pe Property sales up 6.8% By www.news.gov.hk Published On :: Tue, 05 May 2020 00:00:00 +0800 The Land Registry recorded 4,866 sale and purchase agreements for all building units for registration in April, up 6.8% from March but 50.9% lower year-on-year. The total consideration for such agreements rose 7.1% from March to $38.4 billion, representing a 55.9% year-on-year decline. Of the agreements, 4,102 were for residential units in April, up 6% from March but 47.6% lower than the same month a year ago. The total consideration for residential units was $33.7 billion, up 6.2% compared with March and 51.9% lower year-on-year. There were 375,802 land register searches last month. Full Article
pe Land sharing scheme opens May 6 By www.news.gov.hk Published On :: Tue, 05 May 2020 00:00:00 +0800 The Development Bureau today announced that the Land Sharing Pilot Scheme will open for applications tomorrow to help unleash the development potential of qualified private land. The private land must be with consolidated ownership that is outside specified environmentally sensitive areas and not covered by the Government's development studies. In connection with the pilot scheme’s launch, the Chief Executive has appointed 10 members from a wide spectrum of sectors to a Panel of Advisors to offer independent opinions on the applications received and advise on the scheme's operation. Chaired by Dr David Wong, the panel members will serve a term of 3.5 years starting May 1. Secretary for Development Michael Wong said while government-led planning and land resumption remains the mainstream and continues to dominate its land creation agenda, the pilot scheme seeks to complement such efforts by tapping into market resources and efficiencies to boost both public and private housing in the short to medium term. Under the scheme, the Government will facilitate infrastructural improvements that will enhance the development intensity of the private lots under application. In return, the applicants are required to hand over part of the lots they own in the form of formed land that is capable of delivering at least 70% of the increased domestic gross floor area for public housing or Starter Homes developments intended by the Government. Each project under the scheme should be capable of delivering an increased domestic gross floor area of no less than 50,000 sq m in total and at least 1,000 additional housing units. The application period lasts for three years until May 5, 2023, subject to a cap of 150 hectares on the total area of private land to be approved. The development chief added that the Government’s target is to convert the agricultural lots into spade-ready sites ready for housing construction within four to 6.5 years from the time applications are received. Full Article
pe CS inspects DSE exam centre By www.news.gov.hk Published On :: Wed, 22 Apr 2020 00:00:00 +0800 Chief Secretary Matthew Cheung today visited Queen Elizabeth School to inspect the preparatory work of an examination centre for the Hong Kong Diploma of Secondary Education (DSE) Examination. Mr Cheung was briefed on anti-epidemic precautionary measures for candidates and examination personnel before they enter the centres. They will be required to wear masks, make health declarations, undergo temperature checks, disinfect the soles of their shoes and clean their hands with alcohol-based sanitiser. He then visited the school hall to understand the preparation required for an examination centre, such as disinfection and widening the distance between candidates’ seats to 1.8m as much as possible. The Chief Secretary also learnt about the arrangements for candidates during the sessional break and the use of washrooms to help ensure that social distancing is maintained. Mr Cheung was pleased to know that the Education Bureau had earlier distributed masks to candidates and made available about 200,000 bottles of alcohol-based sanitiser for candidates at examination centres. The bureau has also set fallback dates, should the DSE examination be halted if the epidemic situation worsens. He thanked the bureau, relevant government departments, the Examinations & Assessment Authority, principals, teachers and school staff for the additional work they have done to protect the candidates’ health and safety. He encouraged the some 50,000 candidates to tackle the examinations positively and optimistically and reminded them to heighten their anti-epidemic awareness and strictly follow examination arrangements. Additionally, Mr Cheung appealed to all employers to allow their staff to follow flexible working hours to divert passenger flows on public transport during the morning peak hours between 7am and 8am, thus enabling candidates to reach examination centres on time. Full Article
pe Non-Periodontal Oral Manifestations of Diabetes: A Framework for Medical Care Providers By spectrum.diabetesjournals.org Published On :: 2011-11-01 Beatrice K. GandaraNov 1, 2011; 24:199-205From Research to Practice Full Article
pe Type 1 Diabetes and Sleep By spectrum.diabetesjournals.org Published On :: 2016-02-01 Sarah S. FarabiFeb 1, 2016; 29:10-13From Research to Practice Full Article
pe Sleep Apnea in Type 2 Diabetes By spectrum.diabetesjournals.org Published On :: 2016-02-01 Jimmy DoumitFeb 1, 2016; 29:14-19From Research to Practice Full Article
pe Secondary Hyperparathyroidism and Chronic Kidney Disease By spectrum.diabetesjournals.org Published On :: 2008-01-01 Sarah TomaselloJan 1, 2008; 21:19-25Articles Full Article
pe Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach By spectrum.diabetesjournals.org Published On :: 2016-11-01 Brenna CholertonNov 1, 2016; 29:210-219From Research to Practice Full Article
pe Management of Type 1 Diabetes in Older Adults By spectrum.diabetesjournals.org Published On :: 2014-02-01 Ruban DhaliwalFeb 1, 2014; 27:9-20Research to Practice Full Article
pe Anti-Diabetes and Anti-Obesity Medications: Effects on Weight in People With Diabetes By spectrum.diabetesjournals.org Published On :: 2007-07-01 Priscilla HollanderJul 1, 2007; 20:159-165Articles Full Article
pe Management of Competitive Athletes With Diabetes By spectrum.diabetesjournals.org Published On :: 2005-04-01 W. Guyton HornsbyApr 1, 2005; 18:102-107Articles Full Article
pe Insulin Initiation and Titration in Patients With Type 2 Diabetes By spectrum.diabetesjournals.org Published On :: 2019-05-01 Ji ChunMay 1, 2019; 32:104-111Feature Articles Full Article
pe Hypertension Management in Diabetes: 2018 Update By spectrum.diabetesjournals.org Published On :: 2018-08-01 Pasquale PassarellaAug 1, 2018; 31:218-224From Research to Practice Full Article
pe Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes By spectrum.diabetesjournals.org Published On :: 2017-08-01 Deborah HinnenAug 1, 2017; 30:202-210Feature Articles Full Article
pe Drug-Induced Glucose Alterations Part 2: Drug-Induced Hyperglycemia By spectrum.diabetesjournals.org Published On :: 2011-11-01 Abdur RehmanNov 1, 2011; 24:234-238Pharmacy and Therapeutics Full Article
pe Vitamin D Deficiency and Type 2 Diabetes in African Americans: The Common Denominators By spectrum.diabetesjournals.org Published On :: 2011-08-01 Shani V. DavisAug 1, 2011; 24:148-153Feature Article/Vitamin D in African Americans Full Article
pe Case Study: A Patient With Type 2 Diabetes Working With an Advanced Practice Pharmacist to Address Interacting Comorbidities By spectrum.diabetesjournals.org Published On :: 2003-01-01 Peggy YarboroughJan 1, 2003; 16:Case Studies Full Article
pe Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome By spectrum.diabetesjournals.org Published On :: 2002-01-01 Guillermo E. UmpierrezJan 1, 2002; 15:Articles Full Article
pe Case Study: A Patient With Uncontrolled Type 2 Diabetes and Complex Comorbidities Whose Diabetes Care Is Managed by an Advanced Practice Nurse By spectrum.diabetesjournals.org Published On :: 2003-01-01 Geralyn SpollettJan 1, 2003; 16:Case Studies Full Article
pe Fixed-rate mortgage scheme opens By www.news.gov.hk Published On :: Tue, 05 May 2020 00:00:00 +0800 The Mortgage Corporation today announced that the pilot scheme for fixed-rate mortgages will start receiving applications from May 7. The aggregate loan amount of the Fixed-rate Mortgage Pilot Scheme is $1 billion, subject to a maximum loan amount of each private residential mortgage of $10 million. Financial Secretary Paul Chan said the pilot scheme, announced in the 2020-21 Budget, provides an alternative financing option to homebuyers for mitigating their risks arising from interest rate volatility, thereby promoting the development of the mortgage market in the long run. In response to the change in market interest rates, mortgage interest rates under the pilot scheme have been lowered, as compared to the levels previously announced in the Budget. The interest rates per annum for 10, 15 and 20 years are 2.55%, 2.65% and 2.75%. Mortgages under the pilot scheme will be offered through Bank of China, Chong Hing Bank, Dah Sing Bank, Industrial & Commercial Bank of China, Shanghai Commercial Bank, Standard Chartered Bank and The Bank of East Asia. At the end of the fixed-rate period, borrowers may either re-fix the mortgage rate under fixed-rate mortgages or convert the mortgage to a loan on a floating rate, which is the prime rate minus 2.35%. The pilot scheme will be effective until October 31. Full Article
pe Patrick Nip inspects public services By www.news.gov.hk Published On :: Tue, 28 Apr 2020 00:00:00 +0800 Secretary for the Civil Service Patrick Nip today visited the Transport Department (TD) and the Social Welfare Department (SWD) to learn more about the preparations made by both departments to resume public services. The Government announced that the resumption of public services will start from May 4 under a phased approach. While the TD will resume road tests on that day, written tests will resume on May 26. The SWD will also gradually resume the services of its Integrated Family Service Centres (IFSC). Mr Nip first visited the driving test centre in Ho Man Tin where he was briefed by the Commissioner for Transport Mable Chan on arrangements for the resumption of road tests and the implementation of infection control measures at driving test centres. Such measures will require candidates to wear surgical masks and undergo body temperature screening at entrances. As for the written tests, Mr Nip said he was pleased to learn that the TD will keep seats apart at appropriate distances and step up cleansing of computers at test centres. Mr Nip then visited the Causeway Bay Integrated Family Service Centre where he was briefed on the plan to gradually resume services at IFSCs and measures to reduce social contact. Mr Nip also learned that various infection control measures to safeguard the health of colleagues as well as service users will be put in place. For example, group activities will be conducted for no more than four participants and physical partitioning will be erected in meeting rooms for counselling services. Mr Nip emphasised that many people hope that the Government can provide more public services when the epidemic situation becomes stable. “I am pleased to learn that the departments have made all the necessary preparations for providing the services needed by the public while striving to safeguard public health. “Government departments will continue to maintain a high degree of vigilance and adopt all the necessary precautionary measures. The Government will also closely monitor the situation and determine when to embark on a full resumption of normal business.” Mr Nip expressed hope that the public will continue to fight the virus together with the Government. He also thanked civil servants for their commitment and dedicated efforts to serve the public during the epidemic. Full Article
pe How Onfido raised $100 million at the peak of a pandemic By www.techworld.com Published On :: Wed, 15 Apr 2020 09:01:00 GMT The UK-based digital identity specialist managed to raise a bumper round during the peak of the COVID-19 pandemic, and is looking at ways to apply its technology to help combat the global crisis Full Article
pe Expa launches UK office for European startups By www.techworld.com Published On :: Wed, 29 Apr 2020 12:00:00 GMT The US-based 'startup studio' will launched a London office to welcome European startups Full Article
pe Coach drivers scheme opens By www.news.gov.hk Published On :: Wed, 06 May 2020 00:00:00 +0800 The Tour Service Coach Drivers (Mainly Serving Tourists) Support Scheme, under the second round of the Anti-epidemic Fund, is open for applications from today to June 5, the Government announced. The scheme will provide each tour service coach driver with a one-off subsidy of $10,000 and aims to benefit about 9,300 drivers. In addition, the Government explained that the second round of the Anti-epidemic Fund includes other tourism industry support measures. Applications for the Hotel Sector Support Scheme are being accepted until May 18, while the deadline to apply for the Travel Agents & Practitioners Support Scheme is June 15. Click here for more details. Full Article
pe Modeling COVID-19: A new video describing the types of models used By www.ams.org Published On :: Thu, 30 Apr 2020 00:00:00 EST 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. Full Article
pe Perturbation de la Dynamique de Diffeomorphismes en Topologie (C^{1}) By www.ams.org Published On :: Sylvain Crovisier, University of Paris-Sud - A publication of the Societe Mathematique de France, 2013, 164 pp., Softcover, ISBN-13: 978-2-85629-764-3, List: US$67, All AMS Members: US$53.60, AST/354 This memoir deals with the dynamics of diffeomorphisms of compact manifolds. For the study of generic properties or for the construction of examples,... Full Article
pe Persistence of Stratifications of Normally Expanded Laminations By www.ams.org Published On :: Pierre Berger, Universite Paris 13 - A publication of the Societe Mathematique de France, 2013, 113 pp., Softcover, ISBN-13: 978-2-85629-767-4, List: US$45, All AMS Members: US$36, SMFMEM/134 This manuscript complements the Hirsch-Pugh-Shub (HPS) theory on persistence of normally hyperbolic laminations and implies several structural... Full Article
pe Transformations Birationnelles de Petit Degre By www.ams.org Published On :: Dominique Cerveau, Universite de Rennes 1, and Julie Deserti, Universite Paris 7 - A publication of the Societe Mathematique de France, 2013, 223 pp., Softcover, ISBN-13: 978-2-85629-770-4, List: US$108, All AMS Members: US$86.40, COSP/19 Since the end of the 19th century, we have known that each birational map of the complex projective plane is the product of a finite number of... Full Article
pe European Congress of Mathematics: Krakow, July 2-7, 2012 By www.ams.org Published On :: Rafal Latala, University of Warsaw, Andrzei Rucinski, Adam Mickiewicz University, Pawel Strzelecki, University of Warsaw, Jacek Swiatkowski, University of Wroclaw, and Dariusz Wrzosek and Piotr Zakrzewski, University of Warsaw, Editors - A publication of the European Mathematical Society, 2013, 824 pp., Hardcover, ISBN-13: 978-3-03719-120-0, List: US$128, All AMS Members: US$102.40, EMSEMC/2012 The European Congress of Mathematics, held every four years, has become a well-established major international mathematical event. Following those in... Full Article
pe Perspectives in Representation Theory By www.ams.org Published On :: Pavel Etingof, Massachusetts Institute of Technology, Mikhail Khovanov, Columbia University, and Alistair Savage, University of Ottawa, Editors - AMS, 2014, 370 pp., Softcover, ISBN-13: 978-0-8218-9170-4, List: US$126, All AMS Members: US$100.80, CONM/610 This volume contains the proceedings of the conference Perspectives in Representation Theory, held from May 12-17, 2012, at Yale University, in honor... Full Article
pe Spectra of Symmetrized Shuffling Operators By www.ams.org Published On :: Victor Reiner, University of Minnesota, Franco Saliola, Universite du Quebec a Montreal, and Volkmar Welker, Philipps-Universitaet Marburg - AMS, 2014, 109 pp., Softcover, ISBN-13: 978-0-8218-9095-0, List: US$76, All AMS Members: US$60.80, MEMO/228/1072 For a finite real reflection group (W) and a (W)-orbit (mathcal{O}) of flats in its reflection arrangement--or equivalently a conjugacy class of... Full Article
pe Pearls from a Lost City: The Lvov School of Mathematics By www.ams.org Published On :: Roman Duda, University of Wroclaw - Translated by Daniel Davies - AMS, 2014, approx. 216 pp., Hardcover, ISBN-13: 978-1-4704-1076-6, List: US$39, All AMS Members: US$31.20, HMATH/40 The fame of the Polish school at Lvov rests with the diverse and fundamental contributions of Polish mathematicians working there during the interwar... Full Article
pe Global and Local Regularity of Fourier Integral Operators on Weighted and Unweighted Spaces By www.ams.org Published On :: David Dos Santos Ferreira, Universite Paris 13, and Wolfgang Staubach, Uppsala University - AMS, 2013, 65 pp., Softcover, ISBN-13: 978-0-8218-9119-3, List: US$63, All AMS Members: US$50.40, MEMO/229/1074 The authors investigate the global continuity on (L^p) spaces with (pin [1,infty]) of Fourier integral operators with smooth and rough amplitudes... Full Article
pe Operator-Valued Measures, Dilations, and the Theory of Frames By www.ams.org Published On :: Deguang Han, University of Central Florida, David R. Larson, Texas A&M University, Bei Liu, Tianjin University of Technology, and Rui Liu, Nankai University - AMS, 2013, 84 pp., Softcover, ISBN-13: 978-0-8218-9172-8, List: US$65, All AMS Members: US$52, MEMO/229/1075 The authors develop elements of a general dilation theory for operator-valued measures. Hilbert space operator-valued measures are closely related to... Full Article
pe Semiclassical Standing Waves with Clustering Peaks for Nonlinear Schrodinger Equations By www.ams.org Published On :: Jaeyoung Byeon, KAIST, and Kazunaga Tanaka, Waseda University - AMS, 2013, 89 pp., Softcover, ISBN-13: 978-0-8218-9163-6, List: US$71, All AMS Members: US$56.80, MEMO/229/1076 The authors study the following singularly perturbed problem: (-epsilon^2Delta u+V(x)u = f(u)) in (mathbf{R}^N). Their main result is the... Full Article
pe On the Spectra of Quantum Groups By www.ams.org Published On :: Milen Yakimov, Louisiana State University - AMS, 2013, 91 pp., Softcover, ISBN-13: 978-0-8218-9174-2, List: US$71, All AMS Members: US$56.80, MEMO/229/1078 Joseph and Hodges-Levasseur (in the A case) described the spectra of all quantum function algebras (R_q[G]) on simple algebraic groups in terms of... Full Article
pe Water-splitting module a source of perpetual energy By www.eurekalert.org Published On :: Mon, 04 May 2020 00:00:00 EDT (Rice University) Rice University researchers have integrated high-efficiency solar cells and electrode catalysts into an efficient, low-cost device that splits water to produce hydrogen fuel. Full Article
pe CE inspects CuMask production By www.news.gov.hk Published On :: Wed, 06 May 2020 00:00:00 +0800 Chief Executive Carrie Lam inspected one of the CuMask production sites in Tsuen Wan today and expressed gratitude to those manufacturing the reusable masks for Hong Kong residents to fight against the COVID-19 epidemic. She chatted with the staff and noted that many of them are retired textile industry workers who have re-joined the production workforce to combat the virus. Mrs Lam praised them for their commitment to serving the community and thanked them for their hard work. The masks produced in the workshop will be delivered to a clean workspace for sterilising with ozone and packing before distribution. There is no need to wash the mask before it is used for the first time. In the face of the tight supply of masks amid the epidemic, the Government set aside funds to subsidise projects on technology applications of reusable masks under the first round of the Anti-epidemic Fund. The CuMask complies with the American Society for Testing & Materials F2100 Level 1 standard and can be washed up to 60 times. It can also be used for a longer period after replacing the filter. Mrs Lam said she is pleased to note that CuMask is well received by the public and the registration process has been very smooth. “CuMask is a home-grown scientific research achievement with local application. The whole process has involved co-operation between the Government, industry, academia and the research sector and is an outstanding example of the use of technology to improve people’s lives. “It will also help solve the problem of the supply of face masks during an epidemic in the long run. I highly commend all the people who have participated in the relevant work and I am fully confident in the development of innovation and technology in Hong Kong.” Mrs Lam appealed to the public to make use of the registration quota of up to six people to minimise delivery resources and enhance efficiency. She added that relevant departments will deliver the masks as soon as possible. Full Article
pe Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase [Metabolism] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
pe Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization [Glycobiology and Extracellular Matrices] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
pe Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
pe Evolution, expression, and substrate specificities of aldehyde oxidase enzymes in eukaryotes [Enzymology] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles. Full Article
pe Development of a novel {beta}-1,6-glucan-specific detection system using functionally-modified recombinant endo-{beta}-1,6-glucanase [Methods and Resources] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
pe The transcriptional regulator IscR integrates host-derived nitrosative stress and iron starvation in activation of the vvhBA operon in Vibrio vulnificus [Gene Regulation] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection. Full Article
pe A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function. Full Article
pe Structures of the MHC-I molecule BF2*1501 disclose the preferred presentation of an H5N1 virus-derived epitope [Protein Structure and Folding] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens. Full Article
pe Heterotrimeric Gq proteins as therapeutic targets? [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts. Full Article
pe ABC transporters control ATP release through cholesterol-dependent volume-regulated anion channel activity [Signal Transduction] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
pe Structural insight into the recognition of pathogen-derived phosphoglycolipids by C-type lectin receptor DCAR [Protein Structure and Folding] By www.jbc.org Published On :: 2020-04-24T06:08:45-07:00 The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs. Full Article
pe An enzyme-based protocol for cell-free synthesis of nature-identical capsular oligosaccharides from Actinobacillus pleuropneumoniae serotype 1 [Enzymology] By www.jbc.org Published On :: 2020-04-24T06:08:45-07:00 Actinobacillus pleuropneumoniae (App) is the etiological agent of acute porcine pneumonia and responsible for severe economic losses worldwide. The capsule polymer of App serotype 1 (App1) consists of [4)-GlcNAc-β(1,6)-Gal-α-1-(PO4-] repeating units that are O-acetylated at O-6 of the GlcNAc. It is a major virulence factor and was used in previous studies in the successful generation of an experimental glycoconjugate vaccine. However, the application of glycoconjugate vaccines in the animal health sector is limited, presumably because of the high costs associated with harvesting the polymer from pathogen culture. Consequently, here we exploited the capsule polymerase Cps1B of App1 as an in vitro synthesis tool and an alternative for capsule polymer provision. Cps1B consists of two catalytic domains, as well as a domain rich in tetratricopeptide repeats (TPRs). We compared the elongation mechanism of Cps1B with that of a ΔTPR truncation (Cps1B-ΔTPR). Interestingly, the product profiles displayed by Cps1B suggested processive elongation of the nascent polymer, whereas Cps1B-ΔTPR appeared to work in a more distributive manner. The dispersity of the synthesized products could be reduced by generating single-action transferases and immobilizing them on individual columns, separating the two catalytic activities. Furthermore, we identified the O-acetyltransferase Cps1D of App1 and used it to modify the polymers produced by Cps1B. Two-dimensional NMR analyses of the products revealed O-acetylation levels identical to those of polymer harvested from App1 culture supernatants. In conclusion, we have established a protocol for the pathogen-free in vitro synthesis of tailored, nature-identical App1 capsule polymers. Full Article