A total of 27 Hong Kong residents who left Morocco on a chartered flight arranged by the Chinese Embassy in the Kingdom of Morocco arrived in Guangzhou today.

Among them, 26 people subsequently took the coaches arranged by the Hong Kong Special Administrative Region Government to return to Hong Kong through the Shenzhen Bay Port and have arrived at AsiaWorld-Expo.

One Hong Kong resident chose to stay in Guangzhou for a 14-day isolation period for medical surveillance in accordance with the relevant requirements.

Secretary for Justice Teresa Cheng today emphasised that Chief Justice Geoffrey Ma had stated he has not experienced interference from Mainland authorities.

Speaking to the media at the Legislative Council, Ms Cheng called on the public to read the Chief Justice’s statement in response to a media report about Hong Kong’s judicial independence.

Ms Cheng said: "The Chief Justice stated that since his taking office in 2010, he has not encountered nor experienced any interference from the Mainland authorities in any shape or form that affects judicial independence, including the appointment of judges.

"Nothing is better than the direct evidence of the Chief Justice himself telling us that there is not any such interference."

We are less than two weeks into the new year and already, geo-political concerns, large and alarming, dominate the news. Still, I believe the year ahead will mark a milestone for Asia. Asian economies, in terms of purchasing power parity, will become larger than the rest of the world combined for the first time since the 19th century. That represents a quantum leap from about one-third just two decades ago. Asia this year will also be home to half of the middle class of the world. That heralds enormous business opportunities for the world at large. Indeed, Asia, powered by Mainland China, has for some time been a global growth engine.

Hong Kong, with its strategic regional location, and its extensive, ever-deepening cultural and financial links with the Mainland, is China's international financial centre, contributing to the sustainable progress of the country, the region and the world.

In pursuing sustainable development, quality as well as quantity counts. Today's economies are exploring growth through innovation and technology, while seeking inclusiveness. They are, to be sure, hard-won goals given the unprecedented challenges we've faced over the past two years: the global economic slowdown, trade disputes among major economies, geopolitical uncertainties and local issues. But if we cannot direct the wind, we can surely adjust our sails, which has been what we are doing here in Hong Kong. Thanks to lessons learned and measures implemented, particularly since the Asian financial crisis, Hong Kong's financial system remains stable and remarkably successful.

Globally competitive

Our core competitiveness, and our status as one of the world's premier financial centres, continues to be internationally recognised. Last September, we again ranked third in the world in the Global Financial Centres Index, just behind New York and London. That's a compelling statement of confidence in our freely convertible currency, our world-class banking system and stock market and the professionals who power our financial sector. It's a telling reflection of our strategic geographic location and sophisticated connections to global financial markets. It's recognition, too, of the free flow of capital within, into and out of Hong Kong, as enshrined in Article 112 of the Basic Law. More than capital flows, information and people also move effortlessly in and out of Hong Kong.

People around the world are confident in our regimes. They take reassurance in our trusted and bilingual common law system, our sound financial regulatory framework, low taxes and deep connections with the Mainland and the rest of the world. It helps, too, that Hong Kong again topped the world in 2019 in funds raised through initial public offerings, taking in about US$40 billion in 2019. That marked the seventh time in the past 11 years in which Hong Kong has led the world in IPOs.

Hong Kong is also the first international financial centre to have laid down a clearly-defined and comprehensive regulatory regime for listed companies with weighted voting rights structures and additional corporate governance and disclosure requirements. It's clearly working. Hong Kong is now the second-largest fundraising venue in the world for biotech companies. And, of course, the Alibaba Group Holding's secondary listing on our stock market in late November was one of the world's biggest stock offerings of 2019. The decision by the e-commerce giant - one of the Mainland's largest e-commerce companies and Asia's most valuable listed companies - may well encourage other Mainland enterprises listed elsewhere, to expand their investor links into the Asian region, with Hong Kong as their base.

Then there's the Guangdong-Hong Kong-Macao Greater Bay Area development. With a population of 71 million and a combined GDP of US$1.6 trillion, the Greater Bay Area and its huge market potential present boundless promise for Hong Kong, particularly our financial services sector.

Innovation will drive development in the bay area. Measures will be rolled out to expand the flow of capital and people, opening up new markets and business opportunities thanks to enhanced connectivity. Among others, with the support of the Central Government, especially a Leading Group on the Greater Bay Area development chaired by the Vice Premier Han Zheng, a two-way wealth management connect scheme is being drawn up to meet the cross-boundary, wealth-management needs of residents in Hong Kong and the rest of the bay area.

Coupled with the Belt & Road Initiative, the bay area development will ensure long-term prospects for Hong Kong's economy. Through these two national policies, Hong Kong will enhance its role as the business bridge between the Mainland and the rest of the world. I'm talking here of our status as a leading fundraising centre, the world's largest offshore renminbi business hub and a premier asset and wealth management hub.

We are no less committed to Hong Kong's development as a green finance centre. In May 2019, we issued our inaugural green bond under the Government Green Bond Programme. And, with the introduction of a Green Bond Grant Scheme, which subsidises green bond issuers in obtaining certification under the Green Finance Certification Scheme, green bonds issued and arranged in Hong Kong in 2018 reached US$11 billion. A good start, I'd say, in creating financial programmes that also pay off in environmental benefits for our sustainable development.

We are hard at work as well on enabling development of our capital markets. Our open-ended fund company regime has been in operation since end-July 2018. And since last April, onshore and offshore privately offered funds can enjoy profits tax exemption under our tax law.

We're also building on our mutual recognition of funds arrangement. It now covers six economies: the Mainland, Switzerland, France, the United Kingdom, Luxembourg and the Netherlands. Such connections will strengthen our role as the world's premier offshore renminbi hub and wealth management centre.

Our connectivity with the Mainland is also enhanced through such financial schemes as Hong Kong-Shanghai Stock Connect, Hong Kong-Shenzhen Stock Connect and Bond Connect. Since its inception, in late 2014, stock connect has realised cumulative net transactions of about US$150 billion in the Mainland and over US$130 billion in Hong Kong.

We continue to diversify our fund structures. Among other things, we are working on a new regime of limited partnership for the registration of private equity funds. We are also enhancing Hong Kong's status as an international insurance and risk-management hub. And, to broaden the range of risk-management offerings in Hong Kong, we plan to enable the issuance of insurance-linked securities, including catastrophe bonds. Moreover, we will expand the scope of insurable risks by captive insurers in Hong Kong to meet the risk-management needs of multinationals.

To exemplify our commitment to technology, last year, we issued eight virtual banking licences, as well as two virtual insurer licences. These can spur financial innovation, while boosting customer experience and building financial inclusion. And our Faster Payment System, launched in 2018 to enable instant payment, now handles about 168,000 transactions, totalling more than US$307 million, a day.

Bridging East and West

We've been busy making the most of Hong Kong's manifold advantages. In creating connections between businesses, investors and financial markets, East and West, we help you excel. That is also the great strength of the Asian Financial Forum (AFF), bringing East and West together for two intensive days of the latest information and intelligence, deliberation and debate, networking opportunities and business promise.

This year's AFF is, as always, packed with panel discussions and workshops on financial policy, asset and wealth management, insurance, sustainable finance and deal-making sessions. As fintech continues to shake up the financial world, the AFF continues to expand its focus on fintech. This year, we launch the FintechHK Startup Salon, showcasing promising business ideas from fintech startups. It builds on the success of last year's Fintech Showcase, which returns with more than 60 fintech startups. And there's even more on offer this year in areas, ranging from global trade finance to environmental, social and governance, profit with purpose and succession planning for family corporations.

It gives me great pleasure, as well, to tell you that your keynote luncheon speakers today and tomorrow, respectively, are Dr Janet Yellen, formerly the Chair of the US Federal Reserve System's Board of Governors, and Prof Abhijit Banerjee, the 2019 Economics Nobel laureate. I am honoured that they come to Hong Kong and offer us their insight and their inspiration.

The forum is part of International Financial Week in Hong Kong, which brings together some 16 events covering everything from private equity and fund-raising to alternative investment and advertising strategies for financial concerns. A trip to Shenzhen is also featured this year, with visits to leading financial services and technology companies. Shenzhen, of course, is our close partner in the bay area and a global pacesetter in technology.

The Asian Financial Forum symbolises Hong Kong's wide-ranging strengths and resilience as an economy and a community. These strengths and resilience, just like our financial systems, have not been undermined despite that we have experienced considerable social unrest and challenges in recent months. Through the concerted efforts of the Government, and the people of Hong Kong, I am confident that we will bridge our divide, that we will realise the common goal of a reunited community and a flourishing economy.

Chief Executive Carrie Lam gave these remarks at the 13th Asian Financial Forum on January 13.

The Science Museum is presenting the special Unlocking the Secrets - The Science of Conservation at The Palace Museum exhibition to tie in with the 600th anniversary of the Forbidden City in 2020.

More than 100 artefacts from the Palace Museum collection are being showcased to highlight the application of science and technology in conservation.

They include bronzes, clocks, textiles, thangkas, wood furniture, lacquerware and inlaid works along with ceramics, calligraphy and hand-painted copies of ancient paintings.

The show also presents the Conservation Office’s work by showcasing intriguing restoration cases so that visitors can learn more about the work and skills of conservators as well as their mission to preserve Hong Kong’s heritage assets.

The Science Museum will launch a series of interactive family activities, including demonstrations and workshops conducted by Palace Museum conservators, guided tours featuring theatrical plays and storytelling, and visits to conservation laboratories.

Jointly presented by the Leisure & Cultural Services Department and the Palace Museum, the exhibition will run until March 18 next year.

Call 2732 3232 for enquiries.

The Leisure & Cultural Services Department launched a one-stop online resources centre today for the public to view or participate in multi-faceted leisure and cultural activities from the comfort of their homes.

The online resources centre offers demonstrations of home exercises as well as videos of exercise demonstrations and Healthy Exercise for All Campaign interactive games.

The information portal carries knowledge on the plants and animals at the Zoological & Botanical Gardens, old and valuable trees at the department's major parks and colourful Hong Kong Flower Show archives.

The Museum of Art and the Heritage Museum are collaborating with the Google Arts & Culture Project to showcase exhibits in a digital format.

There are also virtual exhibitions that explore previous fascinating collections at the History Museum and the Science Museum.

While extensive content from intangible cultural heritage and modern arts integrating into life from Oi! is also included.

The Hong Kong Public Libraries offers vast e-resources allowing people to explore fun reading at home.

On the performing arts front, digital content covers concert archives from the Hong Kong Philharmonic Orchestra, Hong Kong Chinese Orchestra and Hong Kong Sinfonietta.

The deadline for applications under the first round of funding from the Elder Academy Development Foundation in 2020 has been extended to June 30, the Labour & Welfare Bureau announced today.

The decision aims to provide sufficient time for primary and secondary school sponsoring bodies, post-secondary institutions and organisations, which may be affected by the COVID-19 epidemic, to prepare their submissions.

The fund’s committee accepts funding applications all year round and conducts vetting and disburses funding twice a year. The deadlines were generally May 31 and October 31 respectively.

The committee will continue to monitor the situation and announce arrangements for the next round in due course.

To tie in with the Elder Academy Scheme, the fund mainly provides funding for primary and secondary schools as well as post-secondary institutions to set up academies to provide learning opportunities in a school setting for the elderly.

Funding is also provided for activities that encourage elderly learning and inter-generational harmony.

Call 3655 5861 or 3655 5007 for enquiries.

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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.”

The Government today announced the mechanism for Hong Kong enterprises with manufacturing operations in the Mainland to apply for exemption from the compulsory quarantine arrangement. 

It said the Trade & Industry Department has started processing applications.

The Chief Secretary may designate anybody or category of people for exemption from quarantine if their travelling is necessary for purposes relating to manufacturing operations in the interest of Hong Kong's economic development.

With effect from May 4, the Chief Secretary has exempted two categories of people from the quarantine arrangement.

They include owners of Hong Kong enterprises with a valid business registration certificate and with manufacturing operations in the Mainland and up to one person employed and authorised by the enterprise, as well as up to two people employed and authorised by such an enterprise.

Exempted people must only travel to and stay in the city where the Mainland factory of their Hong Kong enterprise's manufacturing operations is located and must take every precautionary measure to ensure personal hygiene and avoid unnecessary social contact. 

After returning to Hong Kong, they will be subject to medical surveillance arranged by the Department of Health during their stay in Hong Kong and will be required to wear masks and have their body temperatures checked daily.

They will also have to report any discomfort to the Department of Health.

Click here for more information.

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

Chief Executive Carrie Lam today said law enforcement agencies are investigating cases where police officers are suspected of breaching property rules and will give a full account to society.

Speaking to reporters before the Executive Council meeting this morning, Mrs Lam said nobody is above the law.

“The law will be applied in the same manner regardless of the status, the background, the political affiliation of that particular person.

“As far as I am concerned, as the Chief Executive of Hong Kong and also as an individual, no law-breaking behaviour is acceptable. But it is not for me to stand here to judge each and every case because every case or every complaint has to be investigated and analysed by the law enforcement agencies.

“I am sure that they will do it as diligently as possible and will give a full account to society, especially given the recent concerns.”

Several fundamental weaknesses have been exposed in the most common Wi-Fi security protocols.

Here is some insight into the first ever blockchain advert

The 'unicorn letter', sent by some of the best-funded private technology companies in the country, asks the chancellor to form an urgent taskforce to give them access to government-backed lending schemes during the pandemic

The Treasury has announced a new set of financial measures aimed at helping startups during the coronavirus pandemic, including a £250 Future Fund for startups with at least £250,000 in funding

The digital challenger bank is now the most switched to bank in the UK as Nationwide Building Society loses its long-held top spot

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.

The Immigration Department announced today that the operation of all nine Smart Identity Card Replacement Centres will be fully resumed on May 11 in light of the more stabilised epidemic situation.

The department earlier suspended the replacement of Hong Kong identity cards at the centres to avoid the increased risk of spreading COVID-19.

To arrange for people affected by the service suspension to replace their identity cards in an orderly manner, the Secretary for Security has made an amendment order to revise the replacement period for people born in 1957 to 1963 and 1970 to 1976 and the arrangement for members of the sixth term of District Councils.

Click here for the arrangements.

If the replacement of identity cards needs to be suspended again in the future to cope with a sudden turn of the epidemic situation, the amendment order also provides that if all the centres are not in service for a period of 21 working days or more from May 11 to July 27 for public health reasons, the specified period for the above people will be further extended or amended.

The amendment order will be tabled at the Legislative Council on May 13 for negative vetting.

To reduce crowd gatherings, applicants who have not made appointments previously should do so via the Internet, the department’s mobile application or the 24-hour hotline at 2121 1234.

The department also appealed to applicants to pre-fill the application form when making appointments through the Internet or mobile application.

For details click here or call 2824 6111.

17 individuals in the mathematical sciences are among the 126 new members and foreign associates elected to the National Academy of Sciences (NAS) in 2020.

Members: Ivet Bahar, University of Pittsburgh School of Medicine; Abhijit Banerjee, Massachusetts Institute of Technology; Gerard Ben Arous, Courant Institute of Mathematical Sciences, New York University; Bonnie Berger, Massachusetts Institute of Technology; Laura G. DeMarco, Northwestern University; Ronald Fagin, IBM Almaden Research Center; Katherine Freese, The University of Texas at Austin; Dennis Gaitsgory, Harvard University; Robert L. Griess, University of Michigan, Ann Arbor; Jacob Lurie, Institute for Advanced Study; Terence T. Hwa, University of California, San Diego; Wilfried Schmid, Harvard University; Jeffrey D. Ullman, Stanford University; Lai-Sang Young, Courant Institute of Mathematical Sciences, New York University; and Ofer Zeitouni, Weizmann Institute of Science; Foreign Associates: Yoav Benjamini, Tel Aviv University (Israel) and Jürg Fröhlich, ETH Zurich (Switzerland). Berger, DeMarco, Griess, Schmid, and Zeitouni are members of the AMS and Fellows of the AMS. Fagin is a member of the AMS.

The NAS recognizes achievement in science by election to membership, and—along with the National Academy of Engineering and the National Academy of Medicine—provides science, engineering, and health policy advice to the federal government and other organizations. See the full list of this year's honorees. (Image courtesy of the National Academy of Sciences.)

updated April 1, 2020

In response to current challenges that colleges and universities face as a result of the spread of COVID-19, the American Mathematical Society is offering libraries and institutions additional support, in line with recommendations in the ICOLC Statement on the Global COVID-19 Pandemic and Its Impact on Library Services and Resources.

The AMS is also participating in the Copyright Clearance Center Education Continuity License program, providing access to our content for distance learning and other educational uses at no cost to the user.

We are extending grace access for content hosted on our platforms (including MathSciNet) through the end of May for our existing customers. We will re-evaluate this timing as needed.

As courses transition to online, we can provide instructors with complimentary electronic “reserve” copies of our textbooks for cases in which students do not have access to their print copies.

E-books purchased through the perpetual access model on the AMS platform are always available DRM-free with unlimited simultaneous use. In addition, we are partnering with ProQuest to allow multi-user access through mid-June to all e-books purchased on their platforms. Read ProQuest’s statement.

We are providing remote access to all our content, including MathSciNet. In normal circumstances, this remote access can be set up while on campus or while connected via institution VPN (in order to validate IP-based access). We realize many students, faculty, and researchers did not have an opportunity to initiate this access before leaving campus, so we have given instructions to our library partners on how patrons can connect to our content. Please contact your librarian for assistance.

Libraries: if you have not received instructions to share with your patrons, please email us at cust-serv@ams.org or be in touch about any other of your library’s needs.

Review all AMS Resources & Updates.

(College of Engineering, Carnegie Mellon University) Carnegie Mellon University's Maarten de Boer and Gianluca Piazza are developing reliable, mechanical switches the size of a DNA molecule, thanks to a $2M LEAP-HI grant from the National Science Foundation.

(Dartmouth College) Annual award supports the research and teaching careers of talented young faculty in the chemical sciences.

(University of Illinois Grainger College of Engineering) Three Nick Holonyak Jr., Micro and Nanotechnology Lab (HMNTL) faculty members received NSF Rapid Response Research (RAPID) program grants, all of which aim to shorten the amount of time it takes to process a COVID-19 test with less false negatives. Current tests can take as long as five days for results to be.

(Georgia Institute of Technology) The science behind sticky gecko's feet lets gecko adhesion materials pick up about anything. But cost-effective mass production of the materials was out of reach until now. A new method of making them could usher the spread of gecko-inspired grabbers to assembly lines and homes.

Extracytoplasmic sugar decoration of glycopolymer components of the bacterial cell wall contributes to their structural diversity. Typically, the molecular mechanism that underpins such a decoration process involves a three-component glycosylation system (TGS) represented by an undecaprenyl-phosphate (Und-P) sugar-activating glycosyltransferase (Und-P GT), a flippase, and a polytopic glycosyltransferase (PolM GT) dedicated to attaching sugar residues to a specific glycopolymer. Here, using bioinformatic analyses, CRISPR-assisted recombineering, structural analysis of cell wall–associated polysaccharides (CWPS) through MALDI-TOF MS and methylation analysis, we report on three such systems in the bacterium Lactococcus lactis. On the basis of sequence similarities, we first identified three gene pairs, csdAB, csdCD, and csdEF, each encoding an Und-P GT and a PolM GT, as potential TGS component candidates. Our experimental results show that csdAB and csdCD are involved in Glc side-chain addition on the CWPS components rhamnan and polysaccharide pellicle (PSP), respectively, whereas csdEF plays a role in galactosylation of lipoteichoic acid (LTA). We also identified a potential flippase encoded in the L. lactis genome (llnz_02975, cflA) and confirmed that it participates in the glycosylation of the three cell wall glycopolymers rhamnan, PSP, and LTA, thus indicating that its function is shared by the three TGSs. Finally, we observed that glucosylation of both rhamnan and PSP can increase resistance to bacteriophage predation and that LTA galactosylation alters L. lactis resistance to bacteriocin.

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.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context–dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

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.

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.

Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous “heavy chains” (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin core protein. Before ovulation, HCs are transferred onto the polysaccharide hyaluronan (HA) to form covalent HC·HA complexes, thereby stabilizing an extracellular matrix around the oocyte required for fertilization. Additionally, such complexes form during inflammatory processes and mediate leukocyte adhesion in the synovial fluids of arthritis patients and protect against sepsis. Here using X-ray crystallography, we show that human HC1 has a structure similar to integrin β-chains, with a von Willebrand factor A domain containing a functional metal ion-dependent adhesion site (MIDAS) and an associated hybrid domain. A comparison of the WT protein and a variant with an impaired MIDAS (but otherwise structurally identical) by small-angle X-ray scattering and analytical ultracentrifugation revealed that HC1 self-associates in a cation-dependent manner, providing a mechanism for HC·HA cross-linking and matrix stabilization. Surprisingly, unlike integrins, HC1 interacted with RGD-containing ligands, such as fibronectin, vitronectin, and the latency-associated peptides of transforming growth factor β, in a MIDAS/cation-independent manner. However, HC1 utilizes its MIDAS motif to bind to and inhibit the cleavage of complement C3, and small-angle X-ray scattering–based modeling indicates that this occurs through the inhibition of the alternative pathway C3 convertase. These findings provide detailed structural and functional insights into HC1 as a regulator of innate immunity and further elucidate the role of HC·HA complexes in inflammation and ovulation.

β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.

Sulfur is essential for biological processes such as amino acid biogenesis, iron–sulfur cluster formation, and redox homeostasis. To acquire sulfur-containing compounds from the environment, bacteria have evolved high-affinity uptake systems, predominant among which is the ABC transporter family. Theses membrane-embedded enzymes use the energy of ATP hydrolysis for transmembrane transport of a wide range of biomolecules against concentration gradients. Three distinct bacterial ABC import systems of sulfur-containing compounds have been identified, but the molecular details of their transport mechanism remain poorly characterized. Here we provide results from a biochemical analysis of the purified Escherichia coli YecSC-FliY cysteine/cystine import system. We found that the substrate-binding protein FliY binds l-cystine, l-cysteine, and d-cysteine with micromolar affinities. However, binding of the l- and d-enantiomers induced different conformational changes of FliY, where the l- enantiomer–substrate-binding protein complex interacted more efficiently with the YecSC transporter. YecSC had low basal ATPase activity that was moderately stimulated by apo FliY, more strongly by d-cysteine–bound FliY, and maximally by l-cysteine– or l-cystine–bound FliY. However, at high FliY concentrations, YecSC reached maximal ATPase rates independent of the presence or nature of the substrate. These results suggest that FliY exists in a conformational equilibrium between an open, unliganded form that does not bind to the YecSC transporter and closed, unliganded and closed, liganded forms that bind this transporter with variable affinities but equally stimulate its ATPase activity. These findings differ from previous observations for similar ABC transporters, highlighting the extent of mechanistic diversity in this large protein family.