7 complex in regulating replication initiation, which can be used as a novel and effective anticancer strategy with the potential for selective killing of cancer cells. The findings were recently published in the Cell journal. Human life begins with a single fertilised egg in the mother’s womb. This egg propagates through cell divisions and develops into our multicellular body. During each cell division, our genome DNA, the blueprint of genetic information, is accurately replicated. Each cell carries roughly 2 meters of DNA organised into 23 pairs of chromosomes. In our lifetime (~70 years), our body will synthesise more than a light year’s length of DNA of ~1016 meters - the distance light travels in one year. The replication process requires the DNA duplex to be first melted and then separated into two single-stranded templates for DNA polymerases to synthesise as complement strands. Any misregulation of this process can cause dire consequences, such as tumorigenesis and inherited genetic disorders. ‘Unlocking the secret of DNA replication is key to understanding the mystery of life.’ said Dr Yuanliang Zhai, Assistant Professor of HKU School of Biological Sciences, ‘Solving the structures of replication machines is central to inform their molecular functions as seeing is believing.’ Since 1953 when James WATSON and Francis CRICK determined the structure of DNA, how DNA duplex is initially melted has been a long-standing question for biologists. In eukaryotes, the enzyme responsible for unzipping DNA duplex during replication was originally identified as the minichromosome maintenance protein complex (MCM) genes from wine brewing yeast by our collaborator Professor Bik-Kwoon TYE at Cornell University in 1983. The products of six MCM genes, MCM2 to MCM7 (MCM2-7), form a six-subunit ring complex, serving as the catalytic core of the unzipping machine, the DNA replicative helicase. In cells, to initiate DNA replication, MCM2-7 complex must be first assembled into a head-to-head double hexamer (DH) encircling duplex DNA at thousands of places along each chromosome. Among a large reservoir of the assembled MCM2-7 DHs, only a subset of them will be finally selected and transformed into robust replicative helicases for DNA unwinding. It was believed that MCM2-7 DH could directly destabilise DNA to trigger an initial opening of duplex DNA. However, the underlying mechanism remained largely unknown. To address this question, the research team sought to use a cutting-edge technology, cryo-electron microscopy (cryo-EM), to visualise the atomic details of the MCM2-7 DH, which are almost millions smaller than the resolution limit of human eyes. In 2015, the team solved the first cryo-EM structure of MCM2-7 DH isolated from yeast at 3.8 Å, which was documented in the journal Nature. Unfortunately, the captured DNA was unstable and failed to inform the state of the DNA duplex bound by the MCM2-7 DH. Recently, the researchers successfully purified the MCM2-7 DH from cultured human cells and determined its structure at 2.59 Å. This high-resolution structure presents a clear picture of how the MCM2-7 complex destabilises DNA, giving rise to an initial opening of DNA duplex right at the juncture of the two coupled MCM2-7 hexamers. The team also found that the MCM2-7 DHs are loaded onto DNA at tens of thousands of sites across the human genome, which are mutually exclusive with loci of active transcription. Furthermore, when this initial open structure is disturbed, MCM2-7 DHs can no longer assemble onto DNA, leading to a complete suppression of DNA replication initiation. ‘The atomic-resolution cryo-EM structures enabled direct visualisation of the initial DNA melting, which is crucial for us to understand the molecular mechanism of DNA replication,’ said Dr Shangyu DANG, Assistant Professor of Division of Life Science, HKUST, ‘This study also demonstrates the importance of collaboration. Efforts from research groups with complementary expertise are required to answer the fundamental biological questions.’ DNA replication has been targeted by several therapeutic cancer drugs. However, the available drugs indiscriminately kill all dividing cells because both normal and cancer cells must replicate their DNA for cell proliferation. Thus, the specificity of these drugs raises serious concerns about these anticancer chemotherapies. A more desirable alternative is to inhibit DNA replication initiation so that normal cells will be arrested in the G1 phase (first growth phase) or withdraw from the cell cycle into the G0 state (resting phase); but cancer cells will undergo apoptosis. Therefore, inhibition of replication initiation can be used as a novel and effective anticancer strategy with the potential for selective killing of cancer cells. Our findings in this study provide high-resolution structural and mechanistic information on the human pre-initiation complex that can be used to develop nontoxic anticancer drugs using the MCM2-7 complex as targets in future. The journal paper can be accessed here.  About the research team: Led by Dr Yuanliang Zhai of the HKU School of Biological Sciences, the project was conducted by a team of international research groups: Dr Shangyu Dang from Division of Life Science (LIFS) of HKUST, Professor Bik-Kwoon Tye from Institute for Advanced Study (IAS) of HKUST, Dr Chunlong CHEN from Institut Curie, France and Qian ZHAO from Department of Applied Biology and Chemical Technology (ABCT) of Hong Kong Polytechnic University (HKPU). Co-authors include Mr Jian LI, Ms Xinyu FAN, Ms Yan Chit HUI, Dr Clare S. K. LEE and Dr Wai Hei LAM from School of Biological Sciences (SBS) of HKU; Dr Jiangqing DONG, Dr Daqi YU from LIFS of HKUST, Dr Weitao WANG and Mr Nathan ALARY from Institut Curie; Dr Yingyi ZHANG from Biological Cryo-EM Center of HKUST; and Mr Yang YANG from ABCT of HKPU. Learn more about Dr Yuanliang Zhai’s work and his research team. 

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Physicists develop a new method that strengthens electron-triggered light emission with flat bands Shedding light to produce new sources of light and build quantum-based computational and communications systems

The way electrons interact with photons of light is a vital part of many modern technologies, from lasers to solar panels to LEDs. But the interaction is inherently a weak one because of a major mismatch in scale: A wavelength of visible light is about 1,000 times larger than an electron, so the way the two things affect each other is limited by that disparity. Now, researchers at The University of Hong Kong (HKU), MIT and elsewhere say they have come up with an innovative way to make much more robust interactions between photons and electrons possible, in the process producing a hundredfold increase in the emission of light from a phenomenon called Smith-Purcell radiation. The findings have potential ramifications for both commercial applications and fundamental scientific research, although it will require more years of investigation to make it practical. The findings are just published in Nature, a prestigious multidisciplinary journal,  by Dr Yi YANG (Assistant Professor of the Department of Physics at HKU and a former postdoc at MIT), Dr Charles ROQUES-CARMES (Postdoctoral Associate at MIT), Professors Marin SOLJAČIĆ and John JOANNOPOULOS (MIT professors). The research team also included Steven KOOI at MIT’s Institute for Soldier Nanotechnologies, Haoning TANG and Eric MAZUR at Harvard University, Justin BEROZ at MIT, and Ido KAMINER at Technion-Israel Institute of Technology. In a combination of computer simulations and laboratory experiments, the team found that using a beam of electrons with a specially designed photonic crystal — a slab of silicon on an insulator, etched with an array of nanometer-scale holes — they theoretically predicted stronger emission by many orders of magnitude than would ordinarily be possible in conventional Smith-Purcell radiation and experimentally recorded a 100 times increase in radiation in their proof-of-concept measurements. Unlike other approaches to producing sources of light or other electromagnetic radiation, the free-electron-based method is fully tunable — it can produce emissions of any desired wavelength, simply by adjusting the size of the photonic structure and the speed of the electrons. This may make it especially valuable for making emission sources at wavelengths that are difficult to produce efficiently, including terahertz waves, ultraviolet light, and X-rays. The team has demonstrated the hundredfold enhancement in emission using a repurposed electron microscope to function as an electron beam source. But they say that the basic principle involved could potentially enable far greater enhancements using devices specifically adapted for this function. The approach is based on a concept called ‘flatbands’, which have been widely explored in recent years for condensed matter physics and photonics but have never been applied to affect the essential interaction of photons and free electrons. The underlying principle involves the transfer of momentum from the electron to a group of photons or vice versa. Whereas conventional light-electron interactions rely on a single mode of light, the photonic crystal is tuned to enable the production of a whole range of modes at the same frequency at once. The exact process could also be used in the opposite direction, using resonant light waves to propel electrons, increasing their velocity in a way that could potentially be harnessed to build miniaturized particle accelerators on a chip. These might ultimately be able to perform some functions that currently require giant underground tunnels, such as the 30-kilometer-wide Large Hadron Collider in Switzerland. ‘If you could actually build electron accelerators on a chip,’ Soljačić says, ‘you could make much more compact accelerators for some of the applications of interest, which would still produce very energetic electrons. That obviously would be huge, for example, for radiotherapy. For many applications, you wouldn’t have to build these huge facilities.’ The system could also be used to generate multiple entangled photons, a quantum effect that could be useful in creating quantum-based computational and communications systems, the researchers say. ‘You can use electrons to couple many photons together, which is a considerably hard problem if using a purely optical approach,’ says Yang. ‘That is one of the exciting future directions of our work.’ Much work remains to translate these new findings into practical devices. It may take some years to develop the necessary interfaces between the optical and electronic components and how to connect them on a single chip, and to develop the necessary on-chip electron source producing a continuous wavefront, among other challenges. ‘This is exciting,’ Roques-Carmes adds, ‘because this is quite a different type of source.’ While most technologies for generating light are restricted to very specific ranges of color or wavelength, and ‘it’s usually difficult to move that emission frequency. Here it’s completely tunable. Simply by changing the velocity of the electrons, you can change the emission frequency. That excites us about the potential of these sources. Because they’re different, they offer new types of opportunities.’ In order for the research outputs become truly competitive with other types of sources, it will require some more years of research. With some serious effort in two to five years, they might start competing in at least some areas of radiation. This article was adapted from the press release of MIT News Office. More details can be found in the article ‘Photonic flatband resonances for free-electron radiation’. 

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HKU biologists reveal the bioenergetics of pollen tube growth that sustain its rapid growth

  Sexual reproduction of plants requires pollen to land on the stigma, which then germinates and grows pollen tubes through the style to deliver sperm cells to the ovule. Pollen tubes are the fastest-growing plant cells known. Studies have shown that the growth rate of maize pollen tubes can reach up to 2.8 microns per second, while the growth rate of lily pollen tubes can also reach 0.2 to 0.3 microns per second. Its polarised growth process consumes a tremendous amount of energy, which involves coordinated energy fluxes between plastids, the cytosol, and mitochondria. Such an astonishing growth rate requires efficient and tremendous energy for metabolism and continuous synthesis of the plasma membrane and cell wall – the question is: where does the energy come from? A research team led by Dr Boon Leong LIM of the School of Biological Sciences at The University of Hong Kong (HKU) developed practical biosensors to measure real-time dynamic changes of energy currency in living plant cells and organelles, which reveals how Arabidopsis pollen tubes gain energy to sustain their rapid growth. Image 2. Model of the bioenergetics of Arabidopsis pollen tube growth. Image credit: Boon Leong Lim Unlike leaf cells, pollen tubes do not perform photosynthesis and mainly rely on sugar supply from the style to generate energy molecules such as Adenosine triphosphate (ATP), nicotinamide-adenine dinucleotide phosphate (NADPH), and nicotinamide adenine dinucleotide (NADH) to support pollen tube growth. Fatty acids (FA), the building blocks of the plasma membrane of the pollen tube, are synthesised in the pollen plastid, a precursor organelle of the chloroplast that does not contain chlorophyll. The synthesis of FA in pollen plastid consumes a large amount of ATP, NADPH, NADH, and acetyl coenzyme A(acetyl-CoA), an important metabolic intermediate. There are multiple possible routes of supplying ATP, NADPH, NADH, and acetyl-CoA for FA synthesis, but the exact mechanisms are obscure due to the small size of pollen tubes and the lack of tools to measure the concentrations of ATP, NADPH, and NADH in pollen plastids and the cytosol. The team led by Dr Boon Leong Lim recently published their findings in the journal Nature Communications, entitled ‘Bioenergetics of pollen tube growth in Arabidopsis thaliana revealed by ratiometric genetically encoded biosensors’. The team developed second-generation fluorescence NADPH and NADH/NAD+ ratio protein sensors and introduced these biosensors to the plastids and the cytosol of Arabidopsis pollen tube, thereby revealing the bioenergetics of pollen tube growth. By treating germinating pollen tubes with specific drugs, mitochondrial respiration was shown to be the main source of cytosolic ATP in Arabidopsis pollen tubes. Plastid ATP is mainly supplied by plastid glycolysis as well as importation from the cytosol through the nucleotide transporter (NTT) on the plastid membrane. As for the supply of plastid NADPH, the plastid malic enzyme NADP-ME4 is a more important pathway than the oxidative pentose phosphate pathway (OPPP). Although anaerobic respiration and pyruvate dehydrogenase (PDH) bypass are considered vital for supplying acetyl-CoA for plastid FA synthesis in tobacco pollen tubes, these pathways are not important in Arabidopsis pollen tube growth. Instead, plastid glycolysis is a more important source of acetyl-CoA for fatty acid synthesis. The conversion of NADH and NAD+ in plastids appears to be much more complex. While plastid glycolysis and plastid PDH pathway generate a substantial amount of NADH for FA synthesis, surplus NADH has to be converted back to NAD+ in pollen plastid by NAD-malate dehydrogenase (plNAD-MDH) to sustain plastid glycolysis. This research not only developed more practical biosensors to measure real-time dynamic changes of ATP, NADPH, NADH/NAD+ in living plant cells and organelles, but also reveals the exact biochemical routes of supplying ATP, NADPH, NADH, and acetyl-CoA for FA synthesis in pollen plastids. Ms Jinhong LIU, the first author of the article and a PhD student of Lim’s group remarked, ‘The in planta fluorescence protein sensors we developed are powerful tools for solving some key questions in plant bioenergetics. We are happy to publish two manuscripts in Nature Communications in 2022 (Note 1) on our discoveries using this novel technology’. Note 1: An HKU biologist-led team of international plant scientists reveals how guard cell chloroplasts obtain energy The journal paper can be accessed here.   

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