(This article was originally published on EurekAlert! on September 7, 2021)
Scientists from The Hong Kong University of Science and Technology (HKUST) and The Hong Kong Polytechnic University (PolyU) have developed an in-vitro vesicle formation assay, shedding light on cargo clients and factors that mediate vesicular trafficking and providing a robust tool to offer novel insights into the secretory pathway.
The secretory pathway is a very important process that takes place in human cells. Many growth factors, hormones and other important factors in the human body are secreted from cells through the secretory pathway to perform their physiological functions. In addition, many newly synthesized proteins must be transported to specific subcellular localization through the secretory pathways to perform their functions. In the secretory transport pathway, transport vesicles function as vehicles to carry cargo molecules. Similar to logistics and delivery services in our daily lives, the transportation of cargo molecules to the correct target sites depends on whether the cargo molecules are accurately sorted into specific transport vesicles. Defects in cargo sorting would induce defects in establishing cell polarity, immunity, as well as other physiological processes.
The key players that mediate protein sorting in the secretory pathway include small GTPases of the Arf family and cargo adaptors. The Arf family GTPases cycle between a GDP-bound inactive state and a GTP-bound active state. Upon GTP binding, Arf proteins mediate membrane recruitment of various cytosolic cargo adaptors. Once recruited onto the membranes, these cargo adaptors recognize sorting motifs on the cargo proteins to package cargo proteins into vesicles.
Although significant progress has been achieved in understanding the general steps of cargo sorting, the spectrum of cargo clients of a specific Arf family member or cargo adaptors remains largely unexplored. Led by Prof. GUO Yusong, Associate Professor of Division of Life Science at HKUST and Prof. YAO Zhongping from PolyU, the research team used an in-vitro assay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry analyses of the isolated vesicles revealed cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner. One of them, FAM84B interacts with cargo adaptors and regulates transport of transmembrane cargo proteins. In addition, they uncovered novel cargo proteins that depend on GTP hydrolysis to be captured into vesicles.
Then they utilized this assay and identified cytosolic proteins that depend on a specific Arf family protein, SAR1A, to be recruited to vesicle membranes. One of the cytosolic protein, PRRC1, is recruited to endoplasmic reticulum (ER) exit sites, and interacts with the inner COPII coat. Its absence increases membrane association of COPII and affects ER-to-Golgi trafficking.
Utilizing this assay, they also identified the clients of COPII vesicles. These clients include two cargo receptors, SURF4 and ERGIC53. Through analyzing the protein composition of vesicles isolated from control cells or cells depleted of SURF4 or ERGIC53, they revealed specific clients of each of these two cargo receptors.
These results indicate that the vesicle formation assay in combination with quantitative mass spectrometry analysis is a robust and powerful tool to systematically reveal cargo proteins that depend on a specific factor to be packaged into vesicles, to analyze protein profiling of transport vesicles under different physiological conditions, and to uncover cytosolic proteins that interact with a specific factor on vesicle membranes.
This study was recently published in Proceedings of the National Academy of Sciences.
Prof. Guo’s research team focuses on investigating molecular mechanisms regulating protein sorting in the secretory pathway. Dr. HUANG Yan (a postdoctoral research associate from Prof. Guo’s lab at HKUST), Dr. YIN Haidi from PolyU and Dr. LI Baiying from CUHK are co-first authors of this study. Mr. LIU Yang, Dr. TANG Xiao, Miss WANG Wo and Miss WU Zhixiao from the Guo lab also participated in this study.
該工作的器件技術在科大清水灣校區的納米系統制備實驗所（NFF）制備。該工作爲香港研資局的研究影響基金（Research Impact Fund）所支持，並新近得到深圳市科技創新委員會深港澳科技計劃的支持。該工作發表于近期在《自然 · 電子學》期刊上。
可分享鏈接（未訂閱《自然 · 電子學》期刊的讀者亦可查閱文章）https://rdcu.be/cpbR3
A team of researchers from the Hong Kong University of Science and Technology (HKUST) has developed an inexpensive, lightweight, and non-toxic (lead-free) photo-battery that has dual functions in harvesting solar energy and storing energy on a single device, making it possible to charge a battery under the sun, without having to plug the device into the wall.
The increasing demand for sustainable energy sources has driven a surge of interest in solar energy and developing storage devices for it. One such device, the photo-battery, is capable of both generating and storing energy in a single device architecture. In theory, this design should permit increased energy storage efficiency and energy density, while decreasing ohmic losses, relaxing packaging requirements and thus reducing the weight, the bulk, and the cost of the system. In reality, however, the poor interface between materials tends to create problems with charge transport, greatly reducing the efficiency in comparison to the simple system of a solar cell wired to an external battery.
A team led by Prof. Jonathan Eugene HALPERT, Assistant Professor from the Department of Chemistry at HKUST, has made advancements towards developing more efficient photobatteries by expanding the utility of a class of materials known as perovskite, which has had applications in solar cells and most recently in batteries. The perovskite halide the team developed acts as a photoelectrode that can harvest energy under illumination without the assistance of an external load in a lithium-ion battery, and is in stark contrast with its existing counterpart for it does not contain lead, hence it has higher stability in air and is free from the concerns of lead poisoning. For their research, the team has replaced lead with bismuth (Bi), a non-toxic element, and forming a strongly light-absorbing crystalline material.
The lithium-ion battery works by allowing electrons to move from a high energy state to a lower one, while doing work in an external circuit. The photobattery has a mechanism similar to an ordinary battery except that it need not be supplied current or plugged into the wall to be charged electrically, but can be charged photoelectrically under the sun. The active material in this new battery is the lead-free perovskite which, when put under light, absorbs a photon and generates a pair of charges, known as an electron and a hole. The team conducted chrono-amperometry experiments under light and in dark to analyze the increase in charging current caused by the light, and recorded a photo-conversion efficiency rate of 0.428% on photocharging the battery after the first discharge. The next step of the team is to experiment with different materials for better performance and efficiency, so that the photobattery can be commercialized in the market.
“At present, we plug all our appliances into the wall to charge them. With further development in this field of photobatteries, we might not have to plug them in at all in the future,” said Prof. Halpert. “We might be able to harvest solar energy and use it to fulfil the power requirements of any devices with modest power needs. Our work is one of the initial steps taken in this field, and, of course, a lot of improvements will be needed to achieve better performance, but we are confident that we can improve its stability and average efficiency with further refinement.”
This photobattery can serve as the built-in battery for devices such as smartphones or tablets, and even remote energy storage applications, which can be made easy with these photobatteries for they are lightweight and portable. It should also help lower production cost when compared to a system consisting of a solar cell plus an external battery since only the battery part is required.
This study was recently published in the scientific journal Nano Letters on June 16.
(This article was published on EurekAlert! on August 17, 2021)
Scientists from the Hong Kong University of Science and Technology (HKUST) have recently discovered a non-classical nucleation process that can greatly facilitate ice formation on foreign surfaces. This finding lays the foundation to predict and control crystallization processes.
Ice is omnipresent and profoundly impacts our daily life, influencing areas such as climate change, transportation, and energy consumption. Understanding the process of ice formation can decelerate the rate at which glaciers melt and sea levels rise and alleviate other major environmental concerns. Since ice formation is mainly governed by ice nucleation followed by the growth of the nuclei, scientists have put in a great effort to understand the thermodynamics and kinetics behind the nucleation processes. Ice nucleation can occur in two distinctive ways: homogeneously in bulk water or heterogeneously on the surface of a solid material, where heterogeneous ice nucleation (HIN) is the predominant mode of ice formation on earth. However, unlike homogeneous ice nucleation, the water-surface interactions present in HIN make the nucleation process sensitive to surface properties. Understanding how surfaces impact the nucleation process is a promising approach to better predict and control crystallization processes.
A common model used to quantify nucleation kinetics based on a thermodynamic framework, classical nucleation theory (CNT), suggests that water molecules must form an ice nucleus of critical size before a crystallization process occurs. The formation of the critical ice nucleus is associated with a single free energy barrier, which needs to be overcome to trigger further ice growth. However, over the years, both experiments and simulations have revealed that CNT is often insufficient to describe some complex nucleation processes. Consequently, CNT has been a subject of immense debate, and non-classical nucleation theories have been alternatively proposed.
Different from CNT, which is based on overcoming a single free energy barrier, non-classical nucleation theories suggest that nucleation processes consist of two or more steps separated by multiple free energy barriers. Although non-classical nucleation theories may be a more sustainable model, the atomistic mechanisms and structural evolutions during nucleus formation in non-classical nucleation pathways are not well known; and remains a challenge for experimental techniques to unravel.
Now, for the first time, a group of researchers at HKUST led by Prof. Xuhui Huang from the Department of Chemistry combined Markov State Models (MSMs) – which model long-timescale dynamics of chemical molecules - and transition path theory (TPT) – which describes the reaction pathway of rare events - to elucidate the ensemble pathways of HIN. MSMs identify intermediate states of disordered ice mixtures and compare parallel pathways (classical vs. non-classical). This advantage helped unravel the underlying mechanisms of non-classical nucleation processes and the co-existence of the two pathways.
These researchers show that the disordered mixing of ice stabilises the critical nucleus and makes the non-classical nucleation pathway as accessible as the classical pathway, whose critical nucleus mainly consists of potential energy-favoured ice. They also discovered that at elevated temperatures, the nucleation process prefers to proceed via the classical pathway since the potential energy contributions, which favour the classical pathway, prevail.
“Not only does our work uncover the mechanisms of non-classical nucleation processes, but it also demonstrates how the combination of MSMs and TPT offers a powerful framework to study structural evolutions of ice nucleation processes,” said Prof. Huang. “More importantly, this method can be extended to other crystal nucleation processes that are challenging to study, which will open new doors for scientists attempting to predict and control crystallization processes.”
The findings were recently published in the scientific journal Nature Communications. The first author of this work: Dr. Chu Li is a long-time HKUST affiliate who completed his PhD, and currently conducts his post-doctoral training at HKUST.
An international research team led by scientists from the Hong Kong University of Science and Technology (HKUST) has developed a novel strategy using brain-wide genome-editing technology that can reduce Alzheimer’s disease (AD) pathologies in genetically modified AD mouse models. This advanced technology offers immense potential to be translated as a novel long-acting therapeutic treatment for AD patients.
In China alone, over 500,000 patients are estimated to be living with a hereditary form of AD - familial Alzheimer’s disease (FAD), which is a congenital form of AD highly associated with family history. Although FAD has a clear genetic cause and can be diagnosed before cognitive problems occur, no effective treatment currently exists.
There is enormous potential in the use of genome-editing technology1 as therapeutic strategies for diseases caused by inherited mutations, such as FAD. It is especially useful for correcting disease-causing genetic mutations before symptoms appear, for which it is considered a “once-and-for-all” treatment as its effects can last a lifetime. However, several hurdles have prevented its clinical development and application - most notably the lack of an effective, efficient, and non-invasive means to deliver genome-editing agents into the brain. Furthermore, existing genome-editing technologies are unable to generate beneficial outcomes throughout the whole brain.
Recently, a team led by Prof. Nancy Ip, Vice-President for Research and Development at HKUST, developed a new genome-editing system that not only crosses the blood–brain barrier, but also delivers an optimized genome-editing tool to the entire brain. Using a newly engineered delivery vehicle for genome-editing, this strategy achieves efficient brain-wide genome editing through a single non-invasive intravenous administration. This effectively disrupts FAD-inflicted mutations in AD mouse models and ameliorates AD pathologies throughout the entire brain, paving the way to novel therapeutic development for the disease.
Meanwhile, the research team also found in the mouse models that the level of amyloid, a protein thought to drive neurodegeneration in AD, remained low for 6 months post-treatment (about 1/3 of their normal lifespan), demonstrating that this single-shot genome-editing strategy has lasting effects. More importantly, no side effects were detected so far in the mice.
“As the first demonstration of efficient brain-wide genome editing to alleviate Alzheimer’s disease pathology throughout the whole brain, this is really an exciting development,” said Prof. Ip, who is also the Morningside Professor of Life Science and Director of the State Key Laboratory of Molecular Neuroscience at HKUST. “Our work is an important milestone for the use of genome editing in treating hereditary brain diseases, and contributes to the development of precision medicine for inherited forms of neurodegenerative diseases.”
Genome editing of the familial mutation in AD mice improves their memory performance.
This research was a collaborative effort among scientists from HKUST; the California Institute of Technology; and the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. The results were recently published in Nature Biomedical Engineering.
1Genome editing is a technology that precisely modifies a living organism’s genomic DNA by deleting, inserting, or replacing the DNA at specific locations of the genome.
「我們可能要等 100 年或更長時間才看到研究的影響力！但在等上100年之前，我們可以先理解事物運作的根本原理，即使我們還不清楚如何應用，這點十分重要。」
深海管蟲是深海海底熱泉(hydrothermal vent)和冷泉(cold seep) 這種黑暗、高壓並經常含有高濃度有毒物質生態環境的常見生物，它們之所以能於此等極端環境中生存兼迅速生長的原因，實有賴於存活在牠們體內、一種能讓硫化物氧化的細菌。不過，由於缺乏基因組的資料，這段互補「聯姻」的成功一直是一個謎。
身兼科大捷成David von Hansemann 理學教授的錢教授表示：「該細菌擁有完整的新陳代謝途徑，為管蟲輸出營養，包括碳水化合物、氨基酸和維生素/輔因數等生物化合物。」研究團隊亦發現細菌為求與深海管蟲共生，演化出能分散宿主免疫系統注意力的策略，以逃避其防禦機制。與此同時，深海管蟲的基因組亦出現了改變以促進這個共生過程。管蟲不但會製造一種酶去消化這個細菌以獲取營養，更擁有一個可以控制細胞死亡的路徑，以確保細菌數量維持在對自己最有利的水平。
為了解讓管蟲得以從海底獲取無機物、被稱為「幾丁質管」這獨特結構的形成機制，團隊進一步分析了管蟲堅韌的幾丁質管的蛋白質，發現了 35 種幾丁質管基質蛋白，包括合成幾丁質微纖維並將其分泌到細胞外基質的聚合酶、聚合幾丁質並為有機基質提供聚合物框架的幾丁質結合蛋白，以及能增強管韌性及重塑幾丁質支架的的蛋白質。
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現在，由科大副校長(研究及發展)葉玉如教授領導的研究團隊，從 429 種與 AD相關的血漿蛋白中，識別出19 種具有AD患病特徵的血漿蛋白生物標誌物組群。團隊根據這組標誌物，設計了一套評分系統，可將 AD 患者自健康人群中區分出來，其準確率超過 96%。該系統還能辨別AD早、中及晚期三個階段，可用作監測患者的病情發展。
身兼科大晨興生命科學教授及分子神經科學國家重點實驗室主任的葉教授表示：「基於先進的超靈敏血液蛋白檢測技術，我們成功開發了這套簡單、無創而精準的 AD 診斷方法，將為AD的大規模篩查及分期診斷提供重大助力。」
這項研究由科大與倫敦大學學院研究團隊，以及來自包括威爾士親王醫院和伊利沙伯醫院等本地醫院的臨床醫生合作進行。團隊利用尖端的超靈敏高通量鄰近延伸分析技術 (PEA)，從香港 AD 患者所收集的血漿樣本當中，檢測了逾 1,000 種蛋白質的水平變化情況，從而取得是次研究成果。
這項令人振奮的發現令高效的AD血液檢測技術得以誕生，並為開創新型AD治療方法打下基礎。作為迄今為止就 AD 患者血液蛋白方面最全面的研究，有關結果近日被國際權威科學期刊Alzheimer's & Dementia: The Journal of the Alzheimer's Association刊載，並在不同AD 研究和學術交流平台，包括Alzforum，獲得熱烈的關注和討論。
據統計，全球罹患AD的人口數目已超過 5,000萬。患者會喪失腦細胞，並岀現一系列腦功能及認知功能障礙，包括喪失記憶，以及出現行動、推理和判斷能力受損等症狀。然而，儘管AD 早在症狀出現前至少10-20 年已對患者大腦產生顯著影響，患者卻往往只在記憶出現問題時，才會尋求醫生診治。
香港科技大學(科大)及北京天壇醫院的研究團隊近日發現一個新的突變基因，可導致一種名為「腦海綿狀血管瘤」(Cerebral Cavernous Malformation, CCM)的腦血管病變。目前全球約有一千至三千萬的人士患有此症。
現時，磁力共振成像(MRI)是一種醫生常用於診斷CCM的「非入侵性」方法。然而，MRI只能讓醫生知道血管瘤的大小及類別；至於是哪一個基因突變導致CCM，醫生一般則只能透過手術以及化驗得知。不過，科大研究團隊設計了一個電腦程式，可以評估MRI 影像所顯示的血管瘤與MAP3K3 c.1323C>G基因突變關係的概然率。因此，病人毋須「開刀」便得知是否存在MAP3K3 c.1323C>G基因突變，不但能減低施手術可能帶來的腦出血或腦神經功能缺損等風險，亦可令病者及早展開更針對性的治療。
科大王教授表示﹕「研究除了為CCM的基因圖譜開闢新方向，也為MAP3K3 c.1323C>G基因突變與CCM二型患者的關聯性帶來線索。團隊設計的電腦程式，又稱決策樹模型(decision tree model)，為實現CCM基因的非入侵性診斷邁進一步。我們希望有關發現可以有助找出治療CCM的新靶標，促進藥物發展，在不久的將來惠及病人。」
研究成果已在科學期刊《The American Journal of Human Genetics》發表。
(This article was published on EurekAlert! on May 4, 2021)
A group of researchers at the Hong Kong University of Science and Technology (HKUST) has uncovered the mechanism of how DNA is being melted to start bacterial gene transcription and how one class of antibiotics inhibits this process – an important way in killing bacteria. This discovery provides useful insight on the development of new antibiotics for bacteria that is antimicrobial resistance.
The emergence and spread of new forms of resistance remains a concern that urgently demand new antibiotics. Transcription is a vital process in bacterial cell, where genetic information in DNA is transcribed to RNA for the translation of proteins that perform cellular function. Hence, transcription serves as a promising target to develop new antibiotics because inhibition the transcription process should effectively kill the bacteria. Bacterial RNA Polymerase, the core enzyme for transcription, must load the DNA and separate the double-stranded DNA to single stranded DNA to read the genetic information to initiate transcription. This process is also called DNA melting and is facilitated by the opening and closing of the loading gate of RNA Polymerase. The loading gate contains two flexible pincers (clamp and β-lobe) resembling the shape of a crab claw. DNA melting via this loading gate is a multi-step and highly dynamic process, and it provides a promising strategy for the design of novel antibiotics by inhibiting this process. Yet, the understanding of DNA melting requires a detailed understanding in the movements and dynamics of the loading gate, the lack thereof hampers future development of antibiotics.
To offer new direction for more effective therapeutics, a research team led by Prof. Xuhui HUANG, Department of Chemistry and Department of Chemical and Biological Engineering at HKUST, recently discovered the working mechanism of an antibiotics, Myxopyronin, by targeting the movement of the loading gate to inhibit the DNA melting prior to bacterial gene transcription. The research team identified a partially closed form of the flexible clamp domain, into which an antibiotic called Myxopyronin can bind with. The binding of Myxopyronin to the RNA Polymerase diminishes the gate's ability to close, eventually inhibiting the DNA melting, which is vital for the survival of the bacteria.
More interestingly, the research team also found the unprecedented role of the β-lobe during the loading of DNA to the inner cleft of RNA Polymerase. They discovered that the opening of β-lobe is sufficient to accommodate the loading of double helix DNA without opening the Clamp. The role of β-lobe has not been previously reported, and this finding opens the opportunity to the development of new antibiotics targeting the β-lobe of RNA Polymerase to halt transcription.
"The shape of bacterial RNA polymerase resembles a crab claw that works like a pincer. The shape and flexibility of the two pincers are important for RNA Polymerase to hold and separate the double-helix form of DNA into single-stranded. We showed that an antibiotic that targets the movement of the pincers would be a promising as a drug candidate" said Prof. Huang. "What is more exciting, is that we also discovered a novel critical role of the β-lobe that can serve as a new target for future antibiotics development."
This work is made possible only with the quasi-Markov State Model (qMSM) recently developed in Prof. Huang's lab. qMSM is built from extensive all-atom molecular dynamics simulations, and successfully predicts dynamics of RNA Polymerase's loading gate at atomic resolution and millisecond (10-3 second) timescale. This new method adopts the generalized master equation formalism to encode non-Markovian dynamics, which has advantages over the popular Markov State Models based on Master Equation. Hence, it is especially promising to be applied to study complex conformational changes of proteins.
The first author of this work: Dr. Ilona UNARTAR is a long-time HKUST affiliate who completed her undergraduate, PhD, and currently conducts her post-doctoral training all at HKUST from Department of Chemistry and Bioengineering graduate program. Other collaborators of this work come from Kyoto University and King Abdullah University of Science and Technology.
This study was recently published in the scientific journal Proceedings of the National Academy of Sciences.