Donatella Danielli and Irina Mitrea, editors. American Mathematical Society, 2020, CONM, volume 748, approx. 210 pp. ISBN: 978-1-4704-4896-7 (print), 978-1-4704-5516-3 (online). This volume contains the proceedings of the AMS Special Session on Harmonic Analysis and Partial Differential Equations, held from April 21–22,...

Y. Genzmer and M. E. Hernandes
Trans. Amer. Math. Soc. 373 (2020), 3693-3707.
Abstract, references and article information

Time: 10:00 AM (Canceled/see notice), Location: E1.036 (Finance Room)

The challenges, for Hong Kong, are as much local as they are global. I know many of you are concerned about the recent social unrest here in Hong Kong, about whether it is affecting our financial market and whether there has been outflow of funds.

  

First of all, there's the obvious: Hong Kong is undergoing a time of unprecedented turbulence. Dissension has gripped our community for months now. That said, we are working to address and respond to those concerns, determined to find a path to peace, harmony and renewed prosperity in 2020.

 

We have been making progress. But there is still much to be done before we can put this testing time behind us.

 

Competitive advantages

What I can tell is that the advantages Hong Kong has long been recognised for are still very much with us, and they are not going anywhere anytime soon.

 

They begin with our enviable location, at the heart of Asia. Which means that Hong Kong is fully plugged into the round-the-clock global financial trading cycle. We provide certain and seamless connectivity with the financial hubs of Europe and North America, as well as those in the Middle East and across Asia.

 

Hong Kong is blessed with the dual advantages of "one country, two systems". The rule of law, an independent judiciary and an unshakable adherence to free enterprise are among Hong Kong's core values.

 

We offer businesses from the Mainland and all over the world - more than 9,000 at last count - a level-playing field, a competitive market, whatever their businesses, whatever their investments. Our linked exchange rate system remains solid, our currency fully convertible and capital flowing in and out freely, as enshrined in Article 112 of the Basic Law. Our capital markets are deep and liquid.

 

Despite our external and domestic challenges, Hong Kong's financial market remains stable. Our banking system continues to run smoothly and with ample liquidity.

 

The figures speak for themselves. In 2019, Hong Kong again topped the world in funds raised through IPOs - some US$40 billion worth. This is the seventh time we have come first in the past 11 years.

 

Our stock market's capitalisation is about US$4.9 trillion. That's more than 13 times Hong Kong's GDP.

 

As at end November 2019, bank deposits in both Hong Kong dollars and foreign currencies continued to increase over the same period last year, totalling US$1.8 trillion.

 

Our exchange rate remains stable. These and other measures reflect the integrity of Hong Kong's financial and legal system, the confidence it conveys, even as we face formidable external and domestic shocks.

 

In September last year, the Global Financial Centres Index once again ranked Hong Kong among the world's top three financial centres, behind only New York and bearing in on London.

 

Last October, the World Economic Forum's Global Competitiveness Report ranked our financial system top in the world, while the World Bank rated Hong Kong the third-easiest place to do business.

 

Hong Kong is still very much the largest offshore renminbi business hub in the world.

 

We are, as well, the premier asset and wealth management centre. Apart from exempting onshore and offshore funds from profits tax, we are considering introducing a more competitive tax arrangement to attract private equity funds to domicile in Hong Kong.  

 

The insurance industry is equally important. We have, after all, the highest concentration of insurers in Asia - more than 160 at the end of September. And we will enable the issuance of insurance-linked securities, expanding the insurable risks of captive insurers in Hong Kong.

 

On the taxes front, we already have the world's most business-friendly tax system, according to Paying Taxes 2020, a report produced by Pricewaterhouse Coopers and the World Bank. Still, we plan to provide tax relief to promote the development of marine insurance and the underwriting of specialty risks in Hong Kong.

 

Green finance is our policy priority going forward. Green bonds issued and arranged in Hong Kong increased over 200% to US$11 billion in 2018 as compared to the previous year.

 

That was followed by our inaugural government green bond issuance of US$1 billion last May. And we plan to issue more, and encourage more entities to arrange financing for their green projects right here in Hong Kong.

 

Fintech is another area where we strive to excel.

 

Looking at the big picture, the International Monetary Fund (IMF)'s latest projection of global economic growth this year has been adjusted downward to 3.4%. Growth in Asia, however, will continue to outperform the rest of the world.

 

The IMF forecasts the Mainland economy to grow by 5.8% in 2020, down slightly but still far and away leading most other jurisdictions.

 

Robust financial system

As for Hong Kong, the IMF Staff Report last month commended the resilience of our financial system and linked exchange rate, despite its slowing economy. The IMF's Hong Kong report noted, and I quote, that "robust policy frameworks and ample buffers will help the economy weather the challenges ahead".

 

The IMF also expressed approval for the Government's wide-ranging policies to support the economy and safeguard financial stability.

 

While we welcome the IMF's confidence in Hong Kong, I am prepared to roll out further relief measures as necessary.

 

We will also step up efforts to capitalise on emerging opportunities - not only from green finance and fintech but from the development of the Guangdong-Hong Kong-Macao Greater Bay Area and the Belt & Road Initiative, which demonstrates Hong Kong's uniqueness and irreplaceable position in the Mainland's national and economic development strategy.

 

Hong Kong is, and will remain, the business bridge between the Mainland and the rest of the world. Count on Hong Kong, as always, to be your partner, to help you build your business in the Mainland, throughout the Asian region and around the world. Count on Hong Kong to connect you with abundant capital and continuing opportunities.

 

Financial Secretary Paul Chan gave these remarks at the 13th Asian Financial Forum keynote luncheon on January 13.

It has been two months since the Hong Kong Special Administrative Region Government raised the COVID-19 response level to the highest level of “Emergency” on January 25. A month ago, I wrote an article titled “Continue Our Fight Determined to Win” to report on our anti-epidemic work in the first month. Today, I would like to review with you the developments of the epidemic and the Government’s responses over the past month, as well as make some urgent appeals.

 

Developments of the epidemic

 

In the period from mid-February to mid-March, the overall situation of the epidemic in Hong Kong was stable. There were almost no imported cases from the Mainland, and there were only single-digit new confirmed cases each day. If we exclude imported cases/cases with a travel history of Hong Kong residents and their close contacts, there were only sporadic local cases, and even zero local cases in 12 days. This shows that the whole community has a high awareness of disease prevention and has been vigilant in maintaining personal hygiene and social distancing, and the Government’s anti-epidemic measures have attained certain results.

 

However, as the disease is rapidly spreading overseas, the number of confirmed cases and the speed at which it increases are terrifying. The global number of confirmed cases reached 100,000 on March 6, exceeded 200,000 on March 18, and subsequently increased to 300,000 in just three days and to 400,000 today in another three days. Following the outbreak in Korea earlier, outbreaks occurred within a short time in places like Europe and the United States, with Italy and Spain becoming the most heavily hit regions.

 

 Cumulative number of confirmed cases in selected countries in Europe and America

 

 

Since there is a huge difference in the population of every country and region, considering the number of confirmed cases alone may not reflect the severity of the epidemic in different places. The incidence rate of infection per million population is therefore a common indicator:

 

Countries and regions

Cumulative no. of confirmed cases

Population (million)

Incidence rate (cases per million population)

Mainland China

81,218

1,435.0

56.6

Italy

69,176

60.5

1,144.1

United States of America

44,183

331.0

133.5

Spain

39,673

46.8

848.5

Germany

27,436

83.8

327.5

France

22,300

65.3

341.6

Korea

9,137

51.3

178.2

United Kingdom

8,077

67.9

119.0

Switzerland

8,015

8.7

926.1

Australia

1,709

5.5

309.7

Japan

1,193

126.5

9.4

Singapore

558

5.9

95.4

Hong Kong

387

7.5

51.6

Taiwan

216

23.8

9.1

Macau

30

0.65

46.2

(Figures as at March 24)

From the chart and table above, we can actually see that Hong Kong’s situation is better than quite a number of regions in Europe, America and Asia Pacific. During discussions and in literature regarding this disease, I always hear experts say that the Government should strive to flatten the curve. From the chart below, we can see that the curve for Hong Kong, before rising almost linearly in the recent ten days due to the large increase in imported cases, was quite flat. Yet, this relatively stable situation has changed since mid-March, which is worrying. 

 

Cumulative number of confirmed cases in Hong Kong

 

 

Due to the escalating epidemic and the gradual suspension of local universities and boarding schools in Europe and the United States, a large number of Hong Kong residents and students studying abroad returned to Hong Kong. This wave of return to Hong Kong led to a great increase in imported cases. In the past 14 days, close to 90% of confirmed cases (233 cases in total) either have been abroad or are close contacts of these confirmed cases. Just Hong Kong residents studying in the United Kingdom account for 28 confirmed cases.

 

The expert advisory panel of the Government’s Steering Committee & Command Centre pointed out that although the drastic increase in number of cases is worrying, Hong Kong can still contain the epidemic as long as we step up the containment strategy adopted previously and have the support of the general public.

 

Anti-epidemic efforts

 

The inter-departmental Steering Committee & Command Centre chaired by me has remained vigilant over the past month. During the time when the infection situation was rather stable, we still kept a close watch on the developments of the epidemic in the local community and in other places of the world. We also made use of the opportunity to make necessary preparations for future anti-epidemic work. These include enhancing community surveillance through free virus tests, providing more isolation and quarantine centres, increasing the production and procurement of surgical masks and other personal protective equipment, and implementing over 20 initiatives under the Anti-epidemic Fund to support the sectors and members of the public hard hit by the epidemic. In the first half of March when the epidemic became more serious, we acted promptly and implemented numerous measures to cope with the situation within a short period of time.

 

Major measures implemented by the Government to respond to the developments of the epidemic in the past month are set out in the following table.

 

Date

Event

February 28

Issuing the Red Outbound Travel Alert (OTA) on three regions in Italy, and issuing quarantine orders to people arriving in Hong Kong who have been to the above three regions or to Iran where the Red OTA remains in force in the past 14 days (regardless of whether they are Hong Kong residents) starting from March 1.

February 28

The Hospital Authority (HA) extended the Enhanced Laboratory Surveillance Programme to cover patients below 18 years old and those with fever or respiratory symptoms subject to clinical assessment of physician in charge.

March 2

Government bureaus/departments gradually resumed more public services with the implementation of targeted measures to reduce social contact and infection control measures.

March 4

Hong Kong residents returning to Hong Kong from the Diamond Princess cruise ship in Japan  completed quarantine by batches. Nine of them were confirmed to be infected after returning to Hong Kong.

March 4-5

Sending four chartered flights to bring back a total of 469 Hong Kong residents stranded in Hubei Province to Hong Kong, and arranging them to stay in a quarantine centre.

March 8

Expanding the health declaration arrangements at the Hong Kong International Airport from inbound flights from the Mainland to all flights arriving in Hong Kong.

March 9

The Centre for Health Protection (CHP) extended the Enhanced Laboratory Surveillance Programme to cover all private clinics and hospitals.

March 10

Issuing the Red OTA on some regions in France, Germany, Japan and Spain as well as on the entire country of Italy, and issuing quarantine orders to people arriving in Hong Kong who have been to the above regions or countries in the past 14 days (regardless of whether they are Hong Kong residents)
starting from March 14.

March 13

Issuing the Red OTA on 26 European countries in the Schengen Area, and issuing quarantine orders to people arriving in Hong Kong who have been to the above countries in the past 14 days (regardless of whether they are Hong Kong residents) starting from March 17.

March 13

Announcing adjustments to the health quarantine arrangements on inbound travellers from overseas to reserve more quarantine facilities for the close contacts of confirmed cases.

March 14

Following three confirmed cases in Heng Tai House, Fu Heng Estate in Tai Po, some residents had to be evacuated to quarantine centres. Four environmental samples tested positive later.

March 15

Issuing the Red OTA on Ireland, the United Kingdom and the United States, and issuing quarantine orders to people arriving in Hong Kong who have been to the above countries or to Egypt where the Red OTA remains in force in the past 14 days (regardless of whether they are Hong Kong residents) starting from March 19.

March 17

Issuing the Red OTA on all overseas countries/territories and issuing quarantine orders to people arriving in Hong Kong who have been to the above countries/regions in the past 14 days (regardless of whether they are Hong Kong residents) starting from March 19.

19 March

Hong Kong residents returning to Hong Kong from Hubei Province completed quarantine by batches. Only one of them was confirmed to be infected.

March 19

The CHP extended the Enhanced Laboratory Surveillance Programme to cover inbound travellers under quarantine from overseas. Priority was accorded to persons under quarantine aged 65 or above or persons under quarantine residing with elderly aged 65 or above.

March 19

To handle a large number of people arriving in Hong Kong via the Hong Kong International Airport, the HA established test centres at the AsiaWorld-Expo and North Lantau Hospital. People arriving in Hong Kong with upper respiratory symptoms will undergo virus tests and wait for the laboratory results there. Subject to the test results, they will be admitted to hospital or subject to home quarantine.

March 20

The Immigration Department closely monitored anti-epidemic measures implemented by the Moroccan authorities and rendered assistance to Hong Kong residents stranded in the country.

March 21

Announcing enhanced measures to control the disease, which include:

The HA and the DH will fully utilise all resources for testing and enhance testing for people returning to Hong Kong from overseas; Resuming the special work arrangements for civil servants implemented before March 2 to provide limited-scale public services; Deferring the Hong Kong Diploma of Secondary Education examination; Stepping up enforcement actions against contravention of quarantine orders; Strengthening disease prevention at residential care homes for the elderly and people with disabilities.

March 21

Announcing adjustments to the health quarantine arrangements on people arriving in Hong Kong from Hubei Province (except Wuhan) to reserve more quarantine facilities for the close contacts of confirmed cases.

March 23

Announcing more anti-epidemic measures, which include:

Starting from March 25, all non-Hong Kong residents coming from overseas countries and regions by plane will be denied entry to Hong Kong; non-Hong Kong residents coming from the Mainland, Macau and Taiwan will be denied entry to Hong Kong if they have been to any overseas countries and regions in the past 14 days; all transit services at Hong Kong International Airport will be suspended; and all travellers coming from Macau and Taiwan will be subject to compulsory quarantine; Stepping up virus testing for arriving persons from the United Kingdom, other countries in Europe and the United States; Taking stringent enforcement actions to combat breaches of quarantine orders; Strengthening social distancing measures, including a proposal to introduce legislation to temporarily prohibit the sale and supply of alcoholic drinks by restaurants, bars and clubs.

March 24

Stepping up enforcement against breaches of quarantine orders and appealing to the public to make use of the “e-Report Room” online platform to report breaches.

March 25

Sending the second batch of chartered flights to take Hong Kong residents stranded in Hubei Province back to Hong Kong.

 

We have adhered to the people-oriented principle throughout our anti-epidemic work and have proactively supported Hong Kong people affected by the epidemic. For example, we overcame all kinds of challenges to bring back Hong Kong people stranded in Hubei Province by batches; we sent a special team comprising immigration officers and healthcare officers to take care of the Diamond Princess cruise ship passengers who stayed in Japan to receive medical treatment; and we provided support to Hong Kong residents who were stranded in Morocco and Peru. We also exercised discretion to extend the stay of carers on two-way permit in Hong Kong and prioritised the handling of Speedpost items containing surgical masks. We co-operated with the Hong Kong Federation of Trade Unions to deliver prescription medications to Hong Kong people in the Mainland and introduced a flexible arrangement to extend the validity period of the contracts of foreign domestic helpers, etc.

 

We have also continued to uphold the principle of operating in an open and transparent manner in our anti-epidemic efforts. Through the daily press conferences by the CHP and the HA, media sessions by the Chief Executive and secretaries of departments and directors of bureaus, the designated website “coronavirus.gov.hk”, the Facebook pages of the CHP and “Tamar Talk”, the Interactive Map Dashboard, social media and more, we provide the public with the latest information on the disease and clarify rumours. The Interactive Map Dashboard is very popular and has attracted about 16 million views since its launch.

 

Fighting the virus together

 

In the face of the severe situation of the epidemic, I would like to once again thank all the healthcare and government anti-epidemic officers (including auxiliary forces, retired civil servants and volunteers) who fight the disease at the forefront. I would like to also thank the four professors on the expert advisory panel and the research and development teams of universities and innovation and technology companies for making suggestions on the prevention and control of the disease as well as our citizens who have put up with the inconvenience in their daily lives to safeguard Hong Kong. All of them are our anti-epidemic heroes. The governing team and I will stay committed to our duties, remain calm and stay vigilant in our fight against the disease.

 

To win the battle against the disease, the continuous support and co-operation of every Hong Kong citizen are of the utmost importance. We believe that a large number of Hong Kong citizens will continue to come back Hong Kong in the following weeks because of the worsening situation overseas and hence confirmed cases will inevitably continue to increase. The situation will be more severe and difficult to handle than any period in the past two months and may even lead to large-scale and a continuous outbreak in the community. This is a critical moment in the fight against the disease and also a moment for testing the resilience of Hong Kong people in the face of the epidemic.

 

Fighting the virus is a long battle and the process is arduous. It is not easy to stay at home for a long period of time without normal activities and social interactions, but it is definitely not the time to let our guard down, otherwise the hard efforts of Hong Kong citizens in the past two months will be undone and the consequences could be dire. I appeal to all members of the public to continue to fight the disease together. I have no doubt that as long as we stay united, work together and support each other, Hong Kong will finally win the battle against the disease.

 

Chief Executive Carrie Lam issued this article "Two Months into Our Fight, Continue to Stay Vigilant" on March 25.

The onset of COVID-19 has severely affected our economy and the legal sector was not spared. I have discussed with some of the representatives from the industry and we have carefully considered their suggestions with relevant government departments.

 

On Wednesday, the Government announced another package of measures to support individuals and businesses affected by COVID-19. Two of the measures are relevant to the legal sector: the establishment of LawTech Fund and the COVID-19 Online Dispute Resolution (ODR) Scheme. Today, I would like to share with you the arrangement of the LawTech Fund.

 

The Government always attaches great importance to LawTech. In her 2018 Policy Address, the Chief Executive supported the development of an online platform by non-government organisations to facilitate the provision of efficient and cost-effective online dispute resolution services in Hong Kong. The Government would allocate funding for the development of this project.

 

At the Ceremonial Opening of the Legal Year 2019, I emphasised the importance of making use of technology in providing legal services, citing the United Nations General Assembly in 2016 in observing that online dispute resolution "can assist the parties in resolving the dispute in a simple, fast, flexible, and secure manner, without the need for physical presence at a meeting or hearing". The Asia-Pacific Economic Cooperation had responded to the call and embarked on a project to establish an ODR framework with micro, small and medium-sized enterprises as major beneficiaries.

 

Almost 18% of the annual caseload of the courts at all levels have been affected in the first two months of the General Adjourned Period since January 29. The Judiciary has earlier started using video-conferencing facilities for remote hearings on suitable civil cases at the High Court. The media reported the first hearing conducted through video-conferencing, quoting the legal representatives of both parties being supportive of the Judiciary's new measures in view of the low cost and smooth operation.

 

Given the severe impact brought by COVID-19, the Judiciary has been exploring the use of various technological means in conducting different types of hearings to address the growing backlog of cases caused by the postponement of hearings. The legal sector should also take this opportunity to review the wider use of LawTech and enhance their technological capability. The Government introduced the LawTech Fund, which aims to assist some small and medium size law firms/barristers' chambers in procuring and upgrading information technology systems (such as video-conferencing facilities) and attending LawTech training courses. This will be conducive to the promotion of use of technologies in the provision of legal services.

 

Under the scheme, law firms and chambers with not more than five practicing lawyers are eligible for application. Each firm/chamber will be eligible for a reimbursable amount of up to $50,000. Application for the fund will be jointly administered by the Law Society of Hong Kong and the Hong Kong Bar Association. The details will be announced soon and the fund will be opened for application next month.

 

Other measures announced by the Government include: Enhancement of SME Financing Guarantee Scheme, Employment Support Scheme under which the Government will provide wage subsidy to eligible employers to retain employees (details will be available soon), as well as the creation of some time-limited jobs by the Department of Justice.

 

Government measures alone, however, would not be adequate. We must all stand united in solidarity to fight the virus and support Hong Kong.

 

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on April 11.

Recipients of the Individual-based Work Incentive Transport Subsidy (I-WITS) will receive a one-off extra allowance after the passage of the Appropriation Bill 2020, the Government announced today.

 

The extra allowance was proposed in the 2020-21 Budget and would be disbursed one month after the bill’s passage at the earliest.

 

Eligible recipients are those whose I-WITS applications were made in the applicable period - from the first day of the month in which the bill is passed to the date of the bill’s passage, and six calendar months before that month.

 

New applicants or previous I-WITS recipients who have yet to submit applications in the applicable period should do so on or before the date of the bill’s passage to be eligible for the extra allowance.

 

The extra allowance will be the average monthly amount of approved months payable to the applicants in their I-WITS applications which were most recently submitted in the applicable period and eventually approved.

 

Click here for details.

Carla E. Cox
Aug 1, 2017; 30:157-160
From Research to Practice

Howard Craig Zisser
Apr 1, 2007; 20:85-89
Articles

Peggy Yarborough
Jan 1, 2003; 16:
Case Studies

Geralyn Spollett
Jan 1, 2003; 16:
Case Studies

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.

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

David J. Benson, University of Aberdeen, Henning Krause, University of Bielefeld, and Andrzej Skowronski, Nicolaus Copernicus University, Editors - A publication of the European Mathematical Society, 2013, 378 pp., Hardcover, ISBN-13: 978-3-03719-125-5, List: US$98, Institutional Member: US$78.40, All Individuals: US$78.40, EMSSCR/9 This volume presents a collection of articles devoted to representations of algebras and related topics. Dististinguished experts in this field...

(University of Southampton) Scientists have published highly detailed images of lab-grown neurons using Extreme Ultraviolet radiation that could aid the analysis of neurodegenerative diseases.

(DGIST (Daegu Gyeongbuk Institute of Science and Technology)) A drug-loaded microrobotic needle effectively targets and remains attached to cancerous tissue in lab experiments without needing continuous application of a magnetic field, allowing more precise drug delivery. The details were published by researchers at DGIST's Microrobot Research Center in Korea and colleagues in the journal Advanced Healthcare Materials.

(Lancaster University) Lancaster University's Dr Samuli Autti has been awarded a Young Scientist Prize 2020 by the International Union of Pure and Applied Physics. The prestigious prize, awarded only once every three years, was made by the Low Temperature Commission of the IUPAP.

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.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

Mammalian cytochrome P450 enzymes often metabolize many pharmaceuticals and other xenobiotics, a feature that is valuable in a biotechnology setting. However, extant P450 enzymes are typically relatively unstable, with T50 values of ∼30–40 °C. Reconstructed ancestral cytochrome P450 enzymes tend to have variable substrate selectivity compared with related extant forms, but they also have higher thermostability and therefore may be excellent tools for commercial biosynthesis of important intermediates, final drug molecules, or drug metabolites. The mammalian ancestor of the cytochrome P450 1B subfamily was herein characterized structurally and functionally, revealing differences from the extant human CYP1B1 in ligand binding, metabolism, and potential molecular contributors to its thermostability. Whereas extant human CYP1B1 has one molecule of α-naphthoflavone in a closed active site, we observed that subtle amino acid substitutions outside the active site in the ancestor CYP1B enzyme yielded an open active site with four ligand copies. A structure of the ancestor with 17β-estradiol revealed only one molecule in the active site, which still had the same open conformation. Detailed comparisons between the extant and ancestor forms revealed increases in electrostatic and aromatic interactions between distinct secondary structure elements in the ancestral forms that may contribute to their thermostability. To the best of our knowledge, this represents the first structural evaluation of a reconstructed ancestral cytochrome P450, revealing key features that appear to contribute to its thermostability.

VOLUME 292 (2017) PAGES 3531–3540This article has been withdrawn by Shuofeng Hu, Xiaomin Ying, Xiangming Zhang, and Ya Wang. Baocheng Hu, Xiang Wang, Ping Wang, Jian Wang, and Hongyan Wang could not be reached. In Fig. 1C, the DAPI and merged images for the no IR control were switched. The DNA-PKcs and actin immunoblots on the left appear to have been spliced. In Fig. 4C, the DNA-PKcs immunoblot appears to have been spliced. In Fig. 4D, lanes 1 and 5; lanes 2, 6, and 8; and lanes 3 and 7 of the DNA-PKcs immunoblot are the same. In the p-DNA-PKcs immunoblot, lanes 1 and 8, lanes 2 and 6, and lanes 3 and 7 are the same. In the CRY2 immunoblot, lanes 5 and 7 are the same. In the CDC25A immunoblot, lanes 3 and 8 are the same. In the GSK3B immunoblot, lanes 1 and 5 and lanes 3 and 7 are the same. Also in the GSK3B immunoblot, the upper GSK3B bands in lanes 6 and 8 are the same. Lanes 4 and 8 of the cyclin D1 immunoblot are the same. In Fig. 5A, the CDC25A immunoblot appears to have been spliced. Also in Fig. 5A, lanes 2–4 and lanes 6–8 of the CDC25A immunoblot are the same. Lanes 4–6 and 7–9 of the actin immunoblot are the same. In Fig. 5C, lane 1 of the CDC25A immunoblot was reused in lane 5, and lanes 3 and 4 were reused in lanes 7 and 8. In the...

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.

(Institute for Operations Research and the Management Sciences) Job performance has long been understood to be the primary equalizing factor affecting promotions for men and women in the workplace, but research shows, women don't gain as much from the same performance improvements as men do. New research in the INFORMS journal Information Systems Research shows training plays an important part in promotions for women in the field of information technology.