Maria Bras-Amorós and Julio Fernández-González
Math. Comp. 89 (2020), 2017-2030.
Abstract, references and article information

Pietro Mercuri and René Schoof
Math. Comp. 89 (2020), 1969-1991.
Abstract, references and article information

Roberto Ferretti and Michel Mehrenberger
Math. Comp. 89 (2019), 1783-1805.
Abstract, references and article information

Telehealth and GP service Babylon has rolled out a "COVID-19 Care Assistant" with a raft of features designed to help subscribers cope with symptoms during the pandemic, from the safety of their phone screen

Huai-Liang Chang and Mu-lin Li
Trans. Amer. Math. Soc. 373 (2020), 3669-3691.
Abstract, references and article information

Mahbub Alam and Anish Ghosh
Trans. Amer. Math. Soc. 373 (2020), 3357-3374.
Abstract, references and article information

Chief Secretary Matthew Cheung today chaired the fourth meeting of the Anti-epidemic Fund Steering Committee, during which the funding commitment for 33 measures under the second-round of the fund was approved.

The Legislative Council Finance Committee last Saturday approved a funding application of $137.5 billion, including an injection of $120.5 billion to the Anti-epidemic Fund to roll out the second round of measures to provide further assistance or relief to the public and enterprises hard hit by the current epidemic or affected by anti-epidemic measures.

Mr Cheung said: "The pandemic has caused an unprecedented impact on Hong Kong's economy and various sectors have been hard hit.

“The Government will take resolute and unprecedented measures to expeditiously relieve the imminent needs of the businesses and members of the public.

"To provide assistance and relief to relevant enterprises and members of the public as soon as possible, I have asked the bureaus and departments to implement the measures at full steam to address the pressing needs of the community promptly and achieve the effect of safeguarding jobs and supporting enterprises."

Separately, the Education Bureau said the Finance Committee’s approval of the funding application for the second round of the fund and other relief measures included a one-off interest-free deferral of loan repayment for two years to self-financing post-secondary institutions under the Start-up Loan Scheme, non-profit-making international schools and student loan repayers.

All borrowers of the Tertiary Student Finance Scheme - Publicly-funded Programmes, Financial Assistance Scheme for Post-secondary Students, Non-means-tested Loan Scheme for Full-time Tertiary Students, Non-means-tested Loan Scheme for Post-secondary Students and Extended Non-means-tested Loan Scheme will be offered an interest-free deferral of loan repayment from April 1 this year to March 31, 2022, including their loan instalments and interests.

The annual administrative fee of $180 charged on the non-means-tested loan repayers during the suspension period will be waived. The risk-adjusted-factor rate for setting the interest rate will also be maintained at zero.

Additionally, support for the construction sector will be enhanced.

The Development Bureau today said a one-off subsidy of $7,500 will be offered to each eligible construction worker.

More than 530,000 workers will benefit from the subsidy, including workers of construction sites as well as those registered under the Electrical & Mechanical Services Department, the Buildings Department, the Water Supplies Department and the Fire Services Department.

At the same time, a one-off subsidy will be provided to 30,000 construction-related enterprises, generally small-scaled, which cannot benefit from the first round of the Anti-epidemic Fund.

Each eligible contractor, specialist contractor, works contractor and supplier can receive a one-off subsidy of $20,000, while minor works contractors, registered contractors of electrical, gas, lift, escalator and fire service installation along with suppliers of construction-related machinery and equipment rental can receive $10,000 each.

About 600 consultant firms offering engineering, architectural and related professional services will receive a subsidy of $50,000 each to support professionals in the sector.

The Government will also provide a direct subsidy of $3 million to each non-profit-making organisation running the 10 projects under the Revitalising Historic Buildings Through Partnership Scheme, PMQ and the Energizing Kowloon East - Fly the Flyover Operation.

Priscilla Hollander
Jul 1, 2007; 20:159-165
Articles

Caroline Trapp
Feb 1, 2012; 25:38-44
Nutrition FYI

The coach and rail journey app has launched a new AI voice app for automated disruption alerts

Chief Secretary Matthew Cheung today chaired the Anti-epidemic Fund Steering Committee's fifth meeting to examine the implementation progress of the host of measures launched under the fund.

The committee noted the details of over 20 second-round relief measures have been announced since the Legislative Council Finance Committee approved the $120.5 billion injection to the fund on April 18.

Other measures will be launched as soon as possible to provide timely relief to the affected sectors and individuals. 

The committee also noted that the fund has paid out over $13 billion, and many businesses and members of the public have gradually received subsidies.

Mr Cheung said the measures aim to preserve employment and assist the self-employed, provide additional relief to those sectors hard hit by the pandemic and pave the way for the post-pandemic economic recovery. 

“We will continue to process applications and disburse subsidies as soon as possible to help businesses and members of the public tackle the challenges caused by the pandemic and to support enterprises, safeguard jobs and relieve people’s burden," he stressed. 

For the Retail Sector Subsidy Scheme which provides a one-off subsidy of $80,000 to eligible retailers, about 93,000 applications were received.

The committee was pleased to note that the scheme has been disbursing subsidies progressively and over $2.7 billion in subsidies have been approved so far, involving about 33,000 applications.

(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.

(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.

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

Chief Executive Carrie Lam today said because Hong Kong has not reported a local COVID-19 case for over two weeks and imported cases are low, some anti-epidemic measures can be lifted.

During a press conference, Mrs Lam outlined that unlike some European countries, Hong Kong did not need to go into lockdown to contain the spread of the disease.

“Hong Kong has never gone into a stage of a complete city lockdown. In some of the European countries where they practise a city lockdown, residents are simply not allowed to leave their homes, except for some very essential purposes. But we have never adopted that practice.

“And in fact, many renowned experts are now trying to study our situation - why does Hong Kong succeed in keeping the confirmed cases at a low level without drastic measures like a complete city lockdown. And I do think that is a very interesting topic for further research.”

Mrs Lam noted that the Government had adopted the “suppress and lift” strategy under which restrictions are implemented and lifted in accordance with the infection situation.

“The strategy that Hong Kong has been adopting - and advocated by some of our experts - is what we call a ‘suppress and lift strategy’.

“So in light of the number of confirmed cases and likelihood of the spread of the disease in the community, we will have to suppress in order to make sure that there will be no surge in the number of confirmed cases as we have seen in some neighbouring regions.

“When the situation of the infection stabilises, that is the time for lifting, that is, loosening a bit so that society can operate more normally, especially for the businesses and for individuals’ behaviour.”

The Chief Executive said the Government still needed to monitor the COVID-19 situation closely, even though it was in the stage of lifting restrictions.

“We are now right in the stage of lifting because we have not had a local case for 16 days already and the number of imported cases is very, very low.

“We are now quite confident that the system of testing and holding that we have put in place for all arrivals from overseas would enable us to control the number of imported cases. So this is a time for lifting and this afternoon we have announced a number of lifting measures.

“If the situation continues to stay at the current level - no local cases, very few imported cases - then at the end of the 14-day period, that is May 22, of course that would be the time for more relaxation.”

Mrs Lam added that if a local case suddenly surfaced, Hong Kong may have to go back to some suppression measures, which was why the Government had to monitor the situation closely so it could take the necessary and pertinent response measures.

"[W]hen the editors at Quanta Magazine invited me to host a podcast for them, I jumped at the chance...Through this podcast, I've been learning about the inner lives of some of the most intriguing mathematicians and scientists working today. [I]n every case, I wanted to know what makes them tick. I wanted to know why they do what they do, what they’ve discovered, and why it matters to them and to the world." Read "Why I'm Hosting The Joy of x Podcast," by Steven Strogatz, Quanta Magazine, January 14, 2020.

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.

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.

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.

β-1,3-d-Glucan is a ubiquitous glucose polymer produced by plants, bacteria, and most fungi. It has been used as a diagnostic tool in patients with invasive mycoses via a highly-sensitive reagent consisting of the blood coagulation system of horseshoe crab. However, no method is currently available for measuring β-1,6-glucan, another primary β-glucan structure of fungal polysaccharides. Herein, we describe the development of an economical and highly-sensitive and specific assay for β-1,6-glucan using a modified recombinant endo-β-1,6-glucanase having diminished glucan hydrolase activity. The purified β-1,6-glucanase derivative bound to the β-1,6-glucan pustulan with a KD of 16.4 nm. We validated the specificity of this β-1,6-glucan probe by demonstrating its ability to detect cell wall β-1,6-glucan from both yeast and hyphal forms of the opportunistic fungal pathogen Candida albicans, without any detectable binding to glucan lacking the long β-1,6-glucan branch. We developed a sandwich ELISA-like assay with a low limit of quantification for pustulan (1.5 pg/ml), and we successfully employed this assay in the quantification of extracellular β-1,6-glucan released by >250 patient-derived strains of different Candida species (including Candida auris) in culture supernatant in vitro. We also used this assay to measure β-1,6-glucan in vivo in the serum and in several organs in a mouse model of systemic candidiasis. Our work describes a reliable method for β-1,6-glucan detection, which may prove useful for the diagnosis of invasive fungal infections.

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.

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

(Michigan Medicine - University of Michigan) They know it's addictive. They know it's linked to dangerous lung diseases. And they know it delivers more nicotine than the cigarettes it's supposed to replace. But the social aspects of vaping drives young people to use Juul and other e-cigarettes, according to nearly two-thirds of teens and young adults in a new study. Less than 5% say the availability of fruity flavors drives use of e-cigarettes by members of their generation, and only 10% say addiction does.

Tenants of the EcoPark, country park refreshment kiosks and the Hong Kong Wetland Park will benefit from increased rental concessions for government premises.

To help tenants cope with the economic impact of the COVID-19 epidemic, rental concessions of government premises from April to September will be increased from 50% to 75%.

The Environment Bureau said tenants of the EcoPark, country park refreshment kiosks and the Hong Kong Wetland Park will receive additional rental concessions of about $3.6 million.

Together with the 50% rental concessions provided by the Government from last October to March, these tenants will receive concessions of more than $17 million within 12 months, the bureau said.

Meanwhile, tenants of the Hong Kong Wetland Park will receive a full rental waiver during the park’s closure.

(Carnegie Mellon University) A new study developed a model of regulation in which the probability of a stricter standard being enacted increased with the proportion of firms in an industry that could meet the standard. The study found that regulations that consider the proportion of firms that can meet the new standard can motivate the development of a new green technology more effectively than regulations that do not consider this factor.

(NIH/National Institute of Allergy and Infectious Diseases) A randomized, controlled clinical trial evaluating the safety and efficacy of a treatment regimen of the investigational antiviral remdesivir plus the anti-inflammatory drug baricitinib for COVID-19 has begun. The trial is now enrolling hospitalized adults with COVID-19 in the United States. The trial is expected to open at approximately 100 US and international sites. Investigators currently anticipate enrolling more than 1,000 participants. The National Institute of Allergy and Infectious Diseases is sponsoring the trial.

(St. Jude Children's Research Hospital) Funding will help expand collaboration across engineering and physical sciences to expand tools for studying pediatric diseases.

(Simon Fraser University) SFU professor Caroline Colijn’s research and data modelling to map the spread of COVID-19 in British Columbia has helped her procure funding from Genome B.C., a non-profit research organization that leads genomics innovation on Canada’s West Coast.