Igor E. Shparlinski
Proc. Amer. Math. Soc. 148 (2020), 2371-2377.
Abstract, references and article information

Police today welcomed the Communications Authority’s decision that Radio Television Hong Kong (RTHK) should be seriously warned regarding complaints against an episode of its programme Pentaprism broadcast on November 20, 2019.

Police said it had taken note of the press release issued by the authority on April 20 about its decision.

The authority found that the host’s remarks made in the programme were irresponsible and could be regarded as hate speech with the effect of inciting hatred against Police.

The remarks were also unfair to and were capable of adversely affecting Police’s reputation.

The authority took the view that the complaints in respect of accuracy, incitement of hatred and fairness were substantiated and decided that RTHK should be seriously warned.

Since the anti-extradition bill protests in June last year, rumours have been circulating to defame and smear Police in an attempt to disrupt its relations with the community, the force said.

Police reiterated that they are willing to accept criticisms which are constructive and based on goodwill, but they do not accept inaccurate or misleading reports and remarks, and will follow up as appropriate.

With the novel coronavirus expected to further impact Hong Kong’s already slowing economy, the Hong Kong Trade Development Council (HKTDC) is working hand in hand with local small and medium-sized enterprises (SMEs) to brave the...

Chairman of the Hong Kong Trade Development Council (HKTDC) Dr Peter Lam welcomes the new 2020-21 Budget, including the additional HK$150 million funding to the HKTDC to help Hong Kong businesses find new opportunities and to help the...

petrapetruta posted a reply:

jacquesjacobs:


Hello there and welcome!We hope to see some catchy contribution from you too! :-)

Rémi de Valenciennes posted a reply:

Hello,
I'm Rémi from Lille (North of France). I think we need color nowadays !

petrapetruta posted a reply:

Rémi de Valenciennes:


I absolutely agree with you!
And welcome! :-)

Cigaleto posted a reply:

Hello, je suis Agnès de France. J habite en Provence, le pays des cigales et de la lavande. Un région pleine de couleurs.

Alex Borbely posted a reply:

Alex Borbely from the north shore of Lake Ontario, Canada! I have been doing mostly nature photography for just over a decade. Self taught and focus mainly on freezing movement! Be well and safe!
Alex

Banks and financial institutions taking part in providing mortgage loans for the Housing Authority Subsidised Sale Flats Scheme (SSFS) may offer a mortgage principal moratorium plan to the scheme’s mortgagors.

The authority today wrote to these institutions to confirm and agree that such a plan is applicable for SSFS flats.

Principal repayment may be deferred for a maximum 12-month period and the mortgage loan repayment period may be extended correspondingly by a maximum of 12 months.

The principal moratorium period may commence by December 31 this year at the latest.

The arrangement is applicable to the Home Ownership Scheme, the Private Sector Participation Scheme, the Buy or Rent Option Scheme, the Tenants Purchase Scheme and the Green Form Subsidised Home Ownership Scheme in the primary market and under the Secondary Market Scheme.

To encourage participating financial institutions to provide mortgage loans and better mortgage terms for SSFS flat purchasers, the authority provides a mortgage default guarantee for them.

It undertakes to meet the shortfall in repayment in the event of default by the borrowers under specified circumstances during the guarantee period.

Due to the requirements in the guarantee deed on the mortgage loan period and the monthly instalment amount, participating financial institutions may not be able to offer a mortgage principal moratorium plan to SSFS flat owners.

In light of the economic downturn arising from the COVID-19 outbreak, the authority confirmed today that a mortgage principal moratorium plan is applicable for SSFS flats.

The move will encourage participating financial institutions to offer such a plan to SSFS flat owners, reducing their burden of mortgage repayment.

Secretary for Education Kevin Yeung said all the examination centres for the Hong Kong Diploma of Secondary Education (DSE) Examination are well prepared to provide a very safe environment for candidates to take the exams.

Mr Yeung made the statement when asked by reporters this morning about the arrangements schools have made to prepare for the DSE to be held on April 24.

He said: “In terms of the distance between the seats, in terms of all the procedures for cleansing, and also the detailed arrangements including the toilet arrangement and other things, all the schools, all the examination centres, are well prepared to provide a very safe environment for our candidates to take the examinations.”

Regarding school resumption, Mr Yeung said the Government has not made any firm decision nor set any deadline for schools to resume classes.

Erika Leung
Aug 1, 2018; 31:245-253
From Research to Practice

John R. White
May 1, 2014; 27:82-86
From Research to Practice

Belinda S. O’Connell
Aug 1, 2001; 14:
Articles

Katherine S. O’Neal
Nov 1, 2016; 29:249-252
Pharmacy and Therapeutics

Samuel Dagogo-Jack
Jan 1, 2002; 15:
Articles

Property management companies and owners’ organisations which have successfully applied for an anti-epidemic support scheme were reminded today to disburse the hardship allowance to frontline workers as soon as practicable upon receiving the subsidies.

The Home Affairs Department said the workers concerned shall acknowledge receipt of the allowance using the prescribed forms.

The property management companies or owners’ organisations shall submit a report on the allowance’s overall payment to the Property Management Services Authority within three months of receiving the subsidies.

The department and/or the authority will conduct a random review and check to ensure that the frontline property management workers have received the allowance.

As of today, more than 8,160 applications have been received for the Anti-epidemic Support Scheme for Property Management Sector under the Anti-epidemic Fund.

About 2,850 applications have been approved, involving more than $100 million in subsidies and benefitting more than 17,500 building blocks and about 25,500 frontline workers.

Call 3696 1156 or 3696 1166 for enquiries.

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

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

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

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

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

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

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

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

Call 2343 2255 for enquiries about the scheme.

The partnership will join hands with four UK startups as it hopes to reduce plastic waste as part of its retail tech initiative, JLAB

DeepMind's cofounder and head of applied artificial intelligence, Mustafa Suleyman, has abruptly left the company for an indefinite period

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

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

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

Brief Biography of Karin Melnick:

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

About the Fellowship:

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

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

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.)

Below, Mac Hyman, Tulane University, talks about types of mathematical models--their strengths and weaknesses--the data that we currently have and what we really need, and what models can tell us about a possible second wave.

At the beginning of the video, he thanks the mathematics community for its work, and near the end says, "Our mathematical community is really playing a central role in helping to predict the spread, and help mitigate this epidemic, and prioritize our efforts. …Do not underestimate the power that mathematics can have in helping to mitigate this epidemic—-we have a role to play."

See the full set of videos on modeling COVID-19 and see media coverage of mathematics' role in modeling the pandemic.

The AMS is pleased to announce that Scott Hershberger has been chosen as the 2020 AMS Mass Media Fellow. Scott studied mathematics and physics at Washington University in St. Louis and will graduate in May 2020. He will be working at Scientific American this summer.

The Mass Media Science and Engineering Fellows program is organized by the American Association for the Advancement of Science (AAAS). This program is designed to improve public understanding of science and technology by placing advanced undergraduate, graduate and postgraduate science, mathematics and engineering students in media outlets nationwide. The fellows work for ten weeks over the summer as reporters, researchers, and production assistants alongside media professionals to sharpen their communication skills and increase their understanding of the editorial process by which events and ideas become news.

Now in its 45th year, this fellowship program has placed more than 700 fellows in media organizations nationwide as they research, write, and report today’s headlines. The program is designed to report science-related issues in the media in easy-to-understand ways so as to improve public understanding and appreciation for science and technology.

For more information on the AMS Mass Media Fellowship, visit the website.

(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.)

The relaxation of anti-epidemic measures is a step in the right direction, Chief Executive Carrie Lam said today.

Mrs Lam made the statement at a press conference this afternoon.

She said the Government will relax the requirement limiting group gatherings in public places to a maximum of four people. Starting from Friday, up to eight people can gather in public places.

"So raising the number from four to eight for the catering business and also for the prohibition against group gatherings under Cap 599G is not an exact science, but this is a step in the right direction of relaxation.

"Maybe in another 14 days’ time we will raise the number of eight to 10, to 12, to 15 and so on."

Regarding bars and pubs, Mrs Lam said these venues will be able to reopen but the Government will put in place requirements to prevent physical interactions.

"We have decided that perhaps to strike a pragmatic balance is to allow them to reopen for business but to put in far more stringent requirements."

Such requirements include no live music, band performances or dancing in bar premises.

"That would be another way to keep the social distance and prevent as much as possible physical interactions."

Click here for the latest measures.

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.

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.

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.

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.

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.

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 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.

The linear ubiquitin assembly complex (LUBAC) is an essential component of the innate and adaptive immune system. Modification of cellular substrates with linear polyubiquitin chains is a key regulatory step in signal transduction that impacts cell death and inflammatory signaling downstream of various innate immunity receptors. Loss-of-function mutations in the LUBAC components HOIP and HOIL-1 yield a systemic autoinflammatory disease in humans, whereas their genetic ablation is embryonically lethal in mice. Deficiency of the LUBAC adaptor protein Sharpin results in a multi-organ inflammatory disease in mice characterized by chronic proliferative dermatitis (cpdm), which is propagated by TNFR1-induced and RIPK1-mediated keratinocyte cell death. We have previously shown that caspase-1 and -11 promoted the dermatitis pathology of cpdm mice and mediated cell death in the skin. Here, we describe a reciprocal regulation of caspase-1 and LUBAC activities in keratinocytes. We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. HOIP processing impeded substrate ubiquitination in the NF-κB pathway and resulted in enhanced apoptosis. These results highlight a regulatory mechanism underlying efficient apoptosis in keratinocytes and provide further evidence of a cross-talk between inflammatory and cell death pathways.

ATP plays important roles outside the cell, but the mechanism by which it is arrives in the extracellular environment is not clear. Dunn et al. now show that decreases in cellular cholesterol levels mediated by the ABCG1 transporter increase ATP release by volume-regulated anion channels under hypotonic conditions. Importantly, these results may imply that cells that handle cholesterol differently might experience differential extracellular ATP release during hypotonicity.

Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA–based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel–dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling.