Members Event Webinar

Event participants

Pepijn Bergsen, Research Fellow, Europe Programme, Chatham House

Dr Sheri Berman, Professor of Political Science, Barnard College

Chair: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House

Research Event

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity.

Research Event

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have further evaluated and optimized our recent boosting to amplify signal with isobaric labeling (BASIL) approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of proteins in single cells. This improved BASIL (iBASIL) approach enables reliable quantitative single-cell proteomics analysis with greater proteome coverage by carefully controlling the boosting-to-sample ratio (e.g. in general <100x) and optimizing MS automatic gain control (AGC) and ion injection time settings in MS/MS analysis (e.g. 5E5 and 300 ms, respectively, which is significantly higher than that used in typical bulk analysis). By coupling with a nanodroplet-based single cell preparation (nanoPOTS) platform, iBASIL enabled identification of ~2500 proteins and precise quantification of ~1500 proteins in the analysis of 104 FACS-isolated single cells, with the resulting protein profiles robustly clustering the cells from three different acute myeloid leukemia cell lines. This study highlights the importance of carefully evaluating and optimizing the boosting ratios and MS data acquisition conditions for achieving robust, comprehensive proteomic analysis of single cells.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.

15 April 2020

9 January 2020

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.

Expert

One of the most useful tools in analyzing the spread of disease is a system of evolutionary equations that reflects the dynamics among three distinct categories of a population: those susceptible (S) to a disease, those infected (I) with it, and those recovered (R) from it. This SIR model is applicable to a range of diseases, from smallpox to the flu. To predict the impact of a particular disease it is crucial to determine certain parameters associated with it, such as the average number of people that a typical infected person will infect. Researchers estimate these parameters by applying statistical methods to gathered data, which aren.t complete because, for example, some cases aren.t reported. Armed with reliable models, mathematicians help public health officials battle the complex, rapidly changing world of modern disease. Today.s models are more sophisticated than those of even a few years ago. They incorporate information such as contact periods that vary with age (young people have contact with one another for a longer period of time than do adults from different households), instead of assuming equal contact periods for everyone. The capacity to treat variability makes it possible to predict the effectiveness of targeted vaccination strategies to combat the flu, for instance. Some models now use graph theory and matrices to represent networks of social interactions, which are important in understanding how far and how fast a given disease will spread. For More Information: Mathematical Models in Population Biology and Epidemiology, Fred Brauer and Carlos Castillo-Chavez.

One of the most useful tools in analyzing the spread of disease is a system of evolutionary equations that reflects the dynamics among three distinct categories of a population: those susceptible (S) to a disease, those infected (I) with it, and those recovered (R) from it. This SIR model is applicable to a range of diseases, from smallpox to the flu. To predict the impact of a particular disease it is crucial to determine certain parameters associated with it, such as the average number of people that a typical infected person will infect. Researchers estimate these parameters by applying statistical methods to gathered data, which aren.t complete because, for example, some cases aren.t reported. Armed with reliable models, mathematicians help public health officials battle the complex, rapidly changing world of modern disease. Today.s models are more sophisticated than those of even a few years ago. They incorporate information such as contact periods that vary with age (young people have contact with one another for a longer period of time than do adults from different households), instead of assuming equal contact periods for everyone. The capacity to treat variability makes it possible to predict the effectiveness of targeted vaccination strategies to combat the flu, for instance. Some models now use graph theory and matrices to represent networks of social interactions, which are important in understanding how far and how fast a given disease will spread. For More Information: Mathematical Models in Population Biology and Epidemiology, Fred Brauer and Carlos Castillo-Chavez.

Researcher: Christopher Butson, Scientific Computing and Imaging Institute, University of Utah. Christopher Butson talks about work he's done to help treat Parkinson's disease.

Do biodiversity losses aggravate transmission of infectious diseases spread by animals to humans? The jury is still out but several scientists say there is a "biodiversity dilution effect" in which declining biodiversity results in increased infectious-disease transmission.

Healthcare insiders explain their hopes and fears for the government's plan to create a new AI lab within NHSX

The ICO is investigating reports that a property developer has quietly installed a facial recognition system in London's King's Cross. We spoke to experts from the legal and technology sectors to find some clarity about the rules

The proptech startup wanted to democratise investment in prime real estate projects through crowdfunding, but government regulations have limited its reach to high net worth individuals

While coordinated action is urgently needed, should we be racing to download everything that promises a solution?

Cătălin I. Cârstea, Gen Nakamura and Lauri Oksanen
Trans. Amer. Math. Soc. 373 (2020), 3423-3443.
Abstract, references and article information

On this last Sunday of 2019, I wish every Hong Kong citizen a warm, peaceful and hopeful year 2020.

A New Year holds welcome promises of a fresh start and a new beginning. The New Year is also traditionally a time for planning, greeting, reminiscing as well as some soul and heart searching.

I believe that many of you would share my feeling that the year 2019 has been a year of unremitting shocks and turbulence to our community and our economy. Indeed, it has been a severely testing time for all in Hong Kong.

It all began with the introduction into the Legislative Council of the bill to amend the Fugitive Offenders Ordinance in April. Responding to strong public sentiment, the Government suspended all work on the bill in mid-June and declared its death in early July. On September 4, the Chief Executive announced the bill's withdrawal. This was done on October 23 when the Legislative Council resumed normal business.

Despite this, the public protests which began as largely peaceful and orderly marches in June soon got out of control. Unprecedented violence and reckless destruction became the norm. Radical protesters attacked police officers as well as police stations and facilities with petrol bombs, iron bars, bricks and chemicals. Some even used high-tension slingshots, bows and arrows. During the past six months or so, over 2,600 people were injured in the social unrest, including over 500 police officers.

Meanwhile, public infrastructure and transport including a cumulative total of 85 heavy rail stations and 62 light rail stations, as well as countless shops, restaurants and shopping malls had been repeatedly vandalised. More so, nearly 21,000 square metres of paving blocks from footpaths were ripped up and used as weapons to attack Police. Over 52,000 metres of roadside railing were removed and 740 sets of traffic lights destroyed.

Last month, masked protesters battered the Hung Hom Cross-Harbour Tunnel, shutting it down for two full weeks. This vital city artery normally carries 110,000 vehicles a day, accounting for some 43% of the daily cross-harbour vehicular flow. It took a total of 800 government staff and contractor's workers some 100 hours to carry out emergency repair round-the-clock before the tunnel could be reopened. At the same time, nearby Polytechnic University was overrun by radical protesters. The same happened to the Chinese University.

Apart from recklessly damaging our universities, violent protesters turned the two campuses into arsenals on a frightening scale. When the last of the protesters finally left the universities, Police seized altogether nearly 8,000 petrol bombs plus numerous explosives, hundreds of bottles of corrosive liquid and weapons of all sorts.

This level of premeditated and organised destruction and violence could hardly be tolerated in any country or economy that upholds the rule of law. Hong Kong, I am proud to say, is among those economies that believe passionately in the primacy of rule of law. It safeguards our economy, our community, our families and our way of life.

In fact, the rule of law is among Hong Kong's much cherished core values, alongside our fiercely independent judiciary, clean government, level playing field for business and enviable freedoms. These freedoms, as enshrined in the Basic Law and the Hong Kong Bill of Rights Ordinance, include freedom of speech, of the press and free flow of information; freedom of association and assembly; free trade and free port; free flow of capital; freely convertible currency; freedom of religious belief and free education. We have also been the freest economy in the world continuously for 25 years. The unique "one country, two systems" formula has been functioning well and we enjoy the best of both worlds.

Despite the recent social unrest which has affected our economy and labour market, Hong Kong's institutional strengths remain robust and intact. Our fundamentals stay sound and strong. We still enjoy a high rating in various areas by international think tanks and agencies. Allow me to say that whilst Hong Kong may not have the full semblance of Western democracy, we do enjoy for a very long time the full substance of real freedom which underpins Hong Kong's success.

Over the past six months, most of the requests for public meetings, processions and protests were given the greenlight by Police. During these public events, be it small or large, Police had dutifully facilitated and ensured the safety of protesters and other road users. When the requests were not approved, it was generally a decision made in the hopes of preventing violence, ensuring peace and public order, as our society has every right to expect of its police and its government.

On November 24, we witnessed a peaceful and orderly District Council Election with a record high turnout and voting rates. My colleagues and I are looking forward to working with all new District Council members. We also look forward to expanding our dialogue with the community. While we will continue to engage different sectors of society through our usual channels, the Government will broaden and rejuvenate our communication with the public. Less than two weeks ago and after the one by the Chief Executive in September, my Principal Official colleagues have started a dialogue with the public through Facebook live. You will certainly see more of us listening and responding to people's views and concerns on these and other communication channels in the coming year.

We are also establishing an Independent Review Committee comprising experts and community leaders. The committee will look into the causes and full circumstances of the social unrest and probe into Hong Kong's deep-seated social conflicts, from affordable housing, land supply, wealth gap, upward social mobility and opportunities for our young people to social justice. The committee will recommend ways to address the real and long-entrenched community concerns that underlie the discord.

Meanwhile, our economy is inevitably affected by the twin blows of social unrest and the trade dispute between the United States and the Mainland. Businesses and people of Hong Kong are yearning for the restoration of peace and order soonest possible, and the recovery of our economy.

In response, the Government has launched four rounds of relief measures since August. These added up to more than $25 billion. A number of the measures which will benefit grassroots families and small and medium enterprises will be implemented at the beginning of the New Year.

These relief measures would not solve our economic problems. Yet, they could help businesses and people of Hong Kong stay afloat while we strive to heal our divided community and battered economy.

There are deep-seated issues that we must acknowledge and resolve if we are to end the prolonged social unrest that has shaken the familiar Hong Kong which we all love and cherish. We must be patient and perseverant in helping our city to heal, one step at a time.

The past six months have been tough for us, but we will soldier on. Hong Kong is a remarkably resilient and resourceful international city with a strong can-do spirit. We have a New Year waiting for us. We have new and expanded channels of communication opened up for us. We expect the first report of the Independent Police Complaints Council to come out soon. And we have research and concrete recommendations of the Independent Review Committee ahead of us. Working together, I am confident that we can rebuild, reclaim and rejuvenate the remarkably resilient spirit of Hong Kong.

On this note, I wish all of you a New Year blessed with peace, harmony and goodwill.

Chief Secretary Matthew Cheung gave these remarks on RTHK's "Letter to Hong Kong" programme aired on December 29.

Last month, I paid a visit to Yuen Long where I met a few families at Long Shin Estate. Apart from distributing face masks and anti-epidemic supplies to them, I was also given a better understanding of the impact brought by the epidemic on their daily lives. To show our concerted support in the fight against the disease, the Department of Justice (DoJ) Staff Club organised a volunteer activity on Sunday, which I joined with my fellow colleagues in offering our help to those in need.

To echo the Government's move to stay united, the DoJ Staff Club put forth a cash contribution campaign to buy anti-epidemic supplies for donation. The staff club volunteers acquired face masks and alcohol-based handrub in different ways - some were purchased through online shopping and some were bought at medicine stores. Last Sunday, I joined the volunteers in packing the anti-epidemic supplies, supermarket cash coupons and leaflets with health information. Our volunteers took the care packs in person to a non-governmental organisation a few days ago for passing to the elderly and low-income groups.

The staff club has been participating in volunteer services now and then. Given the overwhelming response this time, I am glad to know that more volunteer activities would be organised in the future. I would definitely be joining as many as I could. Through offering our efforts to help those in need, we hope to show our care for the less privileged in society and contribute to building a caring and inclusive community.

The public services of the DoJ, like all other government departments, have gradually resumed back to normal. I inspected the Justice Place on Monday to learn more about the infection control measures in place, such as the body temperature checking arrangement, provision of hand sanitisers and sanitising mats at building entrances.

We must remain vigilant as the epidemic is still severe, and more importantly, we also need to stand in solidarity in the fight against the disease.

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on March 5.

The Lands Department will provide additional rental or fee concessions for tenants of short-term tenancies (STT) and waiver holders in accordance with the new round of support measures announced earlier this month.

The measures aim to strengthen support for enterprises in light of the challenges arising from the COVID-19 epidemic.

In accordance with the support measures launched in 2019 and those announced in the 2020-21 Budget, STTs and waivers for varying the terms of land grants for business and community uses under the department have been granted 50% rental or fee concession from October 2019 to September this year.

Under the new round of support measures, the 5,000 eligible STT tenants and waiver holders already enjoying the previous concession, such as catering facilities, shops, workshops, public fee-paying car parks, and welfare facilities, will see their rental or fee concession rate increase to 75% from April to September.

The 75% concession arrangement will be extended to businesses not covered previously, such as depots for public transport operators, public utilities, petrol filling stations, driving schools and advertising facilities, effective for the same period.

If these tenants and waiver holders are ordered to close or have chosen to close due to the Government’s orders or other restrictions for safeguarding public health under the relevant regulation, they may further apply to the department for full rental or fee concession for the duration of the closure.

The department will issue written notifications to eligible STT tenants and waiver holders on the above concession measures and their implementation details.           

Additionally, to help development projects with construction progress affected by the epidemic, the department will offer extensions of the Building Covenant period at nil premium for up to six months for leases with the covenant not yet discharged as at April 8.

The department will issue a practice note and upload it onto its website by the end of the month to announce the application arrangements for lessees.