J R SOC INTERFACE

Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutationsDepartment of Chemistry, BMC, Uppsala University, Box 576, 751 23 Uppsala, Sweden Departamento de Quimica Fisica, Facultad de Ciencias, University of Granada, 18071 Granada, SpainWallenberg Academy Fellowship to S.C.L.K. from the Knut and Alice Wallenberg Foundation (KAW 2013.0124)Grant RGP0041/2017 from the Human Frontier Science ProgramFEDER Funds and grant BIO2015–66426-R to J.M.S.R. from the Spanish Ministry of Economy and Competitivenes

Characterization of two Achromobacter xylosoxidans isolates from patients with pertussis-like symptoms

[email protected]: To characterize two Achromobacter xylosoxidans recovered from 2 patients diagnosed with pertussis during a Bordetella pertussis surveillance program. Methods: Nasopharyngeal swabs from 2 children under 1 year of age with clinical suspicion of pertussis were analyzed by culture and PCR. Results: Two Achromobacter xylosoxidans A8, closely related to Bordetella spp. were recovered from 2 patients diagnosed of pertussis, both carrying the ptxA gene and IS418 the pertussis toxin encoding gene. Subsequently, antibiotic susceptibility was evaluated by disk-diffusion method and by PCR. Conclusions: Although more detailed studies are needed, the present data highlight the possibility that Achromobacter xylosoxidans, closely related Bordetella pertussis microorganisms and not covered under the vaccine umbrella, might also result in cases of whooping cough. Thereby further surveillance is necessary to determine the extension and relevance of their pathogenic role in order to discriminate their real public health implication.This work has been supported by Sanofi Aventis del Peru. JR has a fellowship from the program I3, of the ISCIII (grant number: CES11/012), CG has a PhD fellowship of the ISCIII (FI12/00561). MJP has a fellowship from CONCYTEC/FONDECYT.Revisión por pare

Interrogation of an Enzyme Library Reveals the Catalytic Plasticity of Naturally Evolved [4+2] Cyclases

\ua9 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.Stereoselective carbon-carbon bond forming reactions are quintessential transformations in organic synthesis. One example is the Diels-Alder reaction, a [4+2] cycloaddition between a conjugated diene and a dienophile to form cyclohexenes. The development of biocatalysts for this reaction is paramount for unlocking sustainable routes to a plethora of important molecules. To obtain a comprehensive understanding of naturally evolved [4+2] cyclases, and to identify hitherto uncharacterised biocatalysts for this reaction, we constructed a library comprising forty-five enzymes with reported or predicted [4+2] cycloaddition activity. Thirty-one library members were successfully produced in recombinant form. In vitro assays employing a synthetic substrate incorporating a diene and a dienophile revealed broad-ranging cycloaddition activity amongst these polypeptides. The hypothetical protein Cyc15 was found to catalyse an intramolecular cycloaddition to generate a novel spirotetronate. The crystal structure of this enzyme, along with docking studies, establishes the basis for stereoselectivity in Cyc15, as compared to other spirotetronate cyclases

Prioritising surveillance for alien organisms transported as stowaways on ships travelling to South Africa

The global shipping network facilitates the transportation and introduction of marine and terrestrial organisms to regions where they are not native, and some of these organisms become invasive. South Africa was used as a case study to evaluate the potential for shipping to contribute to the introduction and establishment of marine and terrestrial alien species (i.e. establishment debt) and to assess how this varies across shipping routes and seasons. As a proxy for the number of species introduced (i.e. 'colonisation pressure') shipping movement data were used to determine, for each season, the number of ships that visited South African ports from foreign ports and the number of days travelled between ports. Seasonal marine and terrestrial environmental similarity between South African and foreign ports was then used to estimate the likelihood that introduced species would establish. These data were used to determine the seasonal relative contribution of shipping routes to South Africa's marine and terrestrial establishment debt. Additionally, distribution data were used to identify marine and terrestrial species that are known to be invasive elsewhere and which might be introduced to each South African port through shipping routes that have a high relative contribution to establishment debt. Shipping routes from Asian ports, especially Singapore, have a particularly high relative contribution to South Africa's establishment debt, while among South African ports, Durban has the highest risk of being invaded. There was seasonal variation in the shipping routes that have a high relative contribution to the establishment debt of the South African ports. The presented method provides a simple way to prioritise surveillance effort and our results indicate that, for South Africa, port-specific prevention strategies should be developed, a large portion of the available resources should be allocated to Durban, and seasonal variations and their consequences for prevention strategies should be explored further. (Résumé d'auteur

Structural insights into cardiolipin transfer from the Inner membrane to the outer membrane by PbgA in Gram-negative bacteria

The outer membrane (OM) of Gram-negative bacteria is a unique asymmetric lipid bilayer in which the outer leaflet is composed of lipopolysaccharide (LPS) and the inner leaflet is formed by glycerophospholipid (GPL). The OM plays a fundamental role in protecting Gram-negative bacteria from harsh environments and toxic compounds. The transport and assembly pathways for phospholipids of bacterial OM are unknown. Cardiolipin (CL) plays an important role in OM biogenesis and pathogenesis, and the inner membrane (IM) protein PbgA, containing five transmembrane domains and a globular domain in periplasm has been recently identified as a CL transporter from the IM to the OM with an unknown mechanism. Here we present the first two crystal structures of soluble periplasmic globular domain of PbgA from S. typhimurium and E. coli, which revealed that the globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting CLs. Our structural and functional studies shed an important light on the mechanism of CL transport in Gram-negative bacteria from the IM to the OM, which offers great potential for the development of novel antibiotics against multi-drug resistant bacterial infections

Study protocol of cost-effectiveness and cost-utility of a biopsychosocial multidisciplinary intervention in the evolution of non-specific sub-acute low back pain in the working population: cluster randomised trial.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain (LBP), with high incidence and prevalence rate, is one of the most common reasons to consult the health system and is responsible for a significant amount of sick leave, leading to high health and social costs. The objective of the study is to assess the cost-effectiveness and cost-utility analysis of a multidisciplinary biopsychosocial educational group intervention (MBEGI) of non-specific sub-acute LBP in comparison with the usual care in the working population recruited in primary healthcare centres. Methods/design: The study design is a cost-effectiveness and cost-utility analysis of a MBEGI in comparison with the usual care of non-specific sub-acute LBP.Measures on effectiveness and costs of both interventions will be obtained from a cluster randomised controlled clinical trial carried out in 38 Catalan primary health care centres, enrolling 932 patients between 18 and 65 years old with a diagnosis of non-specific sub-acute LBP. Effectiveness measures are: pharmaceutical treatments, work sick leave (% and duration in days), Roland Morris disability, McGill pain intensity, Fear Avoidance Beliefs (FAB) and Golberg Questionnaires. Utility measures will be calculated from the SF-12. The analysis will be performed from a social perspective. The temporal horizon is at 3 months (change to chronic LBP) and 12 months (evaluate the outcomes at long term. Assessment of outcomes will be blinded and will follow the intention-to-treat principle. Discussion: We hope to demonstrate the cost-effectiveness and cost-utility of MBEGI, see an improvement in the patients' quality of life, achieve a reduction in the duration of episodes and the chronicity of non-specific low back pain, and be able to report a decrease in the social costs. If the intervention is cost-effectiveness and cost-utility, it could be applied to Primary Health Care Centres. Trial registration: ISRCTN: ISRCTN5871969

Guidelines for the deployment and implementation of manufacturing scheduling systems

It has frequently been stated that there exists a gap between production scheduling theory and practice. In order to put theoretical findings into practice, advances in scheduling models and solution procedures should be embedded into a piece of software - a scheduling system - in companies. This results in a process that entails (1) determining its functional features, and (2) adopting a successful strategy for its development and deployment. In this paper we address the latter question and review the related literature in order to identify descriptions and recommendations of the main aspects to be taken into account when developing such systems. These issues are then discussed and classified, resulting in a set of guidelines that can help practitioners during the process of developing and deploying a scheduling system. In addition, identification of these issues can provide some insights to drive theoretical scheduling research towards those topics more in demand by practitioners, and thus help to close the aforementioned gap.Framiñan Torres, JM.; Ruiz García, R. (2012). Guidelines for the deployment and implementation of manufacturing scheduling systems. International Journal of Production Research. 50(7):1799-1812. doi:10.1080/00207543.2011.564670S17991812507Baek, D. H. (1999). A visualized human-computer interactive approach to job shop scheduling. International Journal of Computer Integrated Manufacturing, 12(1), 75-83. doi:10.1080/095119299130489Comesaña Benavides, J. A., & Carlos Prado, J. (2002). Creating an expert system for detailed scheduling. International Journal of Operations & Production Management, 22(7), 806-819. doi:10.1108/01443570210433562Bensana, E. 1986. An expert-system approach to industrial job-shop scheduling. In: Proceedings of the 1986 IEEE international conference on robotics and automation. 1986. Vol. 3, pp.1645–1650.Berglund, M., & Karltun, J. (2007). Human, technological and organizational aspects influencing the production scheduling process. International Journal of Production Economics, 110(1-2), 160-174. doi:10.1016/j.ijpe.2007.02.024Besbes, W., Teghem, J., & Loukil, T. (2010). Scheduling hybrid flow shop problem with non-fixed availability constraints. European J. of Industrial Engineering, 4(4), 413. doi:10.1504/ejie.2010.035652Bhattacharyya, S., & Koehler, G. J. (1998). Learning by Objectives for Adaptive Shop-Floor Scheduling. Decision Sciences, 29(2), 347-375. doi:10.1111/j.1540-5915.1998.tb01580.xBitran, G. R., & Tirupati, D. (1988). OR Practice—Development and Implementation of a Scheduling System for a Wafer Fabrication Facility. Operations Research, 36(3), 377-395. doi:10.1287/opre.36.3.377Buxey, G. (1989). Production scheduling: Practice and theory. 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F. (1984). ISIS?a knowledge-based system for factory scheduling. Expert Systems, 1(1), 25-49. doi:10.1111/j.1468-0394.1984.tb00424.xFraminan, J. M., & Ruiz, R. (2010). Architecture of manufacturing scheduling systems: Literature review and an integrated proposal. European Journal of Operational Research, 205(2), 237-246. doi:10.1016/j.ejor.2009.09.026Freed, T., Doerr, K. H., & Chang, T. (2007). In-house development of scheduling decision support systems: case study for scheduling semiconductor device test operations. International Journal of Production Research, 45(21), 5075-5093. doi:10.1080/00207540600818351Gao, C and Tang, L. 2008. A decision support system for color-coating line in steel industry. In: Proceedings of the IEEE international conference on automation and logistics, ICAL 2008. 2008. pp.1463–1468.Grant, T. J. (1986). Lessons for O.R. from A.I.: A Scheduling Case Study. Journal of the Operational Research Society, 37(1), 41-57. doi:10.1057/jors.1986.7Graves, S. C. 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Journal of Systems and Software, 19(2), 123-130. doi:10.1016/0164-1212(92)90063-pKnolmayer, G., Mertens, P., & Zeier, A. (2002). Supply Chain Management Based on SAP Systems. doi:10.1007/978-3-540-24816-3Leachman, R. C., Benson, R. F., Liu, C., & Raar, D. J. (1996). IMPReSS: An Automated Production-Planning and Delivery-Quotation System at Harris Corporation—Semiconductor Sector. Interfaces, 26(1), 6-37. doi:10.1287/inte.26.1.6MACCARTHY, B. L., & LIU, J. (1993). Addressing the gap in scheduling research: a review of optimization and heuristic methods in production scheduling. International Journal of Production Research, 31(1), 59-79. doi:10.1080/00207549308956713McKay, K. N., & Black, G. W. (2007). The evolution of a production planning system: A 10-year case study. Computers in Industry, 58(8-9), 756-771. doi:10.1016/j.compind.2007.02.002McKay, K. N., Safayeni, F. R., & Buzacott, J. A. (1988). Job-Shop Scheduling Theory: What Is Relevant? Interfaces, 18(4), 84-90. doi:10.1287/inte.18.4.84McKay, K. N., Morton, T. E., Ramnath, P., & Wang, J. (2000). ?Aversion dynamics? scheduling when the system changes. Journal of Scheduling, 3(2), 71-88. doi:10.1002/(sici)1099-1425(200003/04)3:23.0.co;2-0MCKAY, K., PINEDO, M., & WEBSTER, S. (2009). PRACTICE-FOCUSED RESEARCH ISSUES FOR SCHEDULING SYSTEMS*. Production and Operations Management, 11(2), 249-258. doi:10.1111/j.1937-5956.2002.tb00494.xMissbauer, H., Hauber, W., & Stadler, W. (2009). A scheduling system for the steelmaking-continuous casting process. A case study from the steel-making industry. International Journal of Production Research, 47(15), 4147-4172. doi:10.1080/00207540801950136Numao, M and Morishita, S. 1989. A scheduling environment for steel-making processes. In: Proceedings of the 5th conference on artificial intelligence applications. 1989. pp.279–286.Olhager, J., & Rapp, B. (1995). Operations Research Techniques in Manufacturing Planning and Control Systems. International Transactions in Operational Research, 2(1), 29-43. doi:10.1111/j.1475-3995.1995.tb00003.xPerez-Gonzalez, P., & Framinan, J. M. (2009). Scheduling permutation flowshops with initial availability constraint: Analysis of solutions and constructive heuristics. Computers & Operations Research, 36(10), 2866-2876. doi:10.1016/j.cor.2008.12.018Pinedo, M., & Yen, B. P.-C. (1997). Annals of Operations Research, 70, 359-378. doi:10.1023/a:1018986524234Portougal, V., & Robb, D. J. (2000). Production Scheduling Theory: Just Where Is It Applicable? Interfaces, 30(6), 64-76. doi:10.1287/inte.30.6.64.11623Reisman, A., Kumar, A., & Motwani, J. (1997). Flowshop scheduling/sequencing research: a statistical review of the literature, 1952-1994. IEEE Transactions on Engineering Management, 44(3), 316-329. doi:10.1109/17.618173Steffen, MS. 1986. A survey of artificial intelligence-based scheduling systems. In: Proceedings of the fall industrial engineering conference. 1986.Storer, R. H., Wu, S. D., & Vaccari, R. (1992). New Search Spaces for Sequencing Problems with Application to Job Shop Scheduling. Management Science, 38(10), 1495-1509. doi:10.1287/mnsc.38.10.1495Tang, L., & Wang, G. (2008). Decision support system for the batching problems of steelmaking and continuous-casting production. Omega, 36(6), 976-991. doi:10.1016/j.omega.2007.11.002T’kindt, V., Billaut, J.-C., Bouquard, J.-L., Lenté, C., Martineau, P., Néron, E., … Tacquard, C. (2005). The e-OCEA project: towards an Internet decision system for scheduling problems. Decision Support Systems, 40(2), 329-337. doi:10.1016/j.dss.2004.04.001Wiers, VCS. 1997. Human–computer interaction in production scheduling: Analysis and design of decision support systems for production scheduling tasks. Ph.D. Thesis, Technische Universiteit Eindhoven, NetherlandsWiers, V. C. S. (2002). A case study on the integration of APS and ERP in a steel processing plant. 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Polyfunctional T cell responses in children in early stages of chronic Trypanosoma cruzi infection contrast with monofunctional responses of long-term infected adults

Background: Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. Methodology/Principal Findings: To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children. Conclusions/Significance: Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects.Fil: Albareda, María Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: de Rissio, Ana María. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Tomas, Gonzalo. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Serjan, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Alvarez, María Gabriela. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Viotti, Rodolfo Jorge. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Fichera, Laura Edith. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Potente, Daniel Fernando. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Armenti, Alejandro. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Tarleton, Rick L.. University of Georgia; Estados UnidosFil: Laucella, Susana Adriana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Opening PANDORA's box: APEX observations of CO in PNe

CONTEXT: Observations of molecular gas have played a key role in developing the current understanding of the late stages of stellar evolution. AIMS: The survey Planetary nebulae AND their cO Reservoir with APEX (PANDORA) was designed to study the circumstellar shells of evolved stars with the aim to estimate their physical parameters. METHODS: Millimetre carbon monoxide (CO) emission is the most useful probe of the warm molecular component ejected by low- to intermediate-mass stars. CO is the second-most abundant molecule in the Universe, and the millimetre transitions are easily excited, thus making it particularly useful to study the mass, structure, and kinematics of the molecular gas. We present a large survey of the CO (J = 3−2) line using the Atacama Pathfinder EXperiment (APEX) telescope in a sample of 93 proto-planetary nebulae and planetary nebulae. RESULTS: CO (J = 3−2) was detected in 21 of the 93 objects. Only two objects (IRC+10216 and PN M2-9) had previous CO (J = 3−2) detections, therefore we present the first detection of CO (J = 3−2) in the following 19 objects: Frosty Leo, HD 101584, IRAS 19475+3119, PN M1-11, V* V852 Cen, IC 4406, Hen 2-113, Hen 2-133, PN Fg 3, PN Cn 3-1, PN M2-43, PN M1-63, PN M1-65, BD+30 3639, Hen 2-447, Hen 2-459, PN M3-35, NGC 3132, and NGC 6326. CONCLUSIONS: CO (J = 3−2) was detected in all 4 observed pPNe (100%), 15 of the 75 PNe (20%), one of the 4 wide binaries (25%), and in 1 of the 10 close binaries (10%). Using the CO (J = 3−2) line, we estimated the column density and mass of each source. The H2 column density ranges from 1.7 × 1018 to 4.2 × 1021 cm−2 and the molecular mass ranges from 2.7 × 10−4 to 1.7 × 10−1 M⊙