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P450 enzymes naturally perform selective hydroxylations and epoxidations of unfunctionalized hydrocarbon substrates, among other reactions. The adaptation of P450 enzymes to a particular oxidative reaction involving alkenes is of great interest for the design of new synthetically useful biocatalysts. However, the mechanism that these enzymes utilize to precisely modulate the chemoselectivity and distinguishing between competing alkene double bond epoxidations and allylic C-H hydroxylations is sometimes not clear, which hampers the rational design of specific biocatalysts. In a previous work, a P450 from Labrenzia aggregata (P450LA1) was engineered in the laboratory using directed evolution to catalyze the direct oxidation of trans-ß-methylstyrene to phenylacetone. The final variant, KS, was able to overcome the intrinsic preference for alkene epoxidation to directly generate a ketone product via the formation of a highly reactive carbocation intermediate. Here, additional library screening along this evolutionary lineage permitted to serendipitously detect a mutation that overcomes epoxidation and carbonyl formation by exhibiting a large selectivity of 94 % towards allylic C-H hydroxylation. A multiscalar computational methodology was applied to reveal the molecular basis towards this hydroxylation preference. Enzyme modelling suggests that introduction of a bulky substitution dramatically changes the accessible conformations of the substrate in the active site, thus modifying the enzymatic selectivity towards terminal hydroxylation and avoiding the competing epoxidation pathway, which is sterically hindered.
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Alquenos , Biocatálisis , Sistema Enzimático del Citocromo P-450 , Oxidación-Reducción , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/química , Alquenos/química , Alquenos/metabolismo , Especificidad por SustratoRESUMEN
Tree of Heaven (Ailanthus altissima (Mill.) Swingle) is a tree native to China which has invaded disturbed areas in many regions worldwide. Its presence endangers natural ecosystems by displacing native species, modifying habitats, changing community structures, and affecting ecosystem processes. Its invasive nature is enhanced by its high ability to reproduce both vegetatively through root regrowth and sexually through seeds. Seeds, which are wind dispersed, are the main mechanism by which this species reaches new habitats. When they germinate and develop the root system, roots emit new shoots that contribute to a rapid increase in the tree density and the subsequent expansion of the population nearby. The contradictory results about the ecological requirements for seeds to germinate and their degree of dormancy and longevity indicate the complexity and difficulty of understanding the mechanisms that govern the biology and adaptability of this plant. The management of this weed aims at its eradication, with programs based on herbicide applications carried out by injecting the active ingredient directly to the trunk. But, not many active ingredients have shown total control, so new ones should be tested in order to increase the range of available herbicides. During the last few decades, some biological agents have been identified, but their efficacy in controlling the tree and their safety for the local flora have not yet been determined. A correct management strategy should take into account all these aspects in order to contain the expansion of this species and, ultimately, allow its eradication.
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BACKGROUND AND HYPOTHESIS: There is uncertainty about the relationship between the family intelligence quotient (IQ) deviation and the risk for schizophrenia spectrum disorders (SSD). This study tested the hypothesis that IQ is familial in first episode psychosis (FEP) patients and that their degree of familial resemblance is associated with different profiles. STUDY DESIGN: The participants of the PAFIP-FAMILIAS project (129 FEP patients, 143 parents, and 97 siblings) completed the same neuropsychological battery. IQ-familiality was estimated through the Intraclass Correlation Coefficient (ICC). For each family, the intra-family resemblance score (IRS) was calculated as an index of familial similarity. The FEP patients were subgrouped and compared according to their IRS and IQ. STUDY RESULTS: IQ-familiality was low-moderate (ICC = 0.259). A total of 44.9% of the FEP patients had a low IRS, indicating discordancy with their family-IQ. Of these patients, those with low IQ had more schizophrenia diagnosis and a trend towards poorer premorbid adjustment in childhood and early adolescence. Whereas FEP patients with low IQ closely resembling their family-IQ were characterized by having the lowest performance in executive functions. CONCLUSIONS: The deviation from the familial cognitive performance may be related to a particular pathological process in SSD. Individuals with low IQ who do not reach their cognitive familial potential show difficulties in adjustment since childhood, probably influenced by environmental factors. Instead, FEP patients with high phenotypic family resemblance might have a more significant genetic burden for the disorder.
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Trastornos Psicóticos , Esquizofrenia , Adolescente , Humanos , Trastornos Psicóticos/complicaciones , Esquizofrenia/complicaciones , Pruebas de Inteligencia , Cognición , InteligenciaRESUMEN
Respiratory patterns present great variability, both in healthy subjects and in patients with different diseases and forms of nasal, oral, superficial or deep breathing. The analysis of this variability depends, among others, on the device used to record the signals that describe these patterns. In this study, we propose multivariable regression models to estimate tidal volume (VT) considering different breathing patterns. Twenty-three healthy volunteers underwent continuous multisensor recordings considering different modes of breathing. Respiratory flow and volume signals were recorded with a pneumotachograph and thoracic and abdominal respiratory inductive plethysmographic bands. Several respiratory parameters were extracted from the volume signals, such as inspiratory and expiratory areas (Areains, Areaexp), maximum volume relative to the cycle start and end (VTins, VTexp), inspiratory and expiratory time (Tins, Texp), cycle duration (Ttot), and normalized parameters of clinical interest. The parameters with the greatest individual predictive power were combined using multivariable models to estimate VT. Their performance were quantified in terms of determination coefficient (R2), relative error (ER) and interquartile range (IQR). Using only three parameters, the results obtained for the thoracic band (VTexp, Ttot, Areaexp) were better than those obtained from the abdominal band (VTexp, Tins, Areains) with R2 = 0.94 (IQR: 0.07); ER = 6.99 (IQR: 6.12) vs R2 = 0.91 (IQR: 0.09), ER = 8.70 (IQR: 4.62). Overall performance increased to R2 = 0.97 (IQR: 0.02) and ER = 4.60 (IQR: 3.68) when parameters from the different bands were combined, further improving when was applied to segments with different inspiration-expiration patterns. In particular, the nose-nose ER = 1.39 (IQR: 0.73), nose-mouth ER = 2.11 (IQR: 1.23) and mouth-mouth ER = 2.29 (IQR: 1.44) patterns showed the best results compared to those obtained for basal, shallow and deep breathing.Clinical relevance- Respiratory pattern variability can be described using multivariable regression model for tidal volume.
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Respiración , Frecuencia Respiratoria , Humanos , Volumen de Ventilación Pulmonar , NarizRESUMEN
Accurate monitoring of respiratory activity can lead to early identification and treatment of possible respiratory failure. However, spontaneous breathing can vary considerably. To quantify this variability, this study aimed at comparing the breathing pattern characteristics obtained from several recording sensors during different breathing types. Respiratory activity was recorded with a pneumotachograph and two inductive plethysmographic bands, thoracic and abdominal, in 23 healthy volunteers (age 21.5±1.2 years, 13 females). The subjects were asked to breathe at their natural rate, in successive stages: first freely, then through their nose, nose and mouth, mouth alone, and finally deep and shallow. Both band signals were compared to the pneumotach-derived (gold standard) volume signal. The time series of inspiratory and expiratory duration, total cycle duration and tidal volume were estimated from each of these signals, and also from the sum of the thoracic and abdominal bands. This composite signal showed the highest correlation with the volume signal for almost all subjects, and also had a significantly higher correlation with those obtained from the gold standard volume, compared to either band. In general, breathing parameters increased from basal to nose-mouth breathing, had a minimum in shallow breathing and a maximum in deep breathing. Women exhibited a significantly longer exhalation phase than men during deep breathing, in the combined bands and the gold standard volume. In conclusion, variations in respiratory cycle morphology in different breathing types can be well captured by the simple addition of abdominal and thoracic band signals.Clinical Relevance- Breathing pattern variability can be identified by the combination of abdominal and thoracic bands.
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Espiración , Respiración , Masculino , Humanos , Femenino , Adulto Joven , Adulto , Voluntarios Sanos , Volumen de Ventilación Pulmonar , NarizRESUMEN
Cardiorespiratory interaction is related to the heart rate variability (HRV) synchronized with respiration. These metrics help to comprehend the autonomic nervous system (ANS) functionality in cardiovascular mechanisms. In this work, we aim to study the HRV in healthy subjects aged 18-24 years during the breathing techniques based on deep breaths followed by apnoeas, developed by Wim Hof (WHM). The attributes of all participates have been treated as a group and therefore, separated by gender. A total of 11 intervals have been distinguished: starting of basal respiration (SRI = 1), controlled deep breaths (CDB = 3), long expiratory apnoea (LEA = 3), short inspiratory apnoea (SIA = 3) and ending with basal respiration again (FRI = 1). To strengthen the HRV knowledge extraction from these scenarios, time and frequency analysis is conducted. In general, breathing and apnoea intervals presented significant statistically differences (p < 0.05), heart rate (HR) mean between SRI and FRI (p < 0.001), RR variability of LEA intervals (p < 0.01), root mean square of RR intervals during CDB (p < 0.05), maximum high frequency (HF) peak amplitude between SRI and FRI (p = 0.016), and low frequency (LF) area for LEA intervals (p < 0.001). When performing the frequency analysis, it has been observed that the sympathetic nervous system (SNS) has a higher contribution in the apnoea intervals. In conclusion, the WHM method implementation seems to involve a decrease in the HR. Specific breathing techniques could help to control the body in different conditions.Clinical Relevance- The WHM seems to imply a decrease on HR. Furthermore, after the implementation of the WHM, women presented higher HRV.
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Apnea , Respiración , Humanos , Femenino , Frecuencia Cardíaca/fisiología , Voluntarios Sanos , CorazónRESUMEN
STUDY OBJECTIVES: We aimed to characterize the cerebral hemodynamic response to obstructive sleep apnea/hypopnea events, and evaluate their association to polysomnographic parameters. The characterization of the cerebral hemodynamics in obstructive sleep apnea (OSA) may add complementary information to further the understanding of the severity of the syndrome beyond the conventional polysomnography. METHODS: Severe OSA patients were studied during night sleep while monitored by polysomnography. Transcranial, bed-side diffuse correlation spectroscopy (DCS) and frequency-domain near-infrared diffuse correlation spectroscopy (NIRS-DOS) were used to follow microvascular cerebral hemodynamics in the frontal lobes of the cerebral cortex. Changes in cerebral blood flow (CBF), total hemoglobin concentration (THC), and cerebral blood oxygen saturation (StO2) were analyzed. RESULTS: We considered 3283 obstructive apnea/hypopnea events from sixteen OSA patients (Age (median, interquartile range) 57 (52-64.5); females 25%; AHI (apnea-hypopnea index) 84.4 (76.1-93.7)). A biphasic response (maximum/minimum followed by a minimum/maximum) was observed for each cerebral hemodynamic variable (CBF, THC, StO2), heart rate and peripheral arterial oxygen saturation (SpO2). Changes of the StO2 followed the dynamics of the SpO2, and were out of phase from the THC and CBF. Longer events were associated with larger CBF changes, faster responses and slower recoveries. Moreover, the extrema of the response to obstructive hypopneas were lower compared to apneas (p < .001). CONCLUSIONS: Obstructive apneas/hypopneas cause profound, periodic changes in cerebral hemodynamics, including periods of hyper- and hypo-perfusion and intermittent cerebral hypoxia. The duration of the events is a strong determinant of the cerebral hemodynamic response, which is more pronounced in apnea than hypopnea events.
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Obstrucción de las Vías Aéreas , Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño , Femenino , Humanos , Hemodinámica , Espectroscopía Infrarroja CortaRESUMEN
BACKGROUND: To study whether there is genetic overlap underlying the risk for schizophrenia spectrum disorders (SSDs) and low intelligence quotient (IQ), we reviewed and summarized the evidence on genetic variants associated with both traits. METHODS: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and preregistered it in PROSPERO. We searched the Medline databases via PubMed, PsycInfo, Web of Science and Scopus. We included studies in adults with a diagnosis of SSD that explored genetic variants (single nucleotide polymorphisms [SNPs], copy number variants [CNVs], genomic insertions or genomic deletions), estimated IQ and studied the relationship between genetic variability and both traits (SSD and IQ). We synthesized the results and assessed risk of bias using the Quality of Genetic Association Studies (Q-Genie) tool. RESULTS: Fifty-five studies met the inclusion criteria (45 case-control, 9 cross-sectional, 1 cohort), of which 55% reported significant associations for genetic variants involved in IQ and SSD. The SNPs more frequently explored through candidate gene studies were in COMT, DTNBP1, BDNF and TCF4. Through genome-wide association studies, 2 SNPs in CHD7 and GATAD2A were associated with IQ in patients with SSD. The studies on CNVs suggested significant associations between structural variants and low IQ in patients with SSD. LIMITATIONS: Overall, primary studies used heterogeneous IQ measurement tools and had small samples. Grey literature was not screened. CONCLUSION: Genetic overlap between SSD and IQ supports the neurodevelopmental hypothesis of schizophrenia. Most of the risk polymorphisms identified were in genes relevant to brain development, neural proliferation and differentiation, and synaptic plasticity.
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Esquizofrenia , Adulto , Humanos , Esquizofrenia/genética , Estudio de Asociación del Genoma Completo , Estudios Transversales , Polimorfismo de Nucleótido Simple/genética , Inteligencia/genéticaRESUMEN
Methods for regioselective N-methylation and -alkylation of unsaturated heterocycles with "off the shelf" reagents are highly sought-after. This reaction could drastically simplify synthesis of privileged bioactive molecules. Here we report engineered and natural methyltransferases for challenging N-(m)ethylation of heterocycles, including benzimidazoles, benzotriazoles, imidazoles and indazoles. The reactions are performed through a cyclic enzyme cascade that consists of two methyltransferases using only iodoalkanes or methyl tosylate as simple reagents. This method enables the selective synthesis of important molecules that are otherwise difficult to access, proceeds with high regioselectivity (r.r. up to >99 %), yield (up to 99 %), on a preparative scale, and with nearly equimolar concentrations of simple starting materials.
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Imidazoles , Metiltransferasas , Metilación , Biocatálisis , Metiltransferasas/metabolismo , AlquilaciónRESUMEN
Cardiorespiratory Phase Synchronization (CRPS) is the manifestation of the non-linear coupling between the cardiac and the respiratory systems, different to the Respiratory Sinus Arrythmia (RSA). This takes place when the heartbeats occur at the same relative phase of the breathing, during a succession of respiratory cycles. In this study, we investigated the CRPS in 45 elderly patients admitted to the semi-critical unit of a hospital. The patients were classified according to their respiratory state as non-Periodic Breathing (nPB), Periodic Breathing (PB) and Cheyne-Stokes Respiration (CSR). The phase synchrogram between the electrocardiographic and respiratory signals was computed using the Hilbert transform technique. A continuous measure of the CRPS was obtained from the synchrogram, and was characterized by the average duration of synchronized epochs (A vgDurSync), the percentage of synchronized time (%Sync), the number of synchronized epochs (NumSync), and the frequency ratio between the cardiac and respiratory oscillators (FreqRat). These measures were studied using two different thresholds (0.1 and 0.05) for the amplitude of the synchronization and a minimum duration threshold of 10s. According to the results, the AvgDurSync and %Sync had a decreasing trend in patients with breathing periodicity. In addition, CSR patients presented the lowest values A vgDurSync and %Sync. Therefore, the CRPS method could be a useful tool for characterizing periodic respiratory patterns in elderly patients, which might be related to chronic heart failure. Clinical Relevance- This study analyzes the synchronization between cardiac and respiratory systems in elderly patients with a possible progressive decompensation in the cardiac function.
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Respiración de Cheyne-Stokes , Anciano , Fenómenos Fisiológicos Cardiovasculares , Respiración de Cheyne-Stokes/diagnóstico , Electrocardiografía , Frecuencia Cardíaca , Humanos , RespiraciónRESUMEN
This cross-sectional study aims to explore the prevalence of protein-energy wasting (PEW) in dialysis patients in Catalonia, Spain, using a new and practical online tool which enables rapid calculation and comparison with other nutritional scores. METHODS: A web tool (Nutrendial) was created to introduce different variables and automatically calculate PEW, Malnutrition inflammation Score (MIS) and Subjective Global Assessment (SGA) in 1389 patients (88% in haemodialysis (HD)), 12% in peritoneal dialysis (PD) from different regions of Catalonia. RESULTS: A prevalence of 23.3% (26% HD, 10.2% PD) of PEW was found, with a mean MIS score of 6 and SGA score of C in 7% of the patients. ROC analysis showed MIS as the best nutritional score to diagnose PEW (AUC 0.85). Albumin delivered lower diagnostic precision (AUC 0.77) and sensitivity (66%). A cut off point of 7 (86% sensitivity and 75% specificity) for MIS and 3.7 mg/dL for albumin were found to predict the appearance of PEW in this population. SGA B or C showed an 87% sensitivity and 55% specificity to diagnose PEW. Very low nutritional intervention (14%) was recorded with this tool in patients with PEW. CONCLUSIONS: This new online tool facilitated the calculation of PEW, enabling different professionals-including nephrologists, dieticians and nurses-to efficiently obtain insights into the nutritional status of the Catalonian dialysis population and implement the required nutritional interventions. MIS is the score with more sensitivity to diagnose PEW.
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Caquexia , Desnutrición Proteico-Calórica , Diálisis Renal , Albúminas , Estudios Transversales , Humanos , Inflamación/diagnóstico , Fallo Renal Crónico/terapia , Estado Nutricional , Prevalencia , Desnutrición Proteico-Calórica/diagnóstico , Desnutrición Proteico-Calórica/epidemiología , Desnutrición Proteico-Calórica/etiología , Diálisis Renal/efectos adversosRESUMEN
The aerobic oxidation of alkenes to carbonyls is an important and challenging transformation in synthesis. Recently, a new P450-based enzyme (aMOx) has been evolved in the laboratory to directly oxidize styrenes to their corresponding aldehydes with high activity and selectivity. The enzyme utilizes a heme-based, high-valent iron-oxo species as a catalytic oxidant that normally epoxidizes alkenes, similar to other catalysts. How the evolved aMOx enzyme suppresses the commonly preferred epoxidation and catalyzes direct carbonyl formation is currently not well understood. Here, we combine computational modelling together with mechanistic experiments to study the reaction mechanism and unravel the molecular basis behind the selectivity achieved by aMOx. Our results describe that although both pathways are energetically accessible diverging from a common covalent radical intermediate, intrinsic dynamic effects determine the strong preference for epoxidation. We discovered that aMOx overrides these intrinsic preferences by controlling the accessible conformations of the covalent radical intermediate. This disfavors epoxidation and facilitates the formation of a carbocation intermediate that generates the aldehyde product through a fast 1,2-hydride migration. Electrostatic preorganization of the enzyme active site also contributes to the stabilization of the carbocation intermediate. Computations predicted that the hydride migration is stereoselective due to the enzymatic conformational control over the intermediate species. These predictions were corroborated by experiments using deuterated styrene substrates, which proved that the hydride migration is cis- and enantioselective. Our results demonstrate that directed evolution tailored a highly specific active site that imposes strong steric control over key fleeting biocatalytic intermediates, which is essential for accessing the carbonyl forming pathway and preventing competing epoxidation.
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Alquenos , Hierro , Alquenos/química , Catálisis , Sistema Enzimático del Citocromo P-450/metabolismo , Hierro/química , Oxidación-ReducciónRESUMEN
We report the reprogramming of nonheme iron enzymes to catalyze an abiological C(sp3)âH azidation reaction through iron-catalyzed radical relay. This biocatalytic transformation uses amidyl radicals as hydrogen atom abstractors and Fe(III)âN3 intermediates as radical trapping agents. We established a high-throughput screening platform based on click chemistry for rapid evolution of the catalytic performance of identified enzymes. The final optimized variants deliver a range of azidation products with up to 10,600 total turnovers and 93% enantiomeric excess. Given the prevalence of radical relay reactions in organic synthesis and the diversity of nonheme iron enzymes, we envision that this discovery will stimulate future development of metalloenzyme catalysts for synthetically useful transformations unexplored by natural evolution.
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Evolución Molecular Dirigida , Enzimas , Proteínas de Hierro no Heme , Biocatálisis , Carbono/química , Enzimas/química , Hidrógeno/química , Proteínas de Hierro no Heme/químicaRESUMEN
Unspecific peroxygenases (UPOs) enable oxyfunctionalizations of a broad substrate range with unparalleled activities. Tailoring these enzymes for chemo- and regioselective transformations represents a grand challenge due to the difficulties in their heterologous productions. Herein, we performed protein engineering in Saccharomyces cerevisiae using the MthUPO from Myceliophthora thermophila. More than 5300 transformants were screened. This protein engineering led to a significant reshaping of the active site as elucidated by computational modelling. The reshaping was responsible for the increased oxyfunctionalization activity, with improved k cat/K m values of up to 16.5-fold for the model substrate 5-nitro-1,3-benzodioxole. Moreover, variants were identified with high chemo- and regioselectivities in the oxyfunctionalization of aromatic and benzylic carbons, respectively. The benzylic hydroxylation was demonstrated to perform with enantioselectivities of up to 95% ee. The proposed evolutionary protocol and rationalization of the enhanced activities and selectivities acquired by MthUPO variants represent a step forward toward the use and implementation of UPOs in biocatalytic synthetic pathways of industrial interest.
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Palm oil is one of the most widely used vegetable oils by the food industry but there is limited information on actual intake. A detailed intake assessment of palm oil for Spain and Germany was conducted. For Spain, mean palm oil intakes ranged from 2.06 g/day in the elderly to 4.54 g/day in children and adolescents, while high-level intakes ranged from 10.34 g/day in the elderly to 20.88 g/day in toddlers. For Germany, mean palm oil intakes ranged from 3.06 g/day in toddlers to 6.22 g/day in the very elderly, while high-level intakes ranged from 13.61 g/day in toddlers to 30.10 g/day in the elderly. For both countries, the main contributing food categories to mean palm oil intake were biscuits, cakes, bread, breakfast cereal and margarine. In summary, the present paper provides a realistic assessment of the intake of palm oil in two EU countries for different population groups.
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Dieta , Aceite de Palma , Adolescente , Anciano , Niño , Alemania , Humanos , Lactante , EspañaRESUMEN
Cyclic GMP-AMP Synthase (cGAS) is activated upon DNA binding and catalyzes the synthesis of 2',3'-cGAMP from GTP and ATP. This cyclic dinucleotide is a messenger that triggers the autoimmune system of eukaryotic cells. In this study, we propose a Molecular Dynamics (MD) investigation of cGAS activation. We notably provide insights into the motion of the activation loop, both from a mechanical point of view and considering its role in the catalysis of cGAMP production. We finally shed light on the reaction resulting in cGAMP synthesis. Two possible catalytic routes (referred to as GTP-ATP and ATP-GTP) are proposed based on the active site occupancy, paving the way toward further exploration of the reaction mechanism.
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ADN/metabolismo , Nucleotidiltransferasas/metabolismo , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Biocatálisis , Dominio Catalítico , ADN/química , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Humanos , Simulación de Dinámica Molecular , Nucleotidiltransferasas/química , Unión Proteica , Conformación ProteicaRESUMEN
The significance of tunneling contributions to the rate constants of enzymatic reactions has been described at length using experimental evidence as well as theoretical computations. Within the frame of variational transition state theory (VTST), tunneling corrections are included using the so-called ground-state tunneling transmission coefficient. For the calculation of those enzymatic rate constants using the ensemble-averaged extension of VTST on QM/MM potential energy surfaces, the transmission coefficient at a given temperature is averaged over a set of coefficient values, each one obtained from an individual minimum energy path (MEP). However, the calculation of accurate QM/MM MEPs for tunneling calculations, also using a reliable QM method like DFT, is highly costly in enzyme models. For this reason, more affordable methodologies have been used. In this paper, we validate a feasible computational strategy to compute multidimensional tunneling corrections that describes better than cheaper alternatives the physics of the hydrogen abstraction from linoleic acid catalyzed by the enzyme 15-rLOX-1. Our recommendations to obtain better values of kinetic isotope effects and, especially, of rate constants are based on multidimensional small-curvature tunneling (SCT) coefficients derived from electrostatic embedding QM(DFT)/MM MEPs. The MEPs used must be calculated with a small enough step-size. Also, the number of gradients and Hessians along the reaction path must be checked to cover the whole tunneling region and to obtain converged adiabatic potential energy profiles. Distinguished reaction coordinates (DCPs) that are commonly used to describe enzyme reaction mechanisms are not adequate for tunneling calculations in such biological systems.
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Araquidonato 15-Lipooxigenasa/química , Ácido Linoleico/química , Catálisis , Teoría Funcional de la Densidad , Humanos , Hidrógeno/química , Modelos Químicos , Oxidación-Reducción , TermodinámicaRESUMEN
Respiration rate can be assessed by analyzing respiratory changes of the electrocardiogram (ECG). Several methods can be applied to derive the respiratory signal from the ECG (EDR signal). In this study, four EDR estimation methods based on QRS features were analyzed. A database with 44 healthy subjects (16 females) in supine and sitting positions was analyzed. Respiratory flow and ECG recordings on leads I, II, III and a Chest lead was studied. A QR slope-based method, an RS slope-based method, an QRS angle-based method and an QRS area-based method were applied. Their performance was evaluated by the correlation coefficient with the reference respiratory volume signal. Significantly higher correlation coefficients in the range r = 0.77 - 0.86 were obtained with the Chest lead for all methods. The EDR estimation method based on the QRS angle provided the highest similarity with the volume signal for all recording leads and subject positions. We found no statistically significant differences according to gender or subject position.Clinical Relevance- This work analyzes the EDR signal from four electrocardiographic leads to obtain the respiratory signal and contributes to a simplified analysis of respiratory activity.
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Electrocardiografía , Respiración , Femenino , Voluntarios Sanos , Humanos , Frecuencia RespiratoriaRESUMEN
We analysed the familial aggregation (familiality) of cognitive dimensions and explored their role as liability markers for early-onset bipolar disorder (EOBD). The sample comprised 99 subjects from 26 families, each with an offspring diagnosed with EOBD. Four cognitive dimensions were assessed: reasoning skills; attention and working memory; memory; and executive functions. Their familiality was investigated in the total sample and in a subset of healthy relatives. The intra-family resemblance score (IRS), a family-based index of the similarity of cognitive performance among family members, was calculated. Familiality was detected for the attention and working memory (AW) dimension in the total sample (ICC = 0.37, p = 0.0004) and in the subsample of healthy relatives (ICC = 0.37, p = 0.016). The IRS reflected that there are families with similar AW mean scores (either high or low) and families with heterogeneous scores. Families with the most common background for the AW dimension (IRS > 0) were selected and dichotomized in two groups according to the mean family AW score. This allowed differentiating families whose members had similar high scores than those with similar low scores: both patients (t = - 4.82, p = 0.0005) and relatives (t = - 5.04, p < 0.0001) of the two groups differed in their AW scores. AW dimension showed familial aggregation, suggesting its putative role as a familial vulnerability marker for EOBD. The IRS estimation allowed the identification of families with homogeneous scores for this dimension. This represents a first step towards the investigation of the underlying mechanisms of AW dimension and the identification of etiological subgroups.