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Objetivo: analisar a incidência e os fatores relacionados à obstrução de cateter intravenoso periférico em adultos hospitalizados. Método: uma coorte prospectiva, realizada a partir da observação de 203 cateteres, entre fevereiro de 2019 e maio de 2020, em hospital público e de ensino brasileiro. Foram consideradas variáveis clínicas e do cateter. Os dados foram analisados descritivamente e por estatística inferencial. Resultados: o tempo de permanência variou entre um a 15 dias e a obstrução ocorreu em 7,5% das observações. Houve aumento do risco de obstrução em relação ao sexo (RR=0,49 / p=0,186), à idade (RR=1,20/ p=0,732), aos cateteres de maior calibre (RR=0,53/ p=0,250), à inserção no dorso da mão até antebraço (RR=2,33/ p=0,114) e ao tempo do cateter in situ (RR=033/ p=0,433). Conclusão: O cuidado diário e observação do cateter intravenoso periférico são importantes para minimizar o surgimento de complicações locais e sistêmicas e manter a patência do dispositivo.
Objective: to analyze the incidence and factors related to peripheral intravenous catheter obstruction in hospitalized adults. Method: a prospective cohort, based on the observation of 203 catheters, between February 2019 and May 2020, in a Brazilian public teaching hospital. Clinical and catheter variables were taken into account. The data was analyzed descriptively and using inferential statistics. Results: the length of stay ranged from one to 15 days and obstruction occurred in 7.5% of the observations. There was an increased obstruction risk in relation to gender (RR=0.49 / p=0.186), age (RR=1.20/ p=0.732), larger catheters (RR=0.53/ p=0.250), insertion in the back of the hand up to the forearm (RR=2.33/ p=0.114) and the time length the catheter was in situ (RR=033/ p=0.433). Conclusion: Daily care and observation of the peripheral intravenous catheter is important to minimize the appearance of local and systemic complications and maintain the patency of the device.
Objetivo: analizar la incidencia y los factores relacionados con la obstrucción del catéter intravenoso periférico en adultos hospitalizados. Método: cohorte prospectiva, realizada mediante la observación de 203 catéteres, entre febrero de 2019 y mayo de 2020, en un hospital escuela público brasileño. Se consideraron variables clínicas y del catéter. Los datos se analizaron de forma descriptiva y mediante estadística inferencial. Resultados: el tiempo de permanencia varió entre uno y 15 días y la obstrucción ocurrió en el 7,5% de las observaciones. Hubo mayor riesgo de obstrucción en relación con el sexo (RR=0,49 / p=0,186), la edad (RR=1,20 / p=0,732), los catéteres de mayor calibre (RR=0,53 / p= 0,250), la inserción en el dorso de la mano hasta el antebrazo (RR=2,33/ p=0,114) y el tiempo del catéter in situ (RR=033/ p=0,433). Conclusión: el cuidado diario y la observación del catéter intravenoso periférico son importantes para minimizar la aparición de complicaciones locales y sistémicas y mantener la permeabilidad del dispositivo.
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In this work, a high-fidelity digital twin was developed to support the design and testing of control strategies for drug product manufacturing via direct compression. The high-fidelity digital twin platform was based on typical pharmaceutical equipment, materials, and direct compression continuous processes. The paper describes in detail the material characterization, the Discrete Element Method (DEM) model and the DEM model parameter calibration approach and provides a comparison of the system's response to the experimental results for stepwise changes in the API concentration at the mixer inlet. A calibration method for a cohesive DEM contact model parameter estimation was introduced. To assure a correct prediction for a wide range of processes, the calibration approach contained four characterization experiments using different stress states and different measurement principles, namely the bulk density test, compression with elastic recovery, the shear cell, and the rotating drum. To demonstrate the sensitivity of the DEM contact parameters to the process response, two powder characterization data sets with different powder flowability were applied. The results showed that the calibration method could differentiate between the different material batches of the same blend and that small-scale material characterization tests could be used to predict the residence time distribution in a continuous manufacturing process.
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This paper is the second in a series of two that describes the application of discrete element method (DEM) and reduced order modeling to predict the effect of disturbances in the concentration of drug substance at the inlet of a continuous powder mixer on the concentration of the drug substance at the outlet of the mixer. In the companion publication, small-scale material characterization tests, a careful DEM parameter calibration and DEM simulations of the manufacturing process were used to develop a reliable RTD models. In the current work, the same calibration workflow was employed to evaluate the predictive ability of the resulting reduced-order model for an extended design space. DEM simulations were extrapolated using a relay race method and the cumulative RTD was accurately parameterized using the n-CSTR model. By performing experiments and simulations, a calibrated DEM model predicted the response of a continuous powder mixer to step changes in the inlet concentration of an API. Thus, carefully calibrated DEM models was used to guide and reduce experimental work and to establish an adequate control strategy. In addition, a further reduction in the computational effort was obtained by using the relay race method to extrapolate results. The predicted RTD curves were then parameterized to develop reduced order models and used to simulate the process in a matter of seconds. Overall, a control strategy evaluation tool based on high-fidelity DEM simulations was developed using material-sparing small-scale characterization tests.
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c-Src is involved in multiple signaling pathways and serves as a critical target in various cancers. Growing evidence suggests that prolonging a drug's residence time (RT) can enhance its efficacy and selectivity. Thus, the development of c-Src antagonists with longer residence time could potentially improve therapeutic outcomes. In this study, we employed molecular dynamics simulations to explore the binding modes and dissociation processes of c-Src with antagonists characterized by either long or short RTs. Our results reveal that the long RT compound DAS-DFGO-I (DFGO) occupies an allosteric site, forming hydrogen bonds with residues E310 and D404 and engaging in hydrophobic interactions with residues such as L322 and V377. These interactions significantly contribute to the long RT of DFGO. However, the hydrogen bonds between the amide group of DFGO and residues E310 and D404 are unstable. Substituting the amide group with a sulfonamide yielded a new compound, DFOGS, which exhibited more stable hydrogen bonds with E310 and D404, thereby increasing its binding stability with c-Src. These results provide theoretical guidance for the rational design of long residence time c-Src inhibitors to improve selectivity and efficacy.
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Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteína Tirosina Quinase CSK/química , Proteína Tirosina Quinase CSK/metabolismo , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/química , Quinases da Família src/metabolismo , Ligação Proteica , Interações Hidrofóbicas e Hidrofílicas , Sítio Alostérico , Sítios de LigaçãoRESUMO
Residence time of an element in the ocean is a consequence of its chemical behaviour and the various biogeochemical processes governing its distribution, sources, and sinks. Precise estimation of the residence time of beryllium(Be) is necessary for its application as a tracer for understanding present and paleo-environmental processes. We utilise cosmogenic 10Be and terrestrially derived 9Be measurements from surface sediments to estimate the residence time of Be in the Indian Ocean. Significant variation in Be residence time is observed, which ranges between 370 and 620 years in the central Indian Ocean, 64-205 years in the Bay of Bengal, 41-117 years in the Andaman Sea, and 179-443 years in the Arabian Sea. Large heterogeneity in the residence time of Be can be attributed to its variable scavenging efficiency in different regions. Active scavenging of Be by sediment particles contributed through various major rivers draining into the northern Indian Ocean results in short residence time of Be. The results of this study have significant implications for the selection of sample sites and the use of Be as a tracer in paleo reconstructions.
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Paldang Lake in South Korea is a river-type lake characterized by weak temperature stratification and a short water residence time. It exhibits complex flow structures resulting from the convergence of two major rivers, the North Han River (NHR) and the South Han River (SHR), and one small river, the Gyeongan Stream. Analyzing the spatio-temporal variations in microplastic (MP) concentration in Paldang Lake is important because of its significance as a water supply source for the metropolitan area. In this study, a quasi-three-dimensional MP transport model (MPT-Q3D) based on the Lagrangian particle-tracking technique was developed to analyze the trajectory and concentration distribution of MPs driven by shear dispersion in river-type lakes. Using the simulation results of MPT-Q3D, which were validated with MP monitoring data and EFDC simulations, we investigated the spatio-temporal variations in MP concentration during both low-flow and flood-flow periods. Simulation results showed that horizontal transport by shear flow contributed more to MP transport than vertical transport, including settling movements based on MP density. Thus, the MP transport during the low-flow period was significantly influenced by the recirculating flow induced by hydropeaking of the NHR, as well as flow blockage caused by the strong inflow momentum from the SHR. During the flood-flow period, flood discharge from the three tributary rivers had an equal influence on MP transport and the variation in MP concentrations around the water intake facilities. Furthermore, the MP residence time was primarily affected by variations in the flow characteristics of the inflowing tributaries rather than the properties of the MP types. Analysis of the influx and efflux of MPs in Paldang Lake revealed that polypropylene was the predominant constituent, accounting for 53.9â¯% and 75.2â¯% of all residual MPs during the low-flow and flood-flow periods, respectively.
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In this study, the fluxes of microplastics (mp) were quantified during a 12-month period for three rural headwater lake catchments in Muskoka-Haliburton, south-central Ontario, Canada. A novel catchment particle balance approach was used, incorporating inputs from atmospheric deposition and stream inflows against lake outflow and sedimentation. This approach provides the first reported observation-based estimates of microplastic residence time in freshwater lakes. Atmospheric deposition had the highest daily microplastic flux (3.95-8.09 mp/m2/day), compared to the inflow streams (2.21-2.34 mp/m2/day), suggesting that it is the dominant source of microplastics to rural regions. Approximately 44-71% of the deposited microplastics were retained in the terrestrial catchments and 30-49% of the microplastics in the stream inflows were retained in the study lakes. Given that output fluxes ranged from 0.72-3.76 mp/m2/day in the sediment and 1.18-1.66 mp/m2/day in the lake outflows, the microplastic residence time was estimated to be between 3 and 12 years, suggesting that lakes are an important reservoir for microplastics. Fibers were the dominant shape in atmospheric deposition, streamwater, and lake water; however, in lake sediment, there was a higher proportion of fragments. Across all media, poly(ethylene terephthalate) was the dominant polymer identified (23%).
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Lagos , Microplásticos , Poluentes Químicos da Água , Microplásticos/análise , Poluentes Químicos da Água/análise , Ontário , Monitoramento AmbientalRESUMO
Water quality stability in lakes and reservoirs is essential for drinking water safety and ecosystem health, especially given the frequent occurrence of extreme climate events. However, the relationship between water quality stability and water residence time (WRT) has not been well elucidated. In this study, we explored the relationship based on nitrogen (N) and phosphorus (P) concentrations data in 11 lakes and 49 reservoirs in the Yangtze-Huaihe River basin from 2010 to 2022. Additionally, we examined the effects of hydrometeorological characteristics, the geomorphology of water bodies and catchments, and land use on the WRT, establishing a link between climate change and the stability of N and P in these water bodies. The results showed that a significant correlation between the stability of N and P in lakes and reservoirs and their WRT. The longer WRT tends to coincide with decreased stability and higher nutrient concentrations. Hydrometeorological factors are the primary factors on the WRT, with precipitation exerting the greatest effect, particularly under extreme drought. In recent years, extreme climatic events have intensified the fluctuations of WRT, resulting in a renewed increase in N and P concentrations and deterioration in stability. These findings highlight the importance of incorporating meteorological and hydrological factors alongside reinforcing ecological restoration into lake and reservoir management strategies, and providing a scientific basis for future efforts aimed at enhancing lake and reservoir water quality stability and safeguarding aquatic ecosystems.
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The authors performed an ex vivo and in vivo evaluation of the ultrastructural effects on the conjunctival epithelial cells of a new multiple-action tear substitute containing cross-linked hyaluronic acid, lipids and trehalose (Trimix®), using scanning electron microscopy (SEM) with conjunctival impression cytology. The ex vivo study highlights the persistence and distribution of the product at 5 and 60 min on a monolayer of conjunctival epithelial cells and an increase in microvilli density at the 60 min evaluation. In vivo examination was conducted on three subjects with different grades of ocular surface inflammation, treated with one drop of the product twice daily for thirty days. At the baseline (T0) and twelve hours after the last administration of the tear drop (T30), impression cytology of the upper bulbar conjunctiva for SEM evaluation of conjunctival epithelial cells was carried out. Slit lamp examination (SLE), corneal and conjunctival Fluotest, tear film break-up time (TBUT), and ocular surface disease index (OSDI) questionnaires were also performed to correlate the ultrastructural results with the clinical findings. After 30 days of treatment, a significant improvement in all clinical and symptomatic parameters and in the condition of the ocular surface was detected, with microvillar regeneration and strengthening in all the patients, and a complete restoration in 2/3 of them. The persistence and distribution of the product on the epithelial cells was also noted 12 h after the last administration. The results, therefore, suggest a marked epitheliotropic effect along with a high residence time of the tear substitute.
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Understanding the relationship between a dam's size and its ecological effects is important for prioritization of river restoration efforts based on dam removal. Although much is known about the effects of large storage dams, this information may not be applicable to small dams, which represent the vast majority of dams being considered for removal. To better understand how dam effects vary with size, we conducted a multidisciplinary study of the downstream effect of dams on a range of ecological characteristics including geomorphology, water chemistry, periphyton, riparian vegetation, benthic macroinvertebrates, and fish. We related dam size variables to the downstream-upstream fractional difference in measured ecological characteristics for 16 dams in the mid-Atlantic region ranging from 0.9 to 57 m high, with hydraulic residence times (HRTs) ranging from 30 min to 1.5 years. For a range of physical attributes, larger dams had larger effects. For example, the water surface width below dams was greater below large dams. By contrast, there was no effect of dam size on sediment grain size, though the fraction of fine-grained bed material was lower below dams independently of dam size. Larger dams tended to reduce water quality more, with decreased downstream dissolved oxygen and increased temperature. Larger dams decreased inorganic nutrients (N, P, Si), but increased particulate nutrients (N, P) in downstream reaches. Aquatic organisms tended to have greater dissimilarity in species composition below larger dams (for fish and periphyton), lower taxonomic diversity (for macroinvertebrates), and greater pollution tolerance (for periphyton and macroinvertebrates). Plants responded differently below large and small dams, with fewer invasive species below large dams, but more below small dams. Overall, these results demonstrate that larger dams have much greater impact on the ecosystem components we measured, and hence their removal has the greatest potential for restoring river ecosystems.
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Ecossistema , Invertebrados , Rios , Animais , Invertebrados/fisiologia , Peixes/fisiologia , Conservação dos Recursos Naturais , Movimentos da Água , Monitoramento AmbientalRESUMO
While atmospheric microplastics are known to be transported over long distances, their residence times and transport processes lack clarity. This study utilized natural radionuclides 7Be, 210Pb, and 210Po to explore the transport of atmospheric microplastics in Tianjin, a coastal city in Northern China. Microplastic concentrations ranged from 0.03 to 0.13 particles m-3 over the course of a year. The proportion of microplastic fragments in winter was significantly higher than that in other seasons, with median microplastic sizes in autumn and winter being larger than those in spring and summer. The atmospheric microplastic surface was rough, exhibiting irregular pores and multiple depressions and cracks. Microplastics experienced vertical mixing with the upper atmosphere in April and August and were influenced by rainfall in July. The residence time of atmospheric particles ranged from 9.47 to 22.85 days throughout the year, with an average of 14.41 days. The peak residence time of atmospheric particulates in November may be correlated with increased 210Po levels from coal consumption. Their prolonged atmospheric presence and rough surface allow microplastics to act as carriers for various chemical pollutants, underscoring the complexity and potential risks associated with their presence in the atmosphere.
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Atmosfera , Microplásticos , Microplásticos/análise , Atmosfera/química , China , Radioisótopos de Chumbo/análise , Radioisótopos/análise , Monitoramento Ambiental , Estações do Ano , Berílio/análise , Polônio/análiseRESUMO
Epidemic models of susceptibles, exposed, infected, recovered and deceased (SΕIRD) presume homogeneity, constant rates and fixed, bilinear structure. They produce short-range, single-peak responses, hardly attained under restrictive measures. Tuned via uncertain I,R,D data, they cannot faithfully represent long-range evolution. A robust epidemic model is presented that relates infected with the entry rate to health care units (HCUs) via population averages. Model uncertainty is circumvented by not presuming any specific model structure, or constant rates. The model is tuned via data of low uncertainty, by direct monitoring: (a) of entries to HCUs (accurately known, in contrast to delayed and non-reliable I,R,D data) and (b) of scaled model parameters, representing population averages. The model encompasses random propagation of infections, delayed, randomly distributed entries to HCUs and varying exodus of non-hospitalized, as disease severity subdues. It closely follows multi-pattern growth of epidemics with possible recurrency, viral strains and mutations, varying environmental conditions, immunity levels, control measures and efficacy thereof, including vaccination. The results enable real-time identification of infected and infection rate. They allow design of resilient, cost-effective policy in real time, targeting directly the key variable to be controlled (entries to HCUs) below current HCU capacity. As demonstrated in ex post case studies, the policy can lead to lower overall cost of epidemics, by balancing the trade-off between the social cost of infected and the economic contraction associated with social distancing and mobility restriction measures.
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COVID-19 , Epidemias , Humanos , Epidemias/estatística & dados numéricos , COVID-19/transmissão , COVID-19/epidemiologia , COVID-19/prevenção & controle , Conceitos Matemáticos , Modelos Epidemiológicos , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/transmissão , SARS-CoV-2 , Número Básico de Reprodução/estatística & dados numéricos , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/transmissão , Doença pelo Vírus Ebola/prevenção & controle , Política de SaúdeRESUMO
In river networks, reservoirs are hotspots for nutrient transformations, providing multiple pathways for nitrogen processing. One of the less measured pathways is nitrogen deposition. Here, we investigated the decadal relationship between water residence time and nitrogen deposition using sediment cores from eight mainstem reservoirs within a river system containing two contrasting watersheds. One watershed was significantly urbanized with regulated flow and the other watershed was unregulated with extensive rural land use. We explored the relationship of sediment nitrogen concentrations across a range of residence times, land uses, and other parameters throughout this linked river-reservoir system. Results show that average annual residence time had the strongest relationship to nitrogen deposition when compared to reservoir volume, mean depth, surface area, outflow, and land use. Pigment analysis revealed that residence time influences nitrogen by allowing for longer periods of algal uptake, followed by deposition in particulate organic form. Supporting this mechanism, sedimentary C:N, with low values representing greater algal influence, expressed a strong and negative relationship with average annual residence time, as well as a positive relationship between residence time and photosynthetic pigments diagnostic of cyanobacteria, diatoms, and a combination of green algae+cyanobacteria. Furthermore, we investigated how drought conditions could alter residence times and intensify nitrogen cycling through primary productivity in reservoirs. Drought increased residence time by 45-60 %. This increase was estimated to raise sediment nitrogen concentrations by roughly 2.5-4 %.
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Sedimentos Geológicos , Nitrogênio , Rios , Sedimentos Geológicos/química , Monitoramento Ambiental/métodos , Cianobactérias/metabolismo , SecasRESUMO
The continuous permafrost in the valleys of Svalbard is dotted by pingos, which are small hills formed by the near surface freezing of ascending groundwater. In this study, we used 3H and Ra isotopes to inquire into the sub-surface residence time of groundwater discharging at these pingos. While its low 3H suggests that the pingo-associated groundwater is basically not modern (i.e. older than 60 years), Ra isotopes imply that most water has an underground residence time of several hundred years. This is deduced from the lower than equilibrium ratios (activity ratios<21.7) of the long-lived to short-lived 226Ra/223Ra. Since the freezing age of the main body of permafrost in this area is >4000 years, the presence of younger water at depth suggests that the aquifer has been recharged after permafrost formation, which could take place via faults or through the non-frozen base of wet glaciers. This active hydrology suggests that permafrost in the valleys of Svalbard was at least locally discontinuous during the Late Holocene, with likely further implications to the release of greenhouse gases during the pre-industrial period.
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Lithium tantalate (LiTaO3) perovskite finds wide use in pyroelectric detectors, optical waveguides and piezoelectric transducers, stemming from its good mechanical and chemical stability and optical transparency. Herein, we present a method for synthesis of LiTaO3 nanoparticles using a scalable Flame Spray Pyrolysis (FSP) technology, that allows the formation of LiTaO3 nanomaterials in a single step. Raman, XRD and TEM studies allow for comprehension of the formation mechanism of the LiTaO3 nanophases, with particular emphasis on the penetration of Li atoms into the Ta-oxide lattice. We show that, control of the High-Temperature Particle Residence Time (HTPRT) in the FSP flame, is the key-parameter that allows successful penetration of the -otherwise amorphous- Li phase into the Ta2O5 nanophase. In this way, via control of the HTPRT in the FSP process, we synthesized a series of nanostructured LiTaO3 particles of varying phase composition from {amorphous Li/Ta2O5/LiTaO3} to {pure LiTaO3, 15-25 nm}. Finally, the photophysical activity of the FSP-made LiTaO3 was validated for photocatalytic H2 production from H2O. These data are discussed in conjunction with the role of the phase composition of the LiTaO3 nanoparticles. More generally, the present work allows a better understanding of the mechanism of ABO3 perovskite formation that requires the incorporation of two cations, A and B, into the nanolattice.
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The dimeric kinesin-8 motors have the biological function of depolymerizing microtubules (MTs) from the plus end. However, the molecular mechanism of the depolymerization promoted by the kinesin-8 motors is still undetermined. Here, a model is proposed for the MT depolymerization by the kinesin-8 motors. Based on the model, the dynamics of depolymerization in the presence of the single motor at the MT plus end under no load and under load on the motor is studied theoretically. The dynamics of depolymerization in the presence of multiple motors at the MT plus end is also analyzed. The theoretical results explain well the available experimental data. The studies can also be applicable to other families of kinesin motors such as kinesin-13 mitotic centromere-associated kinesin motors that have the ability to depolymerize MTs.
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Cinesinas , Microtúbulos , Polimerização , Cinesinas/metabolismo , Cinesinas/química , Microtúbulos/metabolismo , Humanos , AnimaisRESUMO
The ecological impact of non-native species arises from their establishment in local assemblages. However, the rates of non-native spread in new regions and their determinants have not been comprehensively studied. Here, we combined global databases documenting the occurrence of non-native species and residence of non-native birds, mammals, and vascular plants at regional and local scales to describe how the likelihood of non-native occurrence and their proportion in local assemblages relate with their residence time and levels of human usage in different ecosystems. Our findings reveal that local non-native occurrence generally increases with residence time. Colonization is most rapid in croplands and urban areas, while it is slower and variable in natural or semi-natural ecosystems. Notably, non-native occurrence continues to rise even 200 years after introduction, especially for birds and vascular plants, and in other land-use types rather than croplands and urban areas. The impact of residence time on non-native proportions is significant only for mammals. We conclude that the continental exchange of biotas requires considerable time for effects to manifest at the local scale across taxa and land-use types. The unpredictability of future impacts, implied by the slow spread of non-native species, strengthens the call for stronger regulations on the exchange of non-native species to reduce the long-lasting invasion debt looming on ecosystems' future.
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Aves , Espécies Introduzidas , Mamíferos , Animais , Plantas , Ecossistema , Biodiversidade , Conservação dos Recursos NaturaisRESUMO
Tuberculosis remains a leading cause of death from a single infection worldwide. Drug resistance to existing and even new antimycobacterials calls for research into novel targets and unexplored mechanisms of action. Recently we reported on the development of tight-binding inhibitors of Mycobacterium tuberculosis (Mtb) lipoamide dehydrogenase (Lpd), which selectively inhibit the bacterial but not the human enzyme based on a differential modality of inhibitor interaction with these targets. Here we report on the striking improvement in inhibitor residence time on the Mtb enzyme associated with scaffold progression from an indazole to 2-cyanoindole. Cryo-EM of Lpd with the bound 2-cyanoindole inhibitor 19 confirmed displacement of the buried water molecule deep in the binding channel with a cyano group. The ensuing hours-long improvement in on-target residence time is associated with enhanced antibacterial activity in axenic culture and in primary mouse macrophages. Resistance to 2-cyanoindole inhibitors involves mutations within the inhibitor binding site that have little effect on inhibitor affinity but change the modality of inhibitor-target interaction, resulting in fast dissociation from Lpd. These findings underscore that on-target residence time is a major determinant of antibacterial activity and in vivo efficacy.
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Di-Hidrolipoamida Desidrogenase , Indazóis , Indóis , Mycobacterium tuberculosis , Indóis/química , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Di-Hidrolipoamida Desidrogenase/antagonistas & inibidores , Di-Hidrolipoamida Desidrogenase/metabolismo , Indazóis/química , Indazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Animais , Testes de Sensibilidade Microbiana , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antituberculosos/farmacologia , Antituberculosos/química , Relação Estrutura-Atividade , Estrutura Molecular , HumanosRESUMO
G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1-4 kT, and timescales of 1-10 µs. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and µs timescales, that we correlate with the annular, intermediate and non-annular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.