(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.
该工作的器件技术在科大清水湾校区的纳米系统制备实验所（NFF）制备。该工作为香港研资局的研究影响基金（Research Impact Fund）所支持，并新近得到深圳市科技创新委员会深港澳科技计划的支持。该工作发表于近期在《自然 · 电子学》期刊上。
可分享链接（未订阅《自然 · 电子学》期刊的读者亦可查阅文章）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.
「我们可能要等 100 年或更长时间才看到研究的影响力！但在等上100年之前，我们可以先理解事物运作的根本原理，即使我们还不清楚如何应用，这点十分重要。」
深海管虫是深海海底热泉(hydrothermal vent)和冷泉(cold seep) 这种黑暗、高压并经常含有高浓度有毒物质生态环境的常见生物，它们之所以能于此等极端环境中生存兼迅速生长的原因，实有赖于存活在牠们体内、一种能让硫化物氧化的细菌。不过，由于缺乏基因组的数据，这段互补「联姻」的成功一直是一个谜。
身兼科大捷成David von Hansemann 理学教授的钱教授表示：「该细菌拥有完整的新陈代谢途径，为管虫输出营养，包括碳水化合物、氨基酸和维生素/辅因子等生物化合物。」研究团队亦发现细菌为求与深海管虫共生，演化出能分散宿主免疫系统注意力的策略，以逃避其防御机制。与此同时，深海管虫的基因组亦出现了改变以促进这个共生过程。管虫不但会制造一种酶去消化这个细菌以获取营养，更拥有一个可以控制细胞死亡的路径，以确保细菌数量维持在对自己最有利的水平。
为了解让管虫得以从海底获取无机物、被称为「几丁质管」这独特结构的形成机制，团队进一步分析了管虫坚韧的几丁质管的蛋白质，发现了 35 种几丁质管基质蛋白，包括合成几丁质微纤维并将其分泌到细胞外基质的聚合酶、聚合几丁质并为有机基质提供聚合物框架的几丁质结合蛋白，以及能增强管韧性及重塑几丁质支架的的蛋白质。
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现在，由科大副校长(研究及发展)叶玉如教授领导的研究团队，从 429 种与 AD相关的血浆蛋白中，识别出19 种具有AD患病特征的血浆蛋白生物标志物组群。团队根据这组标志物，设计了一套评分系统，可将 AD 患者自健康人群中区分出来，其准确率超过 96%。该系统还能辨别AD早、中及晚期三个阶段，可用作监测患者的病情发展。
身兼科大晨兴生命科学教授及分子神经科学国家重点实验室主任的叶教授表示：「基于先进的超灵敏血液蛋白检测技术，我们成功开发了这套简单、无创而精准的 AD 诊断方法，将为AD的大规模筛查及分期诊断提供重大助力。」
这项研究由科大与伦敦大学学院研究团队，以及来自包括威尔士亲王医院和伊利沙伯医院等本地医院的临床医生合作进行。团队利用尖端的超灵敏高通量邻近延伸分析技术 (PEA)，从香港 AD 患者所收集的血浆样本当中，检测了逾 1,000 种蛋白质的水平变化情况，从而取得是次研究成果。
这项令人振奋的发现令高效的AD血液检测技术得以诞生，并为开创新型AD治疗方法打下基础。作为迄今为止就 AD 患者血液蛋白方面最全面的研究，有关结果近日被国际权威科学期刊Alzheimer's & Dementia: The Journal of the Alzheimer's Association刊载，并在不同AD 研究和学术交流平台，包括Alzforum，获得热烈的关注和讨论。
据统计，全球罹患AD的人口数目已超过 5,000万。患者会丧失脑细胞，并岀现一系列脑功能及认知功能障碍，包括丧失记忆，以及出现行动、推理和判断能力受损等症状。然而，尽管AD 早在症状出现前至少10-20 年已对患者大脑产生显著影响，患者却往往只在记忆出现问题时，才会寻求医生诊治。
香港科技大学(科大)及北京天坛医院的研究团队近日发现一个新的突变基因，可导致一种名为「脑海绵状血管瘤」(Cerebral Cavernous Malformation, CCM)的脑血管病变。目前全球约有一千至三千万的人士患有此症。
现时，磁力共振成像(MRI)是一种医生常用于诊断CCM的「非入侵性」方法。然而，MRI只能让医生知道血管瘤的大小及类别；至于是哪一个基因突变导致CCM，医生一般则只能透过手术以及化验得知。不过，科大研究团队设计了一个计算机程序，可以评估MRI 影像所显示的血管瘤与MAP3K3 c.1323C>G基因突变关系的概然率。因此，病人毋须「开刀」便得知是否存在MAP3K3 c.1323C>G基因突变，不但能减低施手术可能带来的脑出血或脑神经功能缺损等风险，亦可令病者及早展开更针对性的治疗。
科大王教授表示﹕「研究除了为CCM的基因图谱开辟新方向，也为MAP3K3 c.1323C>G基因突变与CCM二型患者的关联性带来线索。团队设计的计算机程序，又称决策树模型(decision tree model)，为实现CCM基因的非入侵性诊断迈进一步。我们希望有关发现可以有助找出治疗CCM的新靶标，促进药物发展，在不久的将来惠及病人。」
研究成果已在科学期刊《The American Journal of Human Genetics》发表。
(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.