The project includes two "global technology firsts" resulting in an energy-positive building and an unrivalled carbon footprint the imperative ‘adapt to survive’ has never seemed so urgent While musicians and audiences are exploring the affordances of various livestream platforms to satisfy their collective yen for live performance what will become of the precarious community of venues who provide a network of jazz-friendly oases across the UK Without the enthusiasm and dedication of local promoters and the indulgence of sympathetic landlords there won’t be much of a live circuit to return to once conditions return to some version of what we used to call normality: how can they migrate to the digital world as a survival strategy Sheffield’s Jazz At The Lescar is just such an enterprise and tonight they’re presenting us with a possible solution They’ve joined forces with highly-rated pianist Sam Leak to bring us a solo recital from Sam’s personal isolation in his living room but streamed via a Facebook livestream event set up by the Lescar promoted to its regular patrons (but available to everyone) and accessed after paying an ‘entry fee’ to the Lescar itself There’s a pre-recorded welcome from promoter Jez Matthews and even a post-gig raffle to replicate the ‘in-real-life’ (IRL) experience as closely as possible Sam appears on the event page punctually at 8pm seated at the piano in front of a set of fairy lights artfully deployed to provide a sense of occasion The wide-ranging set demonstrates his adventurous genre-crossing musical sensibility with a surprise at every turn and no source of inspiration off-limits: a chiming right hand figure hovering above a set of plangent descending chords resolves into a reading of The Verve’s ‘Bittersweet Symphony’ which then mutates via a thunderous tremolo into a ballad rendition of the Kink’s ‘Waterloo Sunset’ Leak’s stark harmonies eschew any hint of muzak-y sentimentality and the song’s mournful cadences make for perfect isolation listening There’s a pensive Ingrid Laubrock-inspired deconstruction of the jam session favourite ‘Beatrice’ which leads naturally into a direct tribute to John Taylor via one of the master’s compositions with the harmony slowly shifting and blurring into chords like massed clouds drifting overhead By contrast the venerable standard ‘How About You’ gets a sprightly swinging outing with fluid single note lines bouncing off a lattice of finely meshed left hand figures and ‘Berkshire Blues’ swings just as hard in a joyous interpretation full of melody There’s a reworking of Britten via Jeff Buckley that segues naturally into a Mehldau tune and an original by Sam ­– an un-named Taylor-esque musing that develops over a lilting ostinato then breaks down into an impressionistic fog of harmonic shading ‘If I Should Lose You’ is a perfect finale balanced between a hopeful swing and a bittersweet melancholy The experiment is an artistic success – let’s hope it points the way to a commercial one as well Metrics details chemotherapy remains crucial to prevent and treat malaria Given its key role in haemoglobin degradation falcilysin constitutes an attractive target we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815 an investigational new drug with potent antimalarial activity we determine two binary complexes of falcilysin in a closed state bound with peptide substrates from the haemoglobin α and β chains respectively An antiparallel β-sheet is formed between the substrate and enzyme accounting for sequence-independent recognition at positions P2 and P1 numerous contacts favor tyrosine and phenylalanine at the P1’ position of the substrate Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state These structures give atomic level pictures of the proteolytic cycle in which falcilysin interconverts between a closed state conducive to proteolysis and an open conformation amenable to substrate diffusion and products release MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition These data should inform the design of potent inhibitors of falcilysin to combat malaria FLN first adopts an open conformation allowing substrate diffusion into its large catalytic chamber the protease adopts a closed state conducive to substrate proteolysis The detailed molecular features of this cycle are not known for FLN and genetic evidence points to a degree of involvement of FLN in the mechanism of action of MK-4815 in killing the parasite Given FLN essentiality in the parasite life cycle FLN appears as a promising drug target against malaria although no drug specifically targeting this enzyme is available yet Here we decided to explore how MK-4815 and quinoline drugs inhibit FLN using a combination of structural methods The data reveal at the atomic level (i) how FLN recognizes its hemoglobin peptide substrates (ii) structural changes that occur during the catalytic cycle and (iii) suggest a mechanism for how MK-4815 and—by analogy quinolines—inhibit the proteolytic activity of FLN A FLN in complex with the hemoglobin α-peptide Residues K40 to P44 could be built with confidence and are displayed as sticks colored in orange B FLN in complex with the hemoglobin β-peptide Overlayed are Fo–Fc electron density difference Fourier maps where the peptides were omitted from calculation and zinc-coordinating residues as cyan sticks The N-terminus and C-terminus of FLN are labeled in bold The N-terminal half of FLN is colored in cyan its C-terminal half in green; linker connecting the two halves is blue C magnified views of the α- and β-peptides with the “omit” electron density maps calculated as in panels (A) and (B) D Superposition of FLN-MK-4815 complex structure (PDB accession code: 7DIJ) with the FLN-α- and β-peptide complex structures Distances between the drug and each peptide are indicated E Display of FLN electrostatics molecular surface for its N-half and C-half Peptide substrate from hemoglobin α chain and MK-4815 are shown as sticks and zinc ion as a gray sphere these oppositely charged surfaces are likely to help bring together the N-half and C-half of the enzyme to form a closed state capable of fully encasing the peptide substrate This observation rules out direct competition between the inhibitor and substrate and indicates an allosteric mode of inhibition A Amino-acid sequence alignment of the hemoglobin α- and β-peptides Residues that could be built in clear electron density are colored in orange and purple for the α- and β-peptide respectively Vertical arrows indicate proteolytic cleavage site by FLN Substrate positions having either conserved or chemically similar amino acids are shown in bold C Detailed view of the interactions between FLN and the hemoglobin α-peptide (B) and β-peptide (C) Hydrogen bonds are displayed as yellow dashes; cation–π and π–π interactions as black dashes; salt bridge: orange dash; zinc-coordination: purple dashes and Y42 of α-peptide (panel B) and residues Q39 and F41 of β-peptide (panel C) form a β-strand antiparallel to strand β5 of FLN E Magnified view of the active site with tetrahedral coordination of the zinc ion The fourth coordinating atom is a water molecule (red sphere) in the α-peptide complex (panel D) and a carbonyl oxygen in the β-peptide complex (panel E) Distances in Å between the carbonyl carbon of the scissile bond and Q132 are labeled in gray F Superimposition of complexes between the FLN and α-peptide and the FLN- β-peptide complex The overlay was based on the C-half of FLN N-half domains are shown as molecular surfaces colored in cyan (α-peptide complex) and gray (β-peptide complex) The linker and C-halves are shown as ribbons FLN adopts a slightly more closed conformation when bound with the β-peptide (“C2”) than in the α-peptide complex (“C1”) The slightly more closed conformation in the β-peptide complex is accompanied by a shift in the position of the zinc ion toward the β-peptide further demonstrating the essential roles of N161 and R1043 in stabilizing the interaction between FLN and the α- and β-peptides we found that the “C2” conformation was only observed in a free FLN structure (PDB accession code: 3S5K) while the “C1” conformation was observed in several FLN crystal structures including free FLN structures (PDB accession codes: 3S5I 3S5M) and FLN-inhibitor complexes (PDB accession codes: 7VPE the biological relevance of the existence of two closed conformations in various crystal structures of FLN remains uncertain through a comparison between the FLN-α and β-peptide complexes we found that an apparently minor overall conformational difference between the “C1” and “C2” states is accompanied by a significant difference in zinc coordination network at the FLN active site: In the catalytic mechanism of mono-metallic peptidases direct binding of the carbonyl oxygen from the scissile bond to zinc is essential for Michaelis complex formation The zinc ion helps to polarize the oxygen atom so that the carbonyl carbon becomes susceptible to nucleophilic attack by a solvent molecule the “C2” state observed in the β-peptide complex likely represents a catalytically active closed state of FLN while the “C1” state observed in the α-peptide complex possibly constitutes an inactive closed state because the zinc is not directly coordinated by the carbonyl oxygen of the scissile peptide bond Having observed two distinct closed conformations “C1” and “C2” in FLN-hemoglobin peptide binary complexes We also examined the impact of the allosteric inhibitor MK-4815 on the distribution of FLN molecules adopting either open or closed states A Raw micrograph and 2D classes of free FLN particles B Raw micrograph and 2D classes of MK-4815-treated FLN particles C Falcilysin 3D reconstructions in the absence of MK-4815 A majority of FLN particles are in the open conformation and a minority are in the partially closed (“pC”) conformation FLN structures are colored in “rainbow colors” from N- (blue) to C-terminal end (red) with transparent cryo-EM electron density maps overlaid D Falcilysin 3D reconstructions in the presence of MK-4815 A majority of FLN particles adopt the partially closed conformation (“pC”) Cryo-EM electron density map for FLN preincubated with MK-4815 are displayed at 3σ (lower panels) fitting MK-4815 resulted in too close contact with the side chain of I513 and L514 and fitting MK-4815 introduces no steric hindrance with nearby residues E Falcilysin open structure displayed as a molecular surface The dotted line depicts the hinge axis between N-half and C-half F Superimposition of the partially closed conformation (“pC” obtained in the cryo-EM reconstructions) and the closed conformation (“C1” obtained using X-ray crystallography with the α-peptide) FLN adopts a slightly more open conformation than in the “C1” state (please see text) B Structure alignment based on N-halves (panel A) or C-halves (panel B) The partially closed “pC” conformation of FLN is colored in cyan (N-half) and green (C-half); the open conformation of FLN is colored in purple (N-half) Rotations of N-half and C-half when transitioning from open to “pC” states are indicated by double-headed arrows MK-4815 binds to the N-half domain in “pC” conformation next to the hinge helix α13 which makes direct contact with the C-half domain C Magnified views of the hinge helix from two orthogonal directions The open and “pC” conformations are aligned based on N-halves and displayed as ribbons following the same color code as in panel (A) During the transition from the “pC” to open conformations I739 moves towards the position occupied by the K515 side chain in the “pC” state the hinge helix is shifted toward the binding pocket of MK-4815 the binding of MK-4815 disfavors open conformation (see text) we conclude that the binding of MK-4815 shifts the equilibrium in the distribution of FLN molecules by promoting the formation of the partially closed “pC” conformation of FLN This conclusion is supported by (i) the shift in the open/pC ratio of FLN molecules adopting either the open form or the “pC” state following the addition of MK-4815 to obtain the mixed data set and (ii) the observation of a very similar binding mode of MK-4815 to FLN in both the crystal structure and in the cryo-EM derived complex with the inhibitor As the MK-4815 binding pocket is located next to helix α13, its shape can be affected by even slight movement of this hinge helix. As seen above, MK-4815 was excluded from the binding pocket when FLN adopts its open conformation, due to steric hindrance. In contrast, MK-4815 could bind to FLN in its “pC” state (Fig. 5A) incubation with and binding of MK-4815 affects the equilibrium between the various conformations adopted by FLN in solution by shifting the population to a majority of FLN molecules having the pC conformation and depleting the population with an open state the distance is reduced to 2.5 Å in the open conformation MK-4815 preferentially binds to FLN in its “pC” conformation and hinders the movement of the hinge helix that accompanies the “pC”-to-open state transition of FLN The requirement of residues at other positions appears less stringent although P2 and P1 are polar or charged in the example reported here Both peptide substrates interact extensively with residues from both N-half and C-half of FLN Such interactions are likely to favor a closed conformation as a result of peptide substrate binding two shorter peptide products occupy the catalytic chamber each of which interacts almost exclusively with either the N-half or C-half domain of FLN thus releasing constraints favoring the closed conformation allowing the release of the peptide products and the initiation of a new catalytic cycle A The open conformation of FLN displayed as ribbons (this work PDB accession number: 8WYY) and hPreP (PDB accession number: 6XOU); N-half are colored in cyan; C-half: green; hinge helix: red; linker region of FLN: purple Disordered regions are indicated by dashes PDB accession number: 7DIJ) and hPreP (PDB accession number: 4RPU) The same color code as in panel (A) is used Both allosteric inhibitors MK4815 (this work) and MB60 (PDB code: 4RPU) are displayed as gray spheres and bind next to the hinge region impeding the dynamics of the metalloprotease no denaturation issue during vitrification was observed for FLN these differences suggest the existence of a common ancestor for both metalloproteases a significant degree of divergence between FLN and hPreP was introduced suggesting that inhibitors of one enzyme might not be effective against the other despite an overall conserved mode of action resulting in a final opening angle of approximately 32.5° and an inter-domain distance of approximately 25 Å While the N-half and C-half are covalently connected by the linker they also appear to interact with each other noncovalently through residues near the hinge The observation of a partially closed “pC” conformation of FLN captured in cryo-EM was a surprise as it was previously not described. Being slightly more open than the “C1” conformation (Fig. 4F) the “pC” conformation might constitute a metastable intermediate between the closed conformations (“C1” and “C2”) and the open conformation FLN would first transition from the closed conformations into the “pC” conformation before opening up further into the fully “open” conformation A MK-4815 preferentially binds to FLN in a closed conformation thereby restricting the movements of its hinge helix and preventing transition to an open conformation only a minority of FLN molecules adopt an open conformation and are available for catalysis its peptide substrates are able to diffuse into the catalytic chamber leading to a transient complex between the open state of FLN and the substrate D Binding of the peptide substrate induces the closed conformation of FLN and a concomitant movement of the hinge helix E Cleavage of the peptide substrate into products weakens the interaction between the N-half and C-half allowing the opening of FLN and the release of proteolytic products the transition from the closed state “E” to the open state “B” is impaired and prevents FLN from re-entering the catalytic cycle after hydrolysis when the enzyme converts from open to closed conformations The “favored” direction of the equilibria between different states is denoted by a large arrow while the “disfavored” direction by a small arrow we have identified a mechanism accounting for an allosteric mode of FLN inhibition that can be used to design more potent drugs that could be used as antimalarials denoted as Q76NL8 in UniProtKB with a corresponding gene ID of 814283 was synthesized and incorporated into the pNIC28-Bsa4 vector downstream of a 6xHis tag and a TEV cleavage site resulting in the construction of pNIC-FLN59-1193 This was achieved through ligation-independent cloning (LIC) utilizing a forward primer (5′-TACTTCCAATCCATGGAGTGGATACATGAG-3′) and a reverse primer (5′-TATCCACCTTTACTGTCATTCTATTAATACCTTTTTAAATTC-3′) Following the transformation of BL21 (DE3) Rosetta T1R cells with pNIC-FLN59-1193 cultivation was conducted at 37 °C until the optical density at 600 nm (OD600nm) reached 0.6 Induction of protein expression was accomplished by supplementing the culture with 0.5 mM IPTG for a duration of 16 hours at 16 °C Bacterial harvesting was carried out through centrifugation cells were resuspended in a solution comprising 100 mM Na HEPES Mechanical lysis was performed using an LM20 microfluidizer and the resultant lysate was clarified by centrifugation at 50,000g for 1 h Protein purification was executed through affinity chromatography utilizing Ni-NTA beads (GE Healthcare) with elution performed in a buffer consisting of 20 mM Na HEPES Subsequent size exclusion chromatography employed a Hiload 16/600 Superdex 200 pg column (GE Healthcare) equilibrated in a buffer comprising 20 mM Na HEPES The purity of the protein was assessed through SDS-PAGE prior to a concentration to 22 mg mL−1 The concentrated protein was then flash-frozen and stored at −80 °C until its utilization The FLN mutants were generated by site-directed mutagenesis and subsequently confirmed by DNA sequencing The expression and purification of the mutants were performed following the procedures used for the wild-type falcilysin and N966 to V977 in the complex between FLN and the α-peptide are flexible and N966-M978 are flexible in the FLN β-peptide complex the selection of 961,731 particles from 6764 micrographs was done by autopick via the Laplacian of Gaussian (LoG) method and particles were extracted with data binned by a factor of 2 (box size 128 and pixel size 1.16 Å) Contaminants and bad particles were discarded after reference-free 2D classification and initial 3D classification (257,766 particles left) particles were separated into closed-form (168,840) and open-form (88,926 particles) particles with low resolution of either closed-form or open-form were excluded after 3D classification Selected particles from each population were subjected to Bayesian polishing for per-particle reference-based beam-induced motion correction for the no-drug treated data set (free falcilysin) the selection of 2,511,554 particles from 18,180 micrographs was made by auto-pick via the LoG method and particles were extracted with data binned by a factor of 2 (box size 128 and pixel size 1.146 Å) Contaminants and bad particles were discarded after reference-free 2D classification and initial 3D classification (leaving 171,640 particles of closed-form particles with low resolution of either closed-form or open-form were excluded and selected particles from each population were subjected to Bayesian polishing Isothermal titration calorimetry (ITC) was performed using a MICROCAL PEAQ-ITC instrument (Malvern) operated at 25 °C with 500 rpm stirring speed in a buffer containing 50 mM sodium acetate The α-peptide (LSFPTTKTYFPHFD) or β-peptide (VVYPWTQRFFESFGD) was titrated into 20 µM of the FLN mutants The titration process was started with an initial injection of 0.4 µL over 0.8 s followed by 19 subsequent injections of 2 µL over 3 s each with a spacing of 120 seconds between each injection The enzyme activities of the wild-type FLN enzyme and R1043A single mutant were measured in a buffer containing 50 mM sodium acetate using fluorescently labeled α-peptide (Dabcyl-LSFPTTKTYFPHFD-Edans) or β-peptide (Dabcyl-VVYPWTQRFFESFGD-Edans) as substrate operated at 336 nm and 495 nm wavelengths for excitation and emission The reaction was started with the automated addition of the enzyme (either wild-type FLN or one of the mutants) into the peptide substrate and the reaction was followed for a total duration of 1 min The initial velocity was determined automatically using Magellan® software provided by the manufacturer The measurements were performed in triplicate in the presence of varying concentrations of the fluorescently labeled α-peptide or β-peptide Background subtraction was performed by measuring the addition of buffer alone into a range of concentrations of peptides FLN enzymatic activity was normalized after background subtraction Differential scanning fluorimetry experiments were performed in a buffer containing 20 mM Na HEPES at pH 7.5 and 1 mM TCEP with a total volume of 25 µL To test the stabilization effect of MK-4815 on FLN 5 µM wild-type recombinant FLN protein was incubated with 5× SYPRO orange dye and varying concentrations of MK-4815 followed by RFU measurement using CFX96 Touch Real-Time PCR Detection System (Bio-Rad) on the FRET channel at temperatures ranging from 25 °C to 95 °C raw RFU values were exported and analyzed using the GraphPad Prism software to determine the melting temperatures (Tm) of FLN To test the stabilization effect of hemoglobin peptides on FLN the E132Q mutant was used instead of the wild-type enzyme a concentration of 5 µM recombinant FLN E132Q mutant protein was incubated with 5× SYPRO orange dye and varying concentrations of α-peptide (LSFPTTKTYFPHFD) or β-peptide (VVYPWTQRFFESFGD) followed by RFU measurement from 25 °C to 95 °C Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article All other data are available from the corresponding author upon reasonable request Artemisinin resistance in Plasmodium falciparum malaria Declining efficacy of artemisinin combination therapy against P falciparum malaria on the Thai–Myanmar Border (2003–2013): the role of parasite genetic factors Phenotypic screens in antimalarial drug discovery The open access malaria box: a drug discovery catalyst for neglected diseases Combining stage specificity and metabolomic profiling to advance antimalarial drug discovery Metabolomic profiling of the Malaria Box reveals antimalarial target pathways a potential new oral agent for treatment of malaria Cellular thermal shift assay for the identification of drug–target interactions in the Plasmodium falciparum proteome Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay Identification and structural validation of purine nucleoside phosphorylase from Plasmodium falciparum as a target of MMV00848 Identification and characterization of falcilysin a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme Plasmodium falciparum falcilysin: a metalloprotease with dual specificity Subcellular multitasking—multiple destinations and roles for the Plasmodium falcilysin protease Multiple architectures and mechanisms of latency in metallopeptidase zymogens Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences A role for falcilysin in transit peptide degradation in the Plasmodium falciparum apicoplast Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism The closed structure of presequence protease PreP forms a unique 10 000 Å3 chamber for proteolysis Molecular basis of substrate recognition and degradation by human presequence protease Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition Towards automated crystallographic structure refinement with phenix.refine Coot: model-building tools for molecular graphics RELION: implementation of a Bayesian approach to cryo-EM structure determination CTFFIND4: fast and accurate defocus estimation from electron micrographs High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy UCSF ChimeraX: structure visualization for researchers PHENIX: a comprehensive Python-based system for macromolecular structure solution Addressing preferred specimen orientation in single-particle cryo-EM through tilting Download references This work was supported by grant NRF-CRP24-2020-005 to J.L. and Z.B and by Tier 1 grant RG28/22 from the Singapore Ministry of Education to J.L X-ray diffraction data were collected on the MX II beamline at the Australian Synchrotron Materials and Structural Analysis Division Antimicrobial Resistance Interdisciplinary Research Group Singapore-MIT Alliance for Research and Technology Centre and structural analysis; designed the experiments and prepared and revised the initial draft processed the cryo-EM data and assisted in the methodology and differential scanning fluorimetry experiments provided help and advice with structural studies were responsible for funding acquisition and project conceptualization The authors declare no competing interests Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work Primary Handling Editors: Janesh Kumar and Dario Ummarino Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s42003-024-06774-6 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology About us | Advertise with us | Contact us Posted: 10 December 2019 | | No comments yet Scientists have used cryo-electron microscopy to clarify the structure of one of the key components of RSV and HMPV which could lead to new therapies for the viruses Scientists have found a potential new route to disabling respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) after elucidating the structure of one of its key components The scientists were from Nanyang Technological University, Singapore (NTU Singapore), led by Dr Julien Lescar an Associate Professor at NTU’s School of Biological Sciences Analysis of these model structures revealed key sites for molecules to interact at RSV and HMPV are two closely related viruses causing severe and life-threatening respiratory diseases such as pneumonia and bronchiolitis in anyone with a weak immune system HMPV and RSV commandeer human cells’ machinery to make copies of themselves special proteins released by the virus interact with each other to make distinct protein complexes Dr Lescar his team have used cryo-electron microscopy to image the molecular structure of one of these large complexes The images captured the enzyme at a resolution of 3.7 Angstrom the team then built three-dimensional computer models of the proteins’ L:P molecular structures offering new targets for designing antiviral molecules against both viruses Dr Lescar said with this detailed structural knowledge researchers can now hope to develop inhibitors that disrupt the enzymatic activities of HPMV L:P protein and potentially block infection by the virus “We hope that our work will help researchers in pharma and academia around the world to design much-needed therapies for difficult viral infections that often lead to antibiotic-resistant bacterial infections,” said Dr Lescar Since the HMPV proteins they studied are essentially unchanged through evolution and very similar to those of RSV and other virus species belonging to the Pneumorivridae family the scientists have said they hope that inhibitors developed against HPMV could also work against a broad spectrum of viruses involved in respiratory diseases and inform similar quests against other viral diseases The study was published in Nature Related conditions, Related organisations Related people By No comments yet , All subscriptions include online membership giving you access to the journal and 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functionalities of the website CookieTypeDurationDescriptioncf_ob_infopersistent1 minuteThis cookie is set by Cloudflare content delivery network and in conjunction with the cookie 'cf_use_ob' The group played a superb set of straight-ahead and contemporary originals inspired by Strayhorn There was a buzz of anticipation at The Lescar on 2 March as the pub’s socially distanced capacity audience waited for the band to come on The Alex Merritt / Steve Fishwick Quintet were about to play their fourth gig of a tour promoting their album Mind-Ear-Ladder They’d already played Soho’s Pizza Express Bristol’s Bebop Club and Cambridge Modern Jazz The Lescar crowd were not to be disappointed Alex Merritt on tenor sax and Steve Fishwick on trumpet the quintet with its top-flight rhythm section of John Turville piano Mick Coady bass and Fishwick’s brother Matt on drums delivered a storming performance of straight-ahead and contemporary jazz the acronym for Upper Holloway Dental Clinic being a pun on Billy Strayhorn’s UMMG (Upper Manhattan Medical Group) which referred to the group of Harlem physicians in Duke Ellington’s social circle With something of a medical theme emerging Steve went on to inform us that one of his compositions – Dr Wu – concerned an over-enthusiastic doctor who had caused panic with an erroneous diagnosis during what should have been a routine hospital procedure Three other numbers written by Fishwick and performed tonight were Hollow Man influenced by the music of Stanley Cowell; a minor blues entitled Number Nine and Linda – a meditative composition penned for Fishwick’s mother Four compositions were contributed by Merritt – Pablo-ish in dedication to the German pianist Pablo Held; Ma Ballade written for Merritt’s mother who’d been seriously ill; At St George’s – a church in Camberwell where he’d worked on the album’s music – and his lyrical New Waltz Tonight’s superb set was loudly applauded by the appreciative audience the band were due to play in Aberdeen and the next day they were travelling back down to Leeds for a workshop and concert at the conservatoire You can see them on the last leg of their tour at Norwich Jazz Club on 19 April Bristol Fringe on the 27th and Birmingham Jazz on the 29th For those who haven’t been before, The Lescar in Sheffield is a great pub serving an ever-changing range of craft ales. Its jazz club, run by musicians on a not-for-profit basis every Wednesday has been going since the mid-90s. You can find the details at www.jazzatthelescar.com © Unless otherwise indicated, all content copyright Jazz Journal 1948-2025 <Dialog description or question goes here> This site uses cookies to offer you a better browsing experience. By continuing, you are agreeing to the use of cookies on your device as described in our privacy policy Beware of fake email, SMS and WhatsApp messages: check before clicking. Read more Trained in both biochemistry and crystallography, Assoc Prof Julien Lescar of NTU’s School of Biological Sciences is giving us a glimpse into life at the nanoscale Using X-ray crystallography and cryo-electron microscopy facilities at the NTU Institute of Structural Biology Assoc Prof Lescar and his team have determined the 3D structures of key proteins of major human viruses These structural insights provide clues to designing new antiviral drugs A decade-long collaboration with the Novartis Institute for Tropical Diseases in Singapore to determine the structure of key dengue virus proteins paid off handsomely when the protein structures helped scientists identify homologous structures of the Zika virus a closely related RNA virus that emerged in 2015 Structure of the dengue virus non-structural protein 5 resolved by a team led by Assoc Prof Julien Lescar and Assoc Prof Luo Dahai the molecular structures of important coronavirus proteins determined by Assoc Prof Julien Lescar and colleagues at the French National Centre for Scientific Research 15 years ago now provide crucial information for the identification of molecular drug targets against SARS-CoV-2 Assoc Prof Lescar co-founded the biotech start-up Epitoire in 2018 together with colleagues from the United States and NTU’s Prof James Tam and Assoc Prof Liu Chuan Fa, with the support of NTU’s commercialisation arm, NTUitive Epitoire develops products based on peptide ligases—molecular precision tools that have applications in medicine and biotechnology—and investigates treatments for diseases caused by dysregulated gene expression autoimmunity and neurodegenerative disorders A Singapore team found a way to break down leftover grains from beer brewing and extract much more nutrients from them than before Researchers have found a “switch” in immune cells in the brain that could be targeted as a potential treatment for Alzheimer’s disease Issue 24 (2024) Transforming research into sustainable solutions Mapping the structure of a viral enzyme Catching electrons while they are still hot Space radars show mountain moved by nuclear tests Lost crater found at last in Laos Fatty acid fights ageing Coral chronicles the Indian Ocean’s ups and downs Overcoming a flaw of terahertz radiation Rapidly rising seas could swamp mangroves Hormone-like substances could slow Parkinson’s disease Orange is the new green A pollen paper that moves in moisture All about that BACE2 Speeding up robot response times If you would like to share research stories, comments or views, please contact us at [email protected] Student Intranet Visiting NTU Careers A-Z Directory Contact Us Whistleblowing A team of molecular and structural biologists from Nanyang Technological University Singapore (NTU Singapore) have found a potential new route to disabling respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) after elucidating the structure of one of its key components RSV and HMPV are two closely related viruses causing severe and life-threatening respiratory diseases such as pneumonia and bronchiolitis in premature babies and infants pneumonia killed a child somewhere in the world every 39 seconds in 2018 but there are no vaccines or effective antiviral therapies against it HMPV and RSV commandeer the cell’s machinery to make copies of themselves Dr Julien Lescar from NTU’s School of Biological Sciences and his team report how they have used cryo-electron microscopy to image the molecular structure of one of these large complexes Nanyang Technological University, Singapore Posted in: Medical Research News | Disease/Infection News Cancel reply to comment Learn how experts are advancing benzodiazepine analysis and detection using insights from the lab discusses how he is addressing today’s medical challenges using the technology of the future Explore how the Radian ASAP mass spectrometer is being used to streamline and enhance seized drug screening you can trust me to find commercial scientific answers from News-Medical.net please log into your AZoProfile account first Registered members can chat with Azthena, request quotations, download pdf's, brochures and subscribe to our related newsletter content A few things you need to know before we start Read the full Terms & Conditions You don't have permission to access the page you requested What is this page?The website you are visiting is protected.For security reasons this page cannot be displayed Sheffield’s oldest comedy venue is getting a relaunch… thanks to a familiar name.  The Lescar pub in the Hunter’s Bar area of the city has hosted stand-up since 1992, when comic Roger Monkhouse opened the Last Laugh comedy club there It was taken over by its regular compere Toby Foster who moved the club to the city centre in 2005 settling at its current home – the Memorial Hall – in 2007 Foster admits that ‘when the club opened its new home in the city centre… it’s fair to say audiences at The Lescar dwindled’ It has not hosted comedy since the  Covid lockdown… but next month a new night launches  – run by Foster’s  eldest daughter I’ve grown up with comedians in our house all my life so I suppose it was inevitable that I’d get involved somewhere along the line ‘My Dad always said that there was something very special about the atmosphere at The Lescar and I hope that we can recreate it for a new generation.'  The club is to run on the second Thursday of every month, headlined by Scott Bennett on November 9 and  Nina Gilligan on December 14. Each night will feature a compere Maisie recalled: ‘I spent August in Edinburgh handing out flyers for Nina’s first show when I was 15 She’s a great friend and it’s a real treat that she is playing the club.’ ‘My Dad did his first ever open spot at The Lescar when Roger Monkhouse ran it and he didn’t turn out too bad.’ Maisie said So does that mean she is looking for the next Toby Foster Gig of the day Paul Chowdhry: EnglandiaLeicester De Montfort Hall from 19:30 Coming Soon Michelle De Swarte: The AftersLiverpool Royal Court TheatreFriday 19th Sep Chortle had 173,000 unique visitors in April 2025 We are currently listing 20,977 upcoming comedy events Website and all original content copyright © Chortle 2000 - 2025 Chortle relies on advertisers to fund this website so it’s free for you so we would ask that you disable it for this site Metrics details Malaria causes every year over half-a-million deaths The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria Here we report a crystallographic structure of the catalytic domain of PfCK2α (D179S inactive single mutant) in complex with ATP at a resolution of 3.0 Å the structure reveals a subtly altered ATP binding pocket comprising five substitutions in the vicinity of the adenine base that together with potential allosteric sites could be exploited to design novel inhibitors specifically targeting the Plasmodium enzyme We provide evidence for the dual autophosphorylation of residues Thr63 and Tyr30 of PfCK2 a human CK2 inhibitor in clinical trials against solid tumor cancers is effective against PfCK2 with an IC50 of 13.2 nM (A) Selected constructs from the series generated for identifying the protein boundaries yielding the most soluble and stable PfCK2α enzyme when expressed in E yellow and green rectangles represent insoluble The position of the hexahistidine tag is indicated as “His6” and theTEV cleavage sites and amino- and carboxy terminal residues labelled (B) 12% SDS-PAGE analysis of the purified PfCK2α constructs (wild-type and single mutant) used in this study spanning residues Ile12-Ser335 (C) Needle-shaped PfCK2αD179S crystals obtained after optimization using micro-seeding (see methods) (A) Autoradiograph kinase activity assay was carried out using 2 μg of wild type (lane 1) or D179S mutant PfCK2 (lane 2) with Mg [γ32P]-ATP (B) The proteins were resolved by SDS-PAGE stained with Coomassie blue and their activity analysed by autoradiography (C) Annotated MS/MS spectra showing identification of Y30 phosphorylation using the Mascot protein database search software The Tyr30 (labeled Y16 in the spectrum) is unambiguously identified as it is sandwiched by a series of y-ions [y16,y17,y18(phosphorylation site),y19,y20] y13 ion was trimmed 10 times to show the weaker ions in the spectrum The secondary structures elements for PfCK2 (this work) are displayed above the alignment with the helices depicted as springs and strands as arrows The hCK2 C-terminal tail (ARMGSSSMPGGSTPVSSANMMSGISSVPTPSPLGPLAGSPVIAAANPLGMPVPAAAGAQQ) was removed from the alignment because no equivalent residue is present in PfCK2α PfCK2 having double Tyr30 and Thr63 Aspartate mutant had negligible kinase activity This possibly suggests that sequential autophosphorylation is needed for activation of PfCK2. an event that could not be mimicked by the introduction of a shorter carboxylic side chain as presented in the form of an Asp residue Effect of compound CX4945 on CK2 activity The compound CX4945 displays concentration-dependent inhibition on both CK2 proteins used here The IC50 value of CX4945 for each protein is indicated Data were analysed using the GraphPad Prism software using a Log [inhibitor] vs normalized response fit Analysis of crystal contacts reveals interfaces between the three monomers extending over an area of approximately 700 Å2. Residues brought in extensive intermolecular contact originate from the C-lobe of molecule C and the N terminal arm preceeding the N-Lobe of molecule A. Interestingly, some crystal contacts involve residues from the P-loop, and phosphorylation site around Thr63 whose structure might be affected by crystal packing forces. this work) and hCK2 (PDB code: 2PVR) and AMPPNP (panel E) The P-loop which includes residues Gly49–Tyr54 of PfCK2αD179S adopt an extended conformation similar to the one found in the active forms of CK2 (with RMSD 0.55 Å 0.48 Å and 0.54 Å following superpositions with structures 3NSZ 3WAR (the highest resolution structure available of an active CK2) and 2PVR respectively and it markedly differs from the inactive “collapsed” inactive form of CK2 (PDB code: 3FWQ) several residues preceding the P-loop such as Met46 and Arg51 adopt a conformation distinct from either the active (RMSD 0.52 Å and 0.65 Å for structures 3NSZ and 2PVR respectively) or inactive hCK2 structures (RMSD 1.23 Å with PDB: 3FWQ) the β1 and β2 strands of PfCK2αD179S do not overlap with their counterpart structures in the active human structure (PDB code: 2PVR) Residue Gly50 is 3.28 Å away from the position adopted by the equivalent residue Gly46 in hCK2 which is due to a shift of the entire beta-sheet between the human and Plasmodium proteins Such displacements are induced by ATP binding (see below) and propagate across the beta blade with the Cα of residue Val109 of PfCK2 displaced by 5.83 Å from the position adopted by Val105 in the active human enzyme Conformational changes between the structure adopted by the N-Lobe of PfCK2αD179S (pink) and hCK2 (PDB code: 2PVR colored in pink) and the active form of hCK2 (PDB code: 2PVR) shown in yellow The three arrows show the main displacements described in the text at the level of the p-loop flash-frozen in liquid nitrogen and stored at −80 °C until use The PfCK2αD179S mutant was generated using the QuickChange Protocol with forward primer GAAAATAGACAAATTAGATTAATTAGTTGGGGTCTAGCTGAATTTTATC reverse primer GATAAAATTCAGCTAGACCCCAACTAATTAATCTAATTTGTCTATTTTC and template DNA vc026 Expression and purification of the PfCK2αD179S mutant was performed following the same protocol as for the wild type enzyme Human CK2 (CSNK2 DU813) served as positive control One unit of activity was defined as the incorporation of 1 nanomole of radioactive phosphate into the substrate per minute Specificity was calculated by dividing activity units by the amount in milligrams of assayed purified protein and substracting background level Results were the averages of duplicate measurements Two replicates were performed for hCK2 and PfCK2 2.5 μl of incremental concentrations of CX4945 compound was assayed with either enzyme in 50 μl total volume consisting of 50 mM Tris-HCl at pH 7.5 10 mM magnesium acetate and 100 μM γ33P-ATP The reaction was incubated at 30 °C for 10 mins Reactions were stopped by spotting 40 μl out of the 50 μl assay mixture onto 1.5 cm × 1.5 cm square of Whatman P81 paper which were washed in 75 mM phosphoric acid 1 ml Microscint 0 was added to tubes containing dried filter papers before counting on a liquid scintillation counter Prior to flash-freezing in liquid nitrogen crystals were transferred into a cryoprotectant solution containing the precipitant solution supplemented with 30% (v/v) glycerol Isothermal titration microcalorimetry experiments were performed at 25 °C with a PEAQ-ITC isothermal titration calorimeter (Malvern) Protein concentration in the microcalorimeter cell (0.2 mL) was 50 μM A total of 19 injections of 2 μl of ATP at a concentration of 500 μM were performed at intervals of 180 s while stirring at 600 rpm The experimental data were fitted to theoretical titration curves using the manufacturer’s software PfCK2 wild type and mutant protein gel bands were excised Tryptic peptides were separated and analyzed on a Dionex Ultimate 3000 RSLCnano system coupled to a Q-Exactive mass spectrometer (Thermo Electron A full MS scan (350–1600 m/z range) was acquired at a resolution of 70,000 at m/z 200 and a maximum ion accumulation time of 100 ms Resolution for HCD spectra was set to 17,500 at m/z 200 The AGC setting of full MS scan and MS2 were set as 106 and 2 × 105 000 counts threshold were selected for HCD fragmentation with a maximum ion accumulation time of 100 ms Single and unassigned charged ions were excluded from MS/MS normalized collision energy was set to 28% The MS raw file was converted into mgf format using ProteomeDiscoverer version 1.4 Protein identification was performed using Mascot server (version 2.4.1 MA) against a Plasmodium falciparum protein database including the WT and MT PfCK2α proteins (containing 5,649 sequence and 431,5306 residues) Mascot search was limited to a maximum of two missed trypsin cleavages mass tolerance of 5 ppm for peptide precursors and 0.02 Da mass tolerance for fragment ions Fixed modification was carbamidomethyl at Cys residues while variable modifications included oxidation at methionine residues The extents of phosphorylation of detected phosphorylation sites were determined by integrating the areas of the extracted ion chromatograms of the unphosphorylated and phosphorylated peptides The extracted ion chromatograms were extracted from a windows of +/−5 ppm of the precursor ions (see supplementary data) Protein Data Bank accession code: The atomic coordinates and structure factors have been deposited in the Protein Data Bank with accession code 5XVU http://apps.who.int/iris/bitstream/10665/259492/1/9789241565523-eng.pdf (2017) their function and implication in cancer and other diseases Kinase drug discovery-what’s next in the field Protein kinases as drug targets in trypanosomes and Leishmania Functional analysis of protein kinase CK2 of the human malaria parasite Plasmodium falciparum Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission Functional characterization of both MAP kinases of the human malaria parasite Plasmodium falciparum by reverse genetics A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes Global analysis of protein expression and phosphorylation of three stages of Plasmodium falciparum intraerythrocytic development One-thousand-and-one substrates of protein kinase CK2 Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme GTP plus water mimic ATP in the active site of protein kinase CK2 Protein kinase CK2 in health and disease: Structural bases of protein kinase CK2 inhibition Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 A resolution Structural basis of CX-4945 binding to human protein kinase CK2 The use of systematic N- and C-terminal deletions to promote production and structural studies of recombinant proteins Autocatalytic tyrosine-phosphorylation of protein kinase CK2 alpha and alpha’ subunits: implication of Tyr182 Active Form of the Protein Kinase CK2 alpha2beta2 Holoenzyme Is a Strong Complex with Symmetric Architecture Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond an orally bioavailable selective inhibitor of protein kinase CK2 inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy Overview of the CCP4 suite and current developments Evolved to be active: sulfate ions define substrate recognition sites of CK2alpha and emphasise its exceptional role within the CMGC family of eukaryotic protein kinases the catalytic subunit of protein kinase CK2 2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor The protein kinase family: conserved features and deduced phylogeny of the catalytic domains Active and inactive protein kinases: structural basis for regulation The catalytic subunit of human protein kinase CK2 structurally deviates from its maize homologue in complex with the nucleotide competitive inhibitor emodin The conformational plasticity of protein kinases Protein kinases: evolution of dynamic regulatory proteins Evolution of the eukaryotic protein kinases as dynamic molecular switches Structural basis for decreased affinity of Emodin binding to Val66-mutated human CK2 alpha as determined by molecular dynamics Inference of macromolecular assemblies from crystalline state Inclining the purine base binding plane in protein kinase CK2 by exchanging the flanking side-chains generates a preference for ATP as a cosubstrate Assay of protein kinases using radiolabeled ATP: a protocol The protein kinase 2 inhibitor CX-4945 regulates osteoclast and osteoblast differentiation in vitro space-group assignment and post-refinement Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER A comparative study of electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) versus SCX-IMAC-based methods for phosphopeptide isolation/enrichment Deciphering key features in protein structures with the new ENDscript server LigPlot+: multiple ligand-protein interaction diagrams for drug discovery Download references We acknowledge Ramya Chandrasekaran and Tobias Cornvik (NTU Protein Production Platform, http://www.proteins.sg) for earlier contributions to this work We also acknowledge beam time allocation at the Taiwanese light source (NSRRC) and the Swiss Light Source (SLS) The JL laboratory was supported by a Tier 1 complexity grant RGC2/14 from the MOE Support from grant SGP-PROG3-023 is also acknowledged Jianqing Lin and Abbas El Sahili contributed equally to this work Department of Biological Sciences Xi’an Jiaotong-Liverpool University111 Ren’ai Road Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-018-25738-5 Sorry, a shareable link is not currently available for this article. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Join the conversation You can save this article by registering for free here. Or sign-in if you have an account EDMONTON – Louise Lescar reeled back off the sidewalk She circled twice as if physically stunned “Did you see her?” someone asked the shaken woman Lescar had just shaken the hand of Mother Teresa touch and listen to Mother Teresa’s simple message of love The nun had come to receive a gift of money from the community to help build a leper colony in India “Christ came to give us the good news — and there’s no better news than God loves us and wants us to love one another as he loves us,” she said sandal and sari-clad Catholic nun and missionary also received an honorary doctorate of laws degree from the University of Alberta “No act during my presidency has brought me greater joy,” said U of A president Myer Horowitz who conferred the degree on the 72-year-old Nobel Peace Prize winner “Mother Teresa is our newest graduate and the most distinguished member of our university community.” say abortion was the greatest destroyer of peace She urged people to pray for peace “in a mother’s heart so she will never kill her child.” If a mother kills her child what will stop people from killing each other she said the largest problem society faces is the destruction of the family Children and adults sang as they followed her on foot as she travelled through town in an open car Thousands crushed into the area in front of the outdoor UFO landing pad to see Mother Teresa receive a cheque for $925,000 from the people of St with the help of matching federal and provincial grants Premier Peter Lougheed told her: “I’m so stirred by your coming literally across the globe to inspire us by your compassion Subscribe now to read the latest news in your city and across Canada. Create an account or sign in to continue with your reading experience. transmission or republication strictly prohibited This website uses cookies to personalize your content (including ads), and allows us to analyze our traffic. Read more about cookies here. By continuing to use our site, you agree to our Terms of Use and Privacy Policy You can manage saved articles in your account Singapore (NTU Singapore) have found a potential new route to disabling respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) after elucidating the structure of one of its key components.  Juliette A Le seule et unique village Emmaüs de France se situe à Lescar-Pau à environ 200 km de Bordeaux Dans ce village marginal de 11 hectares qui prône l'anticapitalisme et défend l'écologie vivent environ 120 personnes appellées compagnons en totale auto-suffisance (financière et alimentaire) Celui qui l'a fondé s'appelle Germain Sarhy Ce "vieux de la vieille" comme il le dit en ses mots revient sur l'histoire du Village Emmaüs Lescar-Pau. Crée le 20 mai 1982 à Mirepex le camp a ensuite migré à Lescar pour se transformer en village en 1987 C'est suite à un camp de jeune d'Emmaüs organisé par l'Abbé Pierre qu'est venue au jeune homme engagé de 28 ans à l'époque l'envie de s'engager dans la lutte pour la solidarité et contre l'injustice Doté en plus d'un véritable engagement politique Germain réussit le pari audacieux de construire le seul village communautaire d'entraide et de lutte contre le système néo-libéral et sa dynamique de consumérisme défense du "bien et vieux-manger" et économie circulaire sont les maîtres mots 130 personnes (80% sont des compagnons et leurs familles) vivent sur place dans les 70 maisons ou mobil homes qui occupent le parc Chacun œuvre collectivement pour le village blanchis et perçoivent 500€ d'argent de poche par mois C'est par cela que Germain entend "lutter contre l'assistanat d'inactivité" en mettant à profit les qualités physiques et morales de chacun Sur place parmi les 11h de superficie totale se niche un bric à brac géant de 6000 m2 une déchetterie recyclerie (avec 500 voitures qui déchargent de la marchandise chaque jour) une ferme de 4 hectares ( avec poulets cochons et vaches bearnaises qui se visite) Le tout permettant au village Emmaüs Lescar-Pau de s'alimenter en autonomie à hauteur de 70% Une offre culturelle est aussi travaillée avec soin proposant concerts Et de grands artistes français ont foulé le village Yannick Noah ou encore les Ogres de Barback sur des scènes avec plus de 5000 personnes réunies Aussi une trentaine d'ateliers sont organisés chaque jour À l'instar de l'agroécologie atelier recyclage ... Le bric à brac ouvert le matin de 09h à 12h et de 14h à 18h accueille de 1500 à 3000 personnes tous les jours pour chiner Page Facebook Over 200 grand to live in a shoebox on an industrial estate Given the headline "Sky-House Co Waverley Phase Two completely sold out" clearly you are in the minority people disagree with me or they wouldn’t have bought them but it doesn’t mean I’m in the minority I think you can safely assume that you are in a minirity I’m still entitled to that opinion and I stand by it Would you pay that much to live in that house in that location I wouldn't actually think the homes were that bad if they were about 100 grand cheaper than they are that combined with the lovely view of a mud heap the AMP and the parkway makes me question the sanity of the buyers Don’t forget all the car accidents due to a complete absence of road markings "Numerous" according to this BBC report...www.bbc.co.uk/news/uk-england-south-yorkshire-66502009 I'm surprised that the residents haven't painted their own lines at the junction They did but unfortunely they used whitewash and when it rained the lines were washed into the River The Star has posted an article about this on their Facebook page Currently at 36 comments and not one is positive but apparently I can safely assume I'm in the minority Back to TOP