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.

In view of the severe economic repercussions caused by the COVID-19 pandemic globally and locally, the Government announced another package of measures to support the affected individuals and businesses last Wednesday. Two of which are particularly relevant to the legal and dispute resolution sector - the LawTech Fund and the COVID-19 Online Dispute Resolution (ODR) Scheme. The LawTech Fund was briefly introduced in this blog a few days ago. Today, I would like to give an online explanation of the COVID-19 ODR.

In anticipation of an upsurge of disputes arising from or relating to COVID-19, the scheme aims to provide speedy and cost-effective means to resolve such disputes, especially for those involving micro, small and medium-sized enterprises (MSMEs) that may be adversely affected or hard hit by the pandemic. The scheme will engage eBRAM (electronic Business Related Arbitration & Mediation system) to provide ODR services to the general public and businesses, in particular MSMEs, involved in low value disputes.

The scheme plans to cover COVID-19 related disputes with the claim amount for each case to be capped at $500,000. Either one of the parties (claimant or respondent) must be a Hong Kong resident or company and they will only be required to each pay $200 registration fees. Under the scheme, the parties are required to enter into a dispute resolution agreement to record their consent.

The process to be adopted is a multi-tiered dispute resolution mechanism where the parties will first attempt to negotiate their disputes, followed by mediation and if that does not result in settlement, then subsequently to arbitration for a final and binding award. This is in line with the "Mediate First" policy that we have been advocating under our "Mediate First" Pledge Programmes.

The scheme aims to offer a fast and effective means to resolve disputes among parties. Each tier of dispute resolution will be conducted within a limited time. The tiers are devised with a view to avoiding disputes and differences from being entrenched. If the disputes can be resolved successfully and amicably through negotiation or mediation, we hope it will help build and reinforce a harmonious society and enable the parties to preserve their long term business relationship.

We also hope the scheme will have the benefit of job creation and job advancement for mediators and arbitrators (including their pupils). Parties are at liberty to appoint the third party neutral of their choice and if no agreement is reached, there will be a mechanism for appointment. The third party neutrals and the parties or their representatives can still handle cases under the social distancing measures online and indeed to practice on the handling of cases online. We would like the scheme to be launched in June if funding is provided in April.

It is a global trend to develop and use ODR to provide reliable and efficient platform to facilitate alternative dispute resolution. The scheme is in line with the development under Asia-Pacific Economic Cooperation's Collaborative Framework on ODR (APEC Framework), with MSMEs as the major beneficiary. The mechanism of adopting negotiation and mediation in the first stage under the APEC Framework is also to prevent entrenched views on the conflicts, thereby helping to create harmony in society.

Some forms of alternative dispute resolution, such as mediation, are a more cost-effective way to resolve disputes. The costs of mediation are almost always lower than the disputed amounts, making it an economical way to resolve disputes. Mediation can save time too. Some cases may be resolved following just one day of mediation.

LawTech has greatly helped the development of dispute resolution services. The establishment of a safe, reliable and credible platform to provide enterprises with convenient and cost-effective online dispute resolution will become a new trend.

It is one of the major long-term policy objectives of the Department of Justice (DoJ) in recent years to enhance and promote Hong Kong's status as an international legal hub for deal-making and dispute resolution. A further promotion of the use of ODR will help consolidate Hong Kong's position as an international business and financial centre.

The social media accounts of the DoJ's IDAR Office have been introducing the procedure, characteristics and benefits of mediation and arbitration. You may wish to visit the dedicated pages of the IDAR Office to keep abreast of the dispute resolution services.

In addition to the relief measures announced by the Government, the DoJ has also taken the initiative to speed up payment of fees to counsel. Counsel engaged by the DoJ could submit their interim fee notes together with the interim case reports after certain work has been completed. Each case will be considered individually on a case-by-case basis and interim payments could be made. I have enquired and am also glad to learn from the Legal Aid Department and the Duty Lawyer Service that they made similar arrangements.

We are confident that Hong Kong can weather the storm with our fundamental strengths and resilience. We also trust that we would overcome this unprecedented challenge by standing in solidarity.

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on April 13.

Required reading for any academic is Philip Roth’s “The Human Stain.” In the first few pages an older, tenured professor is “forced to retire.” Why? There were two students who never were present when he called roll. Even after roll … Continue reading →

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The Government is set to revive the economy through different measures and everyone should act together to attain this goal.

Secretary for Financial Services & the Treasury Christopher Hui made the remarks today after attending a radio programme, saying the economy has been seriously affected by the epidemic.

“I think right now the immediate priority is definitely to revive the economy because after all, we have been subjected to many restrictions on all you can imagine in the past few months due to COVID-19.

“So the immediate priority is really for us to act together to revive the economy through different measures.

“And the measures that are subject to the Legislative Council’s approval as you have seen over the past few days, I think are definitely something that we want to do in order to provide a sort of foundation for our economic recovery.”

Some 60,000 workers of over 340 contractors received the first round of allowance under the Anti-epidemic Fund, the Government said today.

The Government explained that it has been making use of the fund to provide allowances to eligible cleansing and security workers engaged by service contractors of the Government and Housing Authority.

Front-line cleansing workers, toilet attendants and security workers employed by the service contractors can receive a monthly allowance of $1,000 for a period of no fewer than four months throughout the epidemic period.

The first round of funding amounted to some $60 million.

Eligible workers who performed duties in March have received the $1,000 allowance applicable to that month.

Arrangements were made for the April allowance to be issued concurrently with the salary of that month.

Front-line workers are not required to submit any application for the allowance.

The departments and the Housing Authority entered into agreements with their contractors to ensure the transfer of the allowance to eligible workers. 

The Government said the allowance aims to provide financial support to cleansing and security staff engaged by service contractors in anti-epidemic efforts, and gives recognition for their committed services at this critical juncture.

Secretary for Constitutional & Mainland Affairs Erick Tsang today visited the temporary operation centre for the special scheme for delivering urgently needed prescription medication to Hong Kong people in Guangdong and Fujian.

Under the compulsory quarantine arrangements, many Hong Kong people who are staying in Guangdong and Fujian provinces are unable to attend follow-up consultations in Hong Kong to replenish their prescription medication and return to the Mainland on the same day.

The Government introduced a special scheme on February 24 to deliver medicine to them, with priority given to those who would run out of prescription medication by end-April.

Mr Tsang was pleased to learn that as of April 29, prescription medication deliveries had been made to more than 7,600 Hong Kong residents in need.

He thanked the Hong Kong Federation of Trade Unions for offering voluntary services for the drug delivery scheme with its well-established service networks on the Mainland.

Mr Tsang also thanked the Pharmaceutical Society of Hong Kong and Hong Kong Pharmaceutical Care Foundation for deploying pharmacists to the temporary operation centre to help verify drug records and patients' information.

During his visit, he gave encouragement to participating volunteers and thanked them for their support for the scheme.

Mr Tsang said as the expiry date for the Compulsory Quarantine of Certain Persons Arriving at Hong Kong Regulation has been extended to June 7, the special scheme will be extended and give priority to cases in which prescription drugs will run out on or before that date.

Call 2343 2255 for enquiries about the scheme.

GitHub is holding its annual 'Universe' conference in San Francisco this week.

The Tour Service Coach Drivers (Mainly Serving Tourists) Support Scheme, under the second round of the Anti-epidemic Fund, is open for applications from today to June 5, the Government announced.

The scheme will provide each tour service coach driver with a one-off subsidy of $10,000 and aims to benefit about 9,300 drivers.

In addition, the Government explained that the second round of the Anti-epidemic Fund includes other tourism industry support measures. 

Applications for the Hotel Sector Support Scheme are being accepted until May 18, while the deadline to apply for the Travel Agents & Practitioners Support Scheme is June 15.

Click here for more details.

Karin Melnick of the University of Maryland, College Park, has been awarded the AMS Joan and Joseph Birman Fellowship for Women Scholars for the 2020–2021 academic year.

Melnick’s research is on differential-geometric aspects of rigidity. This work comprises global and local results relating the automorphisms of a differential-geometric structure with the geometric and topological properties of the space. Melnick also works in smooth dynamics, in which an invariant differential-geometric structure plays an important role in the proof of rigidity theorems. Melnick is a leader in research on the Lorentzian Lichnerowicz conjecture, a statement about conformal transformations of compact Lorentzian manifolds. Together with collaborators, she has developed new techniques in the setting of Cartan connections that have facilitated progress on this problem, as well as many results for other differential-geometric structures and general parabolic Cartan geometries.  

Brief Biography of Karin Melnick:

Melnick received her PhD at the University of Chicago in 2006 under the direction of Benson Farb. With an NSF Postdoctoral Research Fellowship, she went to Yale University as a Gibbs Assistant Professor. She received a Junior Research Fellowship from the Erwin Schrödinger Institute in the spring of 2009 and that fall began at the University of Maryland, where she is now an associate professor. Previously, Melnick has been awarded an AMS Centennial Fellowship and an NSF CAREER grant. She divides her time between the U.S. and Germany with her partner and their young child, and is very grateful for the flexibility provided by the Birman Fellowship and the opportunities it provides to advance her research and career goals.  

About the Fellowship:

Established in 2017, the AMS Joan and Joseph Birman Fellowship for Women Scholars seeks to give exceptionally talented women extra research support during their mid-career years. The primary selection criterion for the Birman Fellowship, which carries a stipend of US$50,000, is the excellence of the candidate’s research. Read an interview with Joan Birman about her decision to create the Fellowship with the goal of "helping more women mathematicians to develop their creative voices." See more information about the Fellowship.

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The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

(University of South Florida (USF Health)) A new preclinical study by researchers at the University of South Florida Health (USF Health) Morsani College of Medicine and Johns Hopkins University School of Medicine offers promise of a specific treatment for NEC, a rare inflammatory bowel disease that is a leading cause of death in premature infants. The team found that inhibiting the inflammatory and blood-clotting molecule thrombin with targeted nanotherapy can protect against NEC-like injury in newborn mice.

(To watch the full press briefing with sign language interpretation, click here.)

A recovered COVID-19 patient has tested positive for the virus again, the Hospital Authority announced today.

The authority’s Chief Manager (Quality & Standards) Dr Lau Ka-hin told a media briefing this afternoon that the patient was first admitted to Queen Mary Hospital on March 24 after having fever for a week. He subsequently tested positive for COVID-19.

He was discharged on April 16 after two consecutive negative tests for the virus.

Dr Lau said: "The patient presented to the Accident & Emergency Department of Queen Mary Hospital on May 5 because of some abdominal pain and diarrhoea.

"He was admitted to our hospital and was found to have a positive result for COVID-19 in the throat saliva, but the cycle threshold value is very high - nearly 36.

"The experts consider that this is the residual virus left in the patient’s body, which is not infective, and it is not likely to be a reinfection at this moment."

He added that the patient is in a stable condition.

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection.

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens.

The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs.

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.

Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C+ monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.

The Agriculture, Fisheries & Conservation Department (AFCD) today said a pet dog has tested positive for the COVID-19 virus. 

The case involves a German Shepherd dog whose owners live in Pok Fu Lam. This follows an earlier case in which a 17-year-old Pomeranian dog tested weak positive during repeated tests for the virus.

When the German Shepherd's owner was confirmed with COVID-19, it was sent for quarantine with another mixed breed dog from the same residence to the animal keeping facility at the Hong Kong-Zhuhai-Macao Bridge's Hong Kong Port yesterday.

No positive results were obtained from the mixed breed dog and neither dog has shown any signs of the disease.

The department will continue to closely monitor both dogs and conduct repeated tests on them.

It strongly advises that mammalian pet animals including dogs and cats from households with people confirmed as infected with COVID-19, or close contacts of COVID-19 infected people, should be put under quarantine in AFCD facilities.

The department emphasised that there is currently no evidence pet animals can be a source of COVID-19 for humans or that this virus can cause the disease in dogs.

Pet owners are reminded to maintain good hygiene practices and under no circumstances should they abandon their pets.

Seventy-year-old Theresa Chan suffers from joint degeneration, which is why she needs a walking stick.

“My joints are severely abraded. They are painful when I walk or stand. My doctor suggested I replace some joints with implants, but I don't want surgery,” she said.

Smart seniors

Interested in how gerontechnology can help improve the quality of life for older adults, Ms Chan joined the Gerontechnology Practitioner Training Course under Lingnan University’s Gerontechnology & Smart Ageing Project.

The course targets elderly people and caregivers. It introduces them to devices that help seniors get around with ease and live more independent lives.

Ms Chan was impressed by a smart walking stick that is equipped with senior-worthy features like a flashlight with an adjustable safety light, a siren for emergency use and a radio.

“I am grateful for the course because I can learn more about gerontechnology in my free time. After class, I can share my knowledge with others who have no idea about this new technology. It is modern and I want to keep up with the times and progress,” she said.

Youth opportunities

Gerontechnology has also opened up career opportunities for young people.

Cecilia Auyeung recently graduated from Lingnan University with a major in marketing. Last year she set up a social enterprise called Gatherly. It provides a platform for the elderly to teach other people handicraft skills and helps them to sell their products online.

Ms Auyeung joined the Socialpreneur Incubation Course under the Lingnan University project. It encourages the development of social enterprises in Hong Kong, gerontechnology and marketing. She quickly drew inspiration from other socialpreneurs.

“I discovered that my social enterprise has to change every two years according to market demands. For example, fabric bags are popular among youngsters. While the elderly at Gatherly are equipped with blue-dye techniques, I make use of their skills to create products that match the market situation.”

University contribution

According to the Census & Statistics Department, in 2036, the proportion of the population aged 65 and over is projected to be 31%. To meet the needs of an ageing population, the Government is promoting gerontechnology, which combines gerontology and technology. It focuses on providing effective solutions to increase vitality and quality of life.

The Lingnan University’s three-year project aims to enhance public understanding of gerontechnology and support smart ageing socialpreneurship development. The project also covers studies with the goal of building a database for gerontech products and services as well as social innovation and startups. The overall vision is to offer policy recommendations to the industry and Government.

Lingnan University Asia-Pacific Institute of Ageing Studies Project Manager Chloe Siu said: “Most of the participating students are willing to think out-of-the-box, using their creativity and knowledge learnt from their courses and to echo the needs of the society. We are trying to facilitate different stakeholders and community partners to create a co-working atmosphere.”

The university has also built a 2,000 sq ft Gerontech-X Lab to display over 40 gerontech products catered to healthcare, dining, living and transport. Anyone interested can book an appointment for a free visit from November 28.

The ambulance service has been part of the Fire Services Department since 1919 and its mobile ambulance technology is keeping pace with the evolution of technology in hospitals.

To aid ambulance crews in the race against time to save lives, the department installed automatic chest compression machines in all ambulances in October.

The advanced device helps medics respond to a cardiac arrest by delivering uninterrupted compressions at the right rhythm and the right amount of pressure.

Fire & Ambulance Services Academy Deputy Commandant (Ambulance Services Training) Terence Ng explained that the device enables paramedics to treat patients on their way to the hospital.

“It has other advantages as well, like reducing the compression pause significantly, lowering the risk of injuries suffered by ambulance personnel as a result of performing chest compressions in different environments, allowing ambulance personnel to perform chest compression continuously in a constrained environment, and releasing more ambulance manpower to carry out other treatment procedures.”

Keeping pace

Such advanced equipment was not available to ambulance crews in the past.

Retired Principal Ambulanceman Simon Wong and Assistant Chief Ambulance Officer Conrad Yung visited the Fire & Ambulance Services Education Centre & Museum to discover the century-long history of ambulance services in the city.

Both have witnessed the continuous improvement and development of equipment, knowledge and techniques of ambulance personnel.

Mr Wong joined the Fire Services Department as an ambulanceman in 1978 and retired after 34 years of service. He noted one of the major changes to the department was the implementation of the Paramedic Ambulance Service in 2005.

“When I joined the department, we were well trained to provide ambulance services. We would arrive at the scene and then transport the patient to the hospital as soon as possible. We rarely provided pre-hospital treatment. However, when I retired, there was an obvious change. Ambulance personnel now provide paramedic care for patients in ambulances.”

Mr Ng said the service provides medications and equipment to help improve the survival rate of emergency patients.

“Advanced treatments like airway insertion and defibrillation used to be confined to the hospital. However, paramedics brought them into pre-hospital settings. Paramedics administer advanced treatments and protocols to the patient at the scene or en route to hospital in order to stabilise the patient and increase the patient’s survival rate. This protocol allows ambulance personnel to treat a wide range of emergencies, including cardiac arrest, shortness of breath and cardiac origin chest pain.”

Mr Yung, who joined the Fire Services Department in 1960, noted that treatment methods have come a long way since then.

“I was an ambulanceman when typhoon Wanda hit Hong Kong in 1962. At that time, ambulances were only equipped with respiratory equipment, a medicine box and blankets. These tools are simple but important. But in the past, even though we knew that a patient had internal bleeding, we could not do anything to help. We did not have the tools and equipment for that.”

Ambulances these days are equipped with ultrasound scanners to detect internal bleeding.

Up-close look

The Fire & Ambulance Services Education Centre & Museum, housed inside the Fire & Ambulance Services Academy in Tseung Kwan O, has a four-story exhibition hall offering interactive and multimedia information facilities.

Visitors can get a close-up look at fire appliances and ambulances parked in the large exhibition areas, as well as uniforms and equipment.

The venue is open for group and individual visits which can be booked on its website.

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(JAMA Network) The considerations and challenges affecting the palliative care specialty and delivery of palliative care in the COVID-19 era, as well as potential solutions, are discussed in this Viewpoint.