RESUMO
Peroral endoscopic myotomy (POEM) is a safe and effective minimally invasive treatment for achalasia. Postoperative reflux rates remain high. The functional luminal imaging probe (FLIP) allows intraoperative measurement of lower esophageal distensibility during POEM. In theory, this enables a tailoring of myotomies to ensure adequate distensibility while minimizing postoperative reflux risk. Two prospectively collected POEM databases were analyzed from two UK tertiary upper GI centers. The operators in each center used FLIP measurements to ensure adequate myotomy. Outcome measures included Eckardt score (where <3 indicated clinical success) and proton-pump inhibitor use (PPI), collected at the first postoperative appointment. Length of stay was recorded as were complications. In all, 142 patients underwent POEM between 2015 and 2019. Overall, 90% (128/142) had postoperative Eckardt scores of <3 at 6 weeks. Clinical success improved to 93% (66/71) in the latter half of each series with a significantly higher rate of complete symptom resolution (53 versus 26%, P = 0.003). In all, 79% of the poor responders had previous interventions compared with 55% of responders (P = 0.09). Median post-myotomy distensibility index was 4.0 mm2/mmHg in responders and 2.9 in nonresponders (P = 0.16). Myotomy length of <7 cm was associated with 93% clinical success and 40% post op PPI use compared with 60% PPI use with longer myotomies. There were two type IIIa, two type IIIb, and one IV Clavien-Dindo complications. This is the largest series of endoluminal functional lumen imaging probe (EndoFLIP)-tailored POEM in the UK to date. The shorter myotomies, allowed through EndoFLIP tailoring, remained clinically effective at 6 weeks. Complete symptom response rates improved in the latter half of each series. More data will be needed from high-volume collaborations to decipher optimal myotomy profiles based on EndoFLIP parameters.
Assuntos
Acalasia Esofágica , Refluxo Gastroesofágico , Miotomia , Cirurgia Endoscópica por Orifício Natural , Humanos , Cirurgia Endoscópica por Orifício Natural/métodos , Acalasia Esofágica/cirurgia , Resultado do Tratamento , Miotomia/métodos , Reino Unido , Esfíncter Esofágico Inferior , Esofagoscopia/métodosRESUMO
The ability to model the activity of a protein using quantitative structure-activity relationships (QSAR) requires descriptors for the 20 naturally coded amino acids. In this work we show that by modifying some established descriptors we were able to model the activity data of 140 mutants of the enzyme epoxide hydrolase with improved accuracy. These new descriptors (referred to as physical descriptors) also gave very good results when tested against a series of four dipeptide data sets. The physical descriptors encode the amino acids using only two orthogonal scales: the first is strongly linked to hydrophilicity/hydrophobicity, and the second, to the volume of the amino acid residue. The use of these new amino acid descriptors should result in simpler and more readily interpretable models for the enzyme activity (and potentially other functions of interest, e.g., secondary and tertiary structure) of peptides and proteins.
Assuntos
Epóxido Hidrolases/química , Peptídeos/química , Proteínas/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores Enzimáticos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Relação Quantitativa Estrutura-Atividade , Especificidade por SubstratoRESUMO
In directed evolution (DE) the assessment of candidate enzymes and their modification is essential. In this study we have investigated genetic algorithms (GAs) in this context and conducted a systematic study of the behavior of GAs on 20 fitness landscapes (FLs) of varying complexity. This has allowed the tuning of the GAs to be explored. On the basis of this study, recommendations for the best GA settings to use for a GA-directed high-throughput experimental program (in which populations and the number of generations is necessarily low) are reported. The FLs were based upon simple linear models and were characterized by the behavior of the GA on the landscape as demonstrated by stall plots and the footprints and adhesion of candidate solutions, which highlighted local optima (LOs). In order to maximize progress of the GA and to reduce the chances of becoming stuck in a LO it was best to use: 1)â a large number of generations, 2)â high populations, 3)â removal of duplicate sequences (clones), 4)â double mutation, and 5)â high selection pressure (the two best individuals go to the next generation), and 6)â to consider using a designed sequence as the starting point of the GA run. We believe that these recommendations might be appropriate starting points for studies employing GAs within DE experiments.
Assuntos
Algoritmos , Evolução Molecular Direcionada/estatística & dados numéricos , Epóxido Hidrolases/genética , Modelos Genéticos , Epóxido Hidrolases/metabolismo , Expressão Gênica , Ensaios de Triagem em Larga Escala , Modelos Lineares , Mutação , Análise de Componente PrincipalRESUMO
Phenolic and nitro-aromatic compounds are extremely toxic components of atmospheric aerosol that are currently not well understood. In this Article, solid and subcooled-liquid-state saturation vapor pressures of phenolic and nitro-aromatic compounds are measured using Knudsen Effusion Mass Spectrometry (KEMS) over a range of temperatures (298-318 K). Vapor pressure estimation methods, assessed in this study, do not replicate the observed dependency on the relative positions of functional groups. With a few exceptions, the estimates are biased toward predicting saturation vapor pressures that are too high, by 5-6 orders of magnitude in some cases. Basic partitioning theory comparisons indicate that overestimation of vapor pressures in such cases would cause us to expect these compounds to be present in the gas state, whereas measurements in this study suggest these phenolic and nitro-aromatic will partition into the condensed state for a wide range of ambient conditions if absorptive partitioning plays a dominant role. While these techniques might have both structural and parametric uncertainties, the new data presented here should support studies trying to ascertain the role of nitrogen containing organics on aerosol growth and human health impacts.
Assuntos
Pressão de Vapor , Volatilização , Nitrocompostos , Hidrocarbonetos Policíclicos Aromáticos , TemperaturaRESUMO
The past 20â years have seen two great changes in the practice of medicine: the widespread adoption of evidence-based medicine, and the increasing challenge of managing complex multimorbid patients. Both these developments have resulted in clinical rules and protocols becoming ever more abundant and increasingly critical to delivering safe and effective patient care. These evidence-based clinical rules perform at least as well as expert opinion, and the increasing volume and quality of available clinical data suggests their performance could continue to improve. This article considers why clinicians deviate from effective rules, highlighting key issues such as the persisting culture of heroism, institutional inertia, deference to authority and personal heuristics. We argue that better rules can be created, and that clinical improvements will follow if there is a 'common knowledge' of these rules. Furthermore, we argue that there is a ceiling to the effectiveness of any rule, even one as simple as ensuring hand hygiene, unless individuals are held accountable for transgressions.
Assuntos
Atitude do Pessoal de Saúde , Protocolos Clínicos , Medicina Baseada em Evidências , Fidelidade a Diretrizes , Humanos , Cultura Organizacional , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Melhoria de Qualidade , Responsabilidade SocialRESUMO
Laboratory measurements of vapour pressures for atmospherically relevant compounds were collated and used to assess the accuracy of vapour pressure estimates generated by seven estimation methods and impacts on predicted secondary organic aerosol. Of the vapour pressure estimation methods that were applicable to all the test set compounds, the Lee-Kesler [Reid et al., The Properties of Gases and Liquids, 1987] method showed the lowest mean absolute error and the Nannoolal et al. [Nannoonal et al., Fluid Phase Equilib., 2008, 269, 117-133] method showed the lowest mean bias error (when both used normal boiling points estimated using the Nannoolal et al. [Nannoolal et al., Fluid Phase Equilib., 2004, 226, 45-63] method). The effect of varying vapour pressure estimation methods on secondary organic aerosol (SOA) mass loading and composition was investigated using an absorptive partitioning equilibrium model. The Myrdal and Yalkowsky [Myrdal and Yalkowsky, Ind. Eng. Chem. Res., 1997, 36, 2494-2499] vapour pressure estimation method using the Nannoolal et al. [Nannoolal et al., Fluid Phase Equilib., 2004, 226, 45-63] normal boiling point gave the most accurate estimation of SOA loading despite not being the most accurate for vapour pressures alone.
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The 1.88-Ga Gunflint biota is one of the most famous Precambrian microfossil lagerstätten and provides a key record of the biosphere at a time of changing oceanic redox structure and chemistry. Here, we report on pyritized replicas of the iconic autotrophic Gunflintia-Huroniospora microfossil assemblage from the Schreiber Locality, Canada, that help capture a view through multiple trophic levels in a Paleoproterozoic ecosystem. Nanoscale analysis of pyritic Gunflintia (sheaths) and Huroniospora (cysts) reveals differing relic carbon and nitrogen distributions caused by contrasting spectra of decay and pyritization between taxa, reflecting in part their primary organic compositions. In situ sulfur isotope measurements from individual microfossils (δ(34)S(V-CDT) +6.7 to +21.5) show that pyritization was mediated by sulfate-reducing microbes within sediment pore waters whose sulfate ion concentrations rapidly became depleted, owing to occlusion of pore space by coeval silicification. Three-dimensional nanotomography reveals additional pyritized biomaterial, including hollow, cellular epibionts and extracellular polymeric substances, showing a preference for attachment to Gunflintia over Huroniospora and interpreted as components of a saprophytic heterotrophic, decomposing community. This work also extends the record of remarkable biological preservation in pyrite back to the Paleoproterozoic and provides criteria to assess the authenticity of even older pyritized microstructures that may represent some of the earliest evidence for life on our planet.
Assuntos
Fósseis , Geologia/métodos , Paleontologia/métodos , Carbono/química , Ecossistema , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Processos Heterotróficos , Microscopia Eletrônica de Transmissão , Software , Análise Espectral Raman , Isótopos de Enxofre/análiseRESUMO
In order to model the properties and chemical composition of secondary organic aerosol (SOA), estimated physical property data for many thousands of organic compounds are required. Seven methods for estimating liquid density are assessed against experimental data for a test set of 56 multifunctional organic compounds. The group contribution method of Schroeder coupled with the Rackett equation using critical properties by Nannoolal was found to give the best liquid density values for this test set. During this work some problems with the representation of certain groups (aromatic amines and phenols) within the critical property estimation methods were identified, highlighting the importance (and difficulties) of deriving the parameters of group contribution methods from good quality experimental data. A selection of the estimation methods are applied to the 2742 compounds of an atmospheric chemistry mechanism, which showed that they provided consistent liquid density values for compounds with such atmospherically important (but poorly studied) functional groups as hydroperoxide, peroxide, peroxyacid, and PAN. Estimated liquid density values are also presented for a selection of compounds predicted to be important in atmospheric SOA. Hygroscopic growth factor (a property expected to depend on liquid density) has been calculated for a wide range of particle compositions. A low sensitivity of the growth factor to liquid density was found, and a single density value of 1350 kg·m(-3) could be used for all multicomponent SOA in the calculation of growth factors for comparison with experimentally measured values in the laboratory or the field without incurring significant error.
Assuntos
Aerossóis/química , Poluentes Atmosféricos/química , Atmosfera/análise , Compostos Orgânicos Voláteis/química , Aminas/química , Modelos Químicos , Peróxidos/química , Transição de Fase , Fenóis/química , Água/químicaRESUMO
A simple approach to calculate liquid-liquid phase separation has been developed based on the derivation of partitioning coefficients between multiple liquid phases and inclusion in a framework used to partition an arbitrary number of compounds between the vapour and particle phases in an atmospheric aerosol. The representation compares favourably with a more complex and expensive benchmark gas-particle thermodynamic model for simple well-constrained systems. The model has then been applied to consider liquid phase separation in multicomponent particles formed by the equilibration of organic products generated by a near-explicit model of VOC oxidation. Inclusion of phase separation decreases the predicted mass of condensed organic material by -10 to -50%, dependent on the concentration of semi-volatile components and ambient conditions in the model scenario. The current study considers only two liquid phases, but the framework can readily accommodate an arbitrary number, though this is beyond the scope of the current work. Uncertainty introduced by the omission of phase separation is far lower than existing uncertainties in pure component vapour pressures, where orders of magnitude differences in predicted mass are found, though the bias introduced when choosing a particular method for estimating the saturation vapour pressure will influence the magnitude of phase separation. The proposed technique is the first to be used to practically deal with the many hundreds or thousands of components present in the ambient atmospheric aerosol.
Assuntos
Aerossóis/química , Gases/química , Compostos Inorgânicos/química , Modelos Químicos , Compostos Orgânicos/químicaRESUMO
This paper reports indoor secondary organic aerosol, SOA, composition based on the results from an improved model for indoor air chemistry. The model uses a detailed chemical mechanism that is near-explicit to describe the gas-phase degradation of relevant indoor VOC species. In addition, gas-to-particle partitioning is included for oxygenated products formed from the degradation of limonene, the most ubiquitous terpenoid species in the indoor environment. The detail inherent in the chemical mechanism permits the indoor SOA composition to be reported in greater detail than currently possible using experimental techniques. For typical indoor conditions in the suburban UK, SOA concentrations are ~1 µg m(-3) and dominated by nitrated material (~85%), with smaller contributions from peroxide (12%), carbonyl (3%), and acidic (1%) material. During cleaning activities, SOA concentrations can reach 20 µg m(-3) with the composition dominated by peroxide material (73%), with a smaller contribution from nitrated material (21%). The relative importance of these different moieties depends crucially (in order) on the outdoor concentration of O(3), the deposition rates employed and the scaling factor value applied to the partitioning coefficient. There are currently few studies that report observation of aerosol composition indoors, and most of these have been carried out under conditions that are not directly relevant. This study highlights the need to investigate SOA composition in real indoor environments. Further, there is a need to measure deposition rates for key indoor air species on relevant indoor surfaces and to reduce the uncertainties that still exist in gas-to-particle phase parametrization for both indoor and outdoor air chemistry models.
Assuntos
Aerossóis/análise , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Nitratos/análise , Peróxidos/análise , Monitoramento Ambiental , Modelos QuímicosRESUMO
The enrichment of redox-sensitive trace metals in ancient marine sedimentary rocks has been used to determine the timing of the oxidation of the Earth's land surface. Chromium (Cr) is among the emerging proxies for tracking the effects of atmospheric oxygenation on continental weathering; this is because its supply to the oceans is dominated by terrestrial processes that can be recorded in the Cr isotope composition of Precambrian iron formations. However, the factors controlling past and present seawater Cr isotope composition are poorly understood. Here we provide an independent and complementary record of marine Cr supply, in the form of Cr concentrations and authigenic enrichment in iron-rich sedimentary rocks. Our data suggest that Cr was largely immobile on land until around 2.48 Gyr ago, but within the 160 Myr that followed--and synchronous with independent evidence for oxygenation associated with the Great Oxidation Event (see, for example, refs 4-6)--marked excursions in Cr content and Cr/Ti ratios indicate that Cr was solubilized at a scale unrivalled in history. As Cr isotope fractionations at that time were muted, Cr must have been mobilized predominantly in reduced, Cr(III), form. We demonstrate that only the oxidation of an abundant and previously stable crustal pyrite reservoir by aerobic-respiring, chemolithoautotrophic bacteria could have generated the degree of acidity required to solubilize Cr(III) from ultramafic source rocks and residual soils. This profound shift in weathering regimes beginning at 2.48 Gyr ago constitutes the earliest known geochemical evidence for acidophilic aerobes and the resulting acid rock drainage, and accounts for independent evidence of an increased supply of dissolved sulphate and sulphide-hosted trace elements to the oceans around that time. Our model adds to amassing evidence that the Archaean-Palaeoproterozoic boundary was marked by a substantial shift in terrestrial geochemistry and biology.
Assuntos
Bactérias Aeróbias/metabolismo , Cromo/química , Sedimentos Geológicos/química , Ferro/metabolismo , Oxirredução , Sulfetos/metabolismo , Cromo/análise , Sedimentos Geológicos/microbiologia , Concentração de Íons de Hidrogênio , Ferro/química , Rios , Água do Mar/química , Fatores de TempoRESUMO
In our earlier work, we have demonstrated that it is possible to characterize binary mixtures using single component descriptors by applying various mixing rules. We also showed that these methods were successful in building predictive QSPR models to study various mixture properties of interest. Here in, we developed a QSPR model of an excess thermodynamic property of binary mixtures i.e. excess molar volume (V(E) ). In the present study, we use a set of mixture descriptors which we earlier designed to specifically account for intermolecular interactions between the components of a mixture and applied successfully to the prediction of infinite-dilution activity coefficients using neural networks (part 1 of this series). We obtain a significant QSPR model for the prediction of excess molar volume (V(E) ) using consensus neural networks and five mixture descriptors. We find that hydrogen bond and thermodynamic descriptors are the most important in determining excess molar volume (V(E) ), which is in line with the theory of intermolecular forces governing excess mixture properties. The results also suggest that the mixture descriptors utilized herein may be sufficient to model a wide variety of properties of binary and possibly even more complex mixtures.
RESUMO
Some of Earth's largest iron-nickel (Fe-Ni) sulfide ore deposits formed during the Archean and early Proterozoic. Establishing the origin of the metals and sulfur in these deposits is critical for understanding their genesis. Here, we present multiple sulfur isotope data implying that the sulfur in Archean komatiite-hosted Fe-Ni sulfide deposits was previously processed through the atmosphere and then accumulated on the ocean floor. High-temperature, mantle-derived komatiite magmas were then able to incorporate the sulfur from seafloor hydrothermal sulfide accumulations and sulfidic shales to form Neoarchean komatiite-hosted Fe-Ni sulfide deposits at a time when the oceans were sulfur-poor.
RESUMO
It has been suggested that a decrease in atmospheric methane levels triggered the progressive rise of atmospheric oxygen, the so-called Great Oxidation Event, about 2.4 Gyr ago. Oxidative weathering of terrestrial sulphides, increased oceanic sulphate, and the ecological success of sulphate-reducing microorganisms over methanogens has been proposed as a possible cause for the methane collapse, but this explanation is difficult to reconcile with the rock record. Banded iron formations preserve a history of Precambrian oceanic elemental abundance and can provide insights into our understanding of early microbial life and its influence on the evolution of the Earth system. Here we report a decline in the molar nickel to iron ratio recorded in banded iron formations about 2.7 Gyr ago, which we attribute to a reduced flux of nickel to the oceans, a consequence of cooling upper-mantle temperatures and decreased eruption of nickel-rich ultramafic rocks at the time. We measured nickel partition coefficients between simulated Precambrian sea water and diverse iron hydroxides, and subsequently determined that dissolved nickel concentrations may have reached approximately 400 nM throughout much of the Archaean eon, but dropped below approximately 200 nM by 2.5 Gyr ago and to modern day values ( approximately 9 nM) by approximately 550 Myr ago. Nickel is a key metal cofactor in several enzymes of methanogens and we propose that its decline would have stifled their activity in the ancient oceans and disrupted the supply of biogenic methane. A decline in biogenic methane production therefore could have occurred before increasing environmental oxygenation and not necessarily be related to it. The enzymatic reliance of methanogens on a diminishing supply of volcanic nickel links mantle evolution to the redox state of the atmosphere.
Assuntos
Euryarchaeota/metabolismo , Níquel/análise , Oxirredução , Água do Mar/química , Água do Mar/microbiologia , Atmosfera/química , Sedimentos Geológicos/química , Ferro/análise , Níquel/metabolismo , Oceanos e MaresRESUMO
The hypothesis that the establishment of a permanently oxygenated atmosphere at the Archaean-Proterozoic transition (approximately 2.5 billion years ago) occurred when oxygen-producing cyanobacteria evolved is contradicted by biomarker evidence for their presence in rocks 200 million years older. To sustain vanishingly low oxygen levels despite near-modern rates of oxygen production from approximately 2.7-2.5 billion years ago thus requires that oxygen sinks must have been much larger than they are now. Here we propose that the rise of atmospheric oxygen occurred because the predominant sink for oxygen in the Archaean era-enhanced submarine volcanism-was abruptly and permanently diminished during the Archaean-Proterozoic transition. Observations are consistent with the corollary that subaerial volcanism only became widespread after a major tectonic episode of continental stabilization at the beginning of the Proterozoic. Submarine volcanoes are more reducing than subaerial volcanoes, so a shift from predominantly submarine to a mix of subaerial and submarine volcanism more similar to that observed today would have reduced the overall sink for oxygen and led to the rise of atmospheric oxygen.
Assuntos
Atmosfera/química , Sedimentos Geológicos/química , Oxigênio/metabolismo , Erupções Vulcânicas , Cianobactérias/metabolismo , História Antiga , Oceanos e Mares , Oxigênio/análise , Fotossíntese , Isótopos de Enxofre , Fatores de TempoRESUMO
In this paper we report an attempt to apply the QSPR approach for the analysis of data for mixtures. This is an extension of the conventional QSPR approach to the analysis of data for single molecules. The QSPR methodology was applied to a data set of experimental measured density of binary liquid mixtures compiled from the literature. The present study is aimed to develop models to predict the "delta" value of a mixture i.e., deviation of the experimental mixture density (MED) from the ideal, mole-weighted calculated mixture density (MCD). The QSPR was investigated in two perspectives (QMD-I and QMD-II) with respect to the creation of training and test sets. The study resulted in significant ensemble neural network and k-nearest neighbor models having statistical parameters r2, q2(10cv) greater than 0.9, and pred_r2 greater than 0.75. The developed models can be used to predict the delta and hence the density of a new mixture. The QSPR analysis shows the importance of hydrogen bond, polar, shape, and thermodynamic descriptors in determining mixture density, thus aiding in the understanding of molecular interactions important in molecular packing in the mixtures.