Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration

Is IT enough? Evidence from a natural experiment in India's agriculture markets

Access to information and communication technologies (ICTs) such as mobile phone networks is widely known to improve market efficiency. In this paper, we examine whether access to timely and accurate information provided through ICT applications has any additional impact. Using a detailed data set from Reuters Market Light (RML), a text message service in India that provides daily price information to market participants, we find that this information reduces the geographic price dispersion of crops in rural communities by an average of 12%, over and above access to mobile phone technology and other means of communication. To identify the effect of information on price dispersion, we exploit a natural experiment where bulk text messages were banned unexpectedly across India for 12 days in 2010. We find that besides reducing geographic price dispersion, RML also increases the rate at which prices converge across India over time. We discuss the implications of this for development organizations and information providers

Proactive Customer Service: Operational Benefits and Economic Frictions

Problem Definition: We study a service setting where the provider has information about some customers' future service needs and may initiate service for such customers proactively, if they agree to be flexible with respect to the timing of service delivery. Academic / Practical Relevance: Information about future customer service needs is becoming increasingly available through remote monitoring systems and data analytics. However, the literature has not systematically examined proactive service as a tool that can be used to better match demand to service supply when customers are strategic. Methodology: We combine i) queueing theory, and in particular a diffusion approximation developed specifically for this problem that allows us to derive analytic approximations for customer waiting times, with ii) game theory, which captures customer incentives to adopt proactive service. Results: We show that proactive service can reduce customer waiting times, even if only a relatively small proportion of customers agree to be flexible, the information lead time is limited, and the system makes occasional errors in providing proactive service - in fact we show that the system's ability to tolerate errors increases with (nominal) utilization. Nevertheless, we show that these benefits may fail to materialize in equilibrium because of economic frictions: customers will under-adopt proactive service (due to free-riding) and over-join the system (due to negative congestion-based externalities). We also show that the service provider can incentivize optimal customer behavior through appropriate pricing. Managerial Implications: Our results suggest that proactive service may offer substantial operational benefits, but caution that it may fail to fulfill its potential due to customer self-interested behavior

Effect of the whistle watch device on bronchodilator use in children with asthma

Objective. To determine if the use of the whistle watch (WW), a simple device to monitor peak flow rate, affects the use of bronchodilators at home.Study design. Prospective, randomised, crossover design.Setting. The asthma outpatients' clinic at Coronation Hospital, a tertiary care centre in Johannesburg.Patients and methods. Children between 6 and 18 years of age with moderate or severe asthma for more than a year were enrolled. They were randomised into two groups, with bronchodilator use determined either by the WW or solely by the patient's perceived symptomatology. The patients acted as their own controls, switching over to the other group after 30 days. Eighty patients were enrolled into the study.Results. Forty-three patients completed the study (54%). There were no significant differences between these patients and those who did not complete the study in terms of sex, age and treatment characteristics. There was a significant reduction in the mean monthly number of bronchodilator doses used by the WW group (5.5 doses v. 16.81 doses, paired t-test, t = 3.64, P < 0.001, 95% confidence interval (CI) 6.1 - 16.55). The change in individual participants varied between 13 extra bronchodilator doses and 71 fewer doses per month with the use of the WW device.Conclusion. The WW device is a cheap, easy-to-use and effective tool that reduces the number of bronchodilator doses used by asthmatic children at home

A structurally conserved motif in γ-herpesvirus uracil-DNA glycosylases elicits duplex nucleotide-flipping

Efficient γ-herpesvirus lytic phase replication requires a virally encoded UNG-type uracil-DNA glycosylase as a structural element of the viral replisome. Uniquely, γ-herpesvirus UNGs carry a seven or eight residue insertion of variable sequence in the otherwise highly conserved minor-groove DNA binding loop. In Epstein–Barr Virus [HHV-4] UNG, this motif forms a disc-shaped loop structure of unclear significance. To ascertain the biological role of the loop insertion, we determined the crystal structure of Kaposi’s sarcoma-associated herpesvirus [HHV-8] UNG (kUNG) in its product complex with a uracil-containing dsDNA, as well as two structures of kUNG in its apo state. We find the disc-like conformation is conserved, but only when the kUNG DNA-binding cleft is occupied. Surprisingly, kUNG uses this structure to flip the orphaned partner base of the substrate deoxyuridine out of the DNA duplex while retaining canonical UNG deoxyuridine-flipping and catalysis. The orphan base is stably posed in the DNA major groove which, due to DNA backbone manipulation by kUNG, is more open than in other UNG–dsDNA structures. Mutagenesis suggests a model in which the kUNG loop is pinned outside the DNA-binding cleft until DNA docking promotes rigid structuring of the loop and duplex nucleotide flipping, a novel observation for UNGs

Cryo-electron microscopy structure of the di-domain core of <em>Mycobacterium tuberculosis</em> polyketide synthase 13, essential for mycobacterial mycolic acid synthesis

Mycobacteria are known for their complex cell wall, which comprises layers of peptidoglycan, polysaccharides and unusual fatty acids known as mycolic acids that form their unique outer membrane. Polyketide synthase 13 (Pks13) of Mycobacterium tuberculosis, the bacterial organism causing tuberculosis, catalyses the last step of mycolic acid synthesis prior to export to and assembly in the cell wall. Due to its essentiality, Pks13 is a target for several novel anti-tubercular inhibitors, but its 3D structure and catalytic reaction mechanism remain to be fully elucidated. Here, we report the molecular structure of the catalytic core domains of M. tuberculosis Pks13 (Mt-Pks13), determined by transmission cryo-electron microscopy (cryoEM) to a resolution of 3.4 \uc5. We observed a homodimeric assembly comprising the ketoacyl synthase (KS) domain at the centre, mediating dimerization, and the acyltransferase (AT) domains protruding in opposite directions from the central KS domain dimer. In addition to the KS–AT di-domains, the cryoEM map includes features not covered by the di-domain structural model that we predicted to contain a dimeric domain similar to dehydratases, yet likely lacking catalytic function. Analytical ultracentrifugation data indicate a pH-dependent equilibrium between monomeric and dimeric assembly states, while comparison with the previously determined structures of M. smegmatis Pks13 indicates architectural flexibility. Combining the experimentally determined structure with modelling in AlphaFold2 suggests a structural scaffold with a relatively stable dimeric core, which combines with considerable conformational flexibility to facilitate the successive steps of the Claisen-type condensation reaction catalysed by Pks13

Crowdsourcing Exploration

Motivated by the proliferation of online platforms that collect and disseminate consumers' experiences with alternative substitutable products/services, we investigate the problem of optimal information provision when the goal is to maximize aggregate consumer surplus. We develop a decentralized multi-armed bandit framework where a forward-looking principal (the platform designer) commits upfront to a policy that dynamically discloses information regarding the history of outcomes to a series of short-lived rational agents (the consumers). We demonstrate that consumer surplus is non-monotone in the accuracy of the designer's information-provision policy. Because consumers are constantly in "exploitation" mode, policies that disclose accurate information on past outcomes suffer from inadequate "exploration." We illustrate how the designer can (partially) alleviate this inefficiency by employing a policy that strategically obfuscates the information in the platform's possession -- interestingly, such a policy is beneficial despite the fact that consumers are aware of both the designer's objective and the precise way by which information is being disclosed to them. More generally, we show that the optimal information-provision policy can be obtained as the solution of a large-scale linear program. Noting that such a solution is typically intractable, we use our structural findings to design an intuitive heuristic that underscores the value of information obfuscation in decentralized learning. We further highlight that obfuscation remains beneficial even if the designer can directly incentivize consumers to explore through monetary payments

GeoTriples: a Tool for Publishing Geospatial Data as RDF Graphs Using R2RML Mappings

In this paper we present the tool GeoTriples that allows the transformation of Earth Observation data and geospatial data into RDF graphs, by using and extending the R2RML mapping language to be able to deal with the specificities of geospatial data. GeoTriples is a semi-automated tool that transforms geospatial information into RDF following the state of the art vocabularies like GeoSPARQL and stSPARQL, but at the same time it is not tightly coupled to a specific vocabulary

Screening and quantification of micro(nano)plastics and plastic additives in the seawater of Mar Menor lagoon

In this work a suspect-screening approach was employed to assess the polymers and plastic additives of micro(nano)plastics (NPL/MPLs) of size ranges from the nm range to 20 μm present in seawater from the top 5 cm of the Mar Menor lagoon during two sampling campaigns (summer and winter), as well of other potentially adsorbed compounds onto the plastic particles surfaces and suspended material. The identification of NPL/MPLs has been based on characteristic Kendrick Mass Defect analysis for each polymer type in mass spectra. The applied methodology allowed to identify NPLs/MPLs of polystyrene (PS), polyethylene (PE), polyisoprene (PI), polybutadiene (PBD), polypropylene (PP), polyamides (PA), polyvinylchloride (PVC), n-isopropylacrylamide (PNIPAm), and polydimethylsiloxanes. In addition, PS, PE, PI, PBD, PP, PA, and PVC were confirmed with standards, and the equivalent concentrations were quantified. The results of this study showed that most frequently found compounds were PP, PE, PA and PNIPAm, while the compound found at higher concentrations was by far PP reaching the 9,303 ± 366 ng/mL in one of the samples. A total number of 135 chemical compounds were tentatively identified, 74 of them plastic additives and compounds used in the polymers manufacture or coming from the polymer’s decomposition. In relation to plastic additives, the more frequently tentatively identified compounds were plasticizers such as phthalates group; stabilizers such as antioxidants (e.g., distearyl 3,3′-thiodipropionate, 2,5-di-tert-butylhydroquinone), and UV filters as benzotriazoles. Several flame retardants of the group of phosphates were as well detected. The other compounds tentatively identified in the samples were pharmaceuticals, pesticides, food additives, flavors and natural products that were attached onto the plastic particles and particulate matter from surrounding waters. In regards to the seasonal variation, during the summer a major number of compounds were tentatively detected, while de concentrations of polymers were slightly higher in winter. The spatial distribution showed higher contamination in the southern part of the coastal lagoon.Postprin