RESUMEN
BACKGROUND: The diagnostics of primary aldosteronism (PA) are usually carried out in patients taking antihypertensive medications. We compared haemodynamics between medicated PA, medicated essential hypertension (EH), never-medicated EH and normotensive controls (n = 130 in all groups). METHODS: The hypertensive groups were matched for age (53 years), sex (84 male/46 female) and body mass index (BMI) (30 kg m-2 ); normotensive controls had similar sex distribution (age 48 years, BMI 27 kg m-2 ). Haemodynamics were recorded using whole-body impedance cardiography and radial pulse wave analysis, and the results were adjusted as appropriate. Radial blood pressure recordings were calibrated by brachial blood pressure measurements from the contralateral arm. RESULTS: Radial and aortic systolic and diastolic blood pressure was similar in PA and never-medicated EH, and higher than in medicated EH and normotensive controls (P ≤ 0.001 for all comparisons). Extracellular water balance was ~ 4% higher in PA than in all other groups (P < 0.05 for all), whilst cardiac output was ~ 8% higher in PA than in medicated EH (P = 0.012). Systemic vascular resistance and augmentation index were similarly increased in PA and both EH groups when compared with controls. Pulse wave velocity was higher in PA and never-medicated EH than in medicated EH and normotensive controls (P ≤ 0.033 for all comparisons). CONCLUSIONS: Medicated PA patients presented with corresponding systemic vascular resistance and wave reflection, but higher extracellular water volume, cardiac output and arterial stiffness than medicated EH patients. Whether the systematic evaluation of these features would benefit the clinical diagnostics of PA remains to be studied in future.
Asunto(s)
Gasto Cardíaco , Hiperaldosteronismo/fisiopatología , Hipertensión/fisiopatología , Rigidez Vascular , Adulto , Anciano , Anciano de 80 o más Años , Antihipertensivos/uso terapéutico , Presión Sanguínea , Estudios Transversales , Líquido Extracelular/fisiología , Femenino , Frecuencia Cardíaca , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Análisis de la Onda del Pulso , Resistencia Vascular , Adulto JovenRESUMEN
PURPOSE: One of the major issues in high intensity focused ultrasound ablation of abdominal lesions is obstruction of the ultrasound beam by the thoracic cage. Beam shaping strategies have been shown by several authors to increase focal point intensity while limiting rib exposure. However, as rib obstruction leaves only part of the aperture available for energy transmission, conserving total emitted acoustic power, the intensity in the near-field tissues inherently increases after beam shaping. Despite of effective rib sparing, those tissues are therefore subjected to increased risk of thermal damage. In this study, for a number of clinically representative intercostal sonication geometries, modeling clinically available hardware, the effect of beam shaping on both the exposure of the ribs and near-field to acoustic energy was evaluated and the implications for the volumetric ablation rate were addressed. METHODS: A relationship between rib temperature rise and acoustic energy density was established by means of in vivo MR thermometry and simulations of the incident acoustic energy for the corresponding anatomies. This relationship was used for interpretation of rib exposure in subsequent numerical simulations in which rib spacing, focal point placement, and the focal point trajectory were varied. The time required to heat a targeted region to 65 °C was determined without and with the application of beam shaping. The required sonication time was used to calculate the acoustic energy density at the fat-muscle interface and at the surface of the ribs. At the fat-muscle interface, exposure was compared to available literature data and rib exposure was interpreted based on the earlier obtained relation between measured temperature rise and simulated acoustic energy density. To estimate the volumetric ablation rate, the cool-down time between periods of energy exposure was estimated using a time-averaged power limit of 100 kJ/h. RESULTS: At the level of the ribs, the temperature rise-energy density proportionality constant was estimated to be 6.0-7.6 °C/(J/mm(2)). Beam shaping by the geometric shadow method typically reduces the acoustic intensity a factor of 2, considering the 1 cm(2) with the highest exposure. For a 4 mm diameter circular sonication trajectory, the near-field energy limit of 2.5 J/mm(2) was exceeded for all considered geometries. The estimated rib temperature was in all but one (sonication 50 mm behind the ribs, with 15 mm rib spacing and a 4 mm diameter circular sonication trajectory) of the considered scenarios within acceptable limits. For those sonication scenarios where a single sonication is considered safe both in terms of near-field as well as rib heating, volumetric ablation rates in the order of 1 ml/h are estimated. CONCLUSIONS: Intercostal sonication is associated with an increased risk of near-field overheating. This risk is strongly dependent on the considered rib spacing, the placement of the focus behind the ribs, and the selected sonication trajectory. For the hardware under simulation, obstruction by the thoracic cage renders ablations of clinically relevant volumes within a practical time-frame unfeasible in a large part of the liver. Improvements maybe expected from transducer designs with a larger active surface and/or nonlinear sonication strategies.
Asunto(s)
Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Hígado/cirugía , Tejido Adiposo/fisiología , Simulación por Computador , Estudios de Factibilidad , Ultrasonido Enfocado de Alta Intensidad de Ablación/instrumentación , Humanos , Hígado/fisiopatología , Modelos Biológicos , Músculos/fisiología , Órganos en Riesgo , Costillas/anatomía & histología , Costillas/fisiología , TemperaturaRESUMEN
BACKGROUND/AIM: Monitoring of lung function alone does not adequately identify the high-risk patients among elderly asthma and COPD cohorts. The additional value of Health-Related Quality of Life (HRQoL) development in the detection of patients with a disabling disease in clinical practice is unclear. The aim of this study was to statistically examine the individual development of HRQoL measured using respiratory-specific AQ20 and generic 15D questionnaires. MATERIALS AND METHODS: The HRQoL of COPD (N = 739) and asthma (N = 1329) patients was evaluated at 0, 1, 2, and 4 years after recruitment. To determine a five-year HRQoL change for each patient we used mixed-effects modelling for linear trend. RESULTS: In COPD, the majority (60-80%) of the individuals showed declining trend, whereas in asthma, the majority (46-71%) showed no attenuation in HRQoL. The proportion of constant decliners was estimated higher with the 15D both in asthma (6.3%) and COPD (6.3%) than with AQ20 (3.5 and 4.5%, respectively). The first measurement of HRQoL was found to predict future development of HRQoL. In asthma, obesity-related diseases such as hypertension, diabetes and gastro-esophageal reflux disease best explained the decline, whereas in COPD, age and the level of bronchial obstruction were the main determinants. CONCLUSION: Based on the five-year follow-up, the HRQoL trends significantly diverging from each other could be identified both among the asthma and COPD patients. Compared to cross-sectional HRQoL, the HRQoL trend over a clinically relevant period of time allows us to ignore, to a great extent, the random error of self-assessed HRQoL and thus, it may offer a more accurate measure to describe the disease process.
Asunto(s)
Asma/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Calidad de Vida , Anciano , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
INTRODUCTION: This is one of the very few studies to investigate the specific executive function/processing speed component of response initiation in subjects at familial risk (FR) for psychosis, and the first such study in subjects at clinical risk (CR) for psychosis. METHODS: Participants (N = 177) were members of the general population-based Northern Finland 1986 Birth Cohort in the following four groups: FR for psychosis (n = 62), CR for psychosis (n = 21), psychosis (n = 25) and control subjects (n = 69). The response initiation of these groups was compared in three different tests: Semantic fluency, Stockings of Cambridge and Spatial working memory. RESULTS: The two risk groups did not differ significantly from control group, but differed from, and outperformed the psychosis group in semantic fluency response initiation. CONCLUSIONS: Response initiation deficits were not evident in a non-help seeking psychosis high-risk sample.
Asunto(s)
Función Ejecutiva/fisiología , Memoria a Corto Plazo/fisiología , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/fisiopatología , Adulto , Análisis de Varianza , Salud de la Familia , Femenino , Finlandia/epidemiología , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Factores de Riesgo , Semántica , Adulto JovenRESUMEN
We present here phenotypic and genetic parameters for the major quality and production traits of farmed European whitefish. A total of 70 families were produced by mating each of 45 sires to an average of 1.6 dams and each of the 52 dams to an average of 1.3 sires. A total of 2,100 individuals were recorded for survival, and 507 individuals for growth and quality-related traits. The 4 major results were as follows: first, all traits exhibited nonzero heritabilities except for fillet gaping and fillet protein%. The heritabilities for the production traits were harvest weight (0.42 ± 0.10), gutted weight (0.40 ± 0.10), fillet weight (0.36 ± 0.09), maturity score (0.27 ± 0.11, on liability scale), survival (0.19 ± 0.05, on liability scale), carcass% (0.14 ± 0.07), and fillet% (0.11 ± 0.06). The heritabilities for the quality traits were condition factor (0.49 ± 0.10), fillet lipid% (0.37 ± 0.10), muscle texture (0.30 ± 0.09), Distell lipid reading (0.26 ± 0.09), fillet lightness (0.16 ± 0.07), fillet gaping (0.04 ± 0.06), and fillet protein% (0.04 ± 0.06). Second, the quality traits that were significantly genetically correlated with each other were all related to lipid deposition. Increasing fillet lipid% (an undesired change in whitefish) was genetically related to desired lighter fillet color [genetic correlation (r(G)) = 0.70 ± 0.22] and to undesired greater condition factor (0.39 ± 0.17). None of the other genetic correlations between condition factor, fillet lipid%, muscle texture, fillet lightness, fillet gaping, and fillet protein% were significant. Third, BW and gutted weight were genetically related to the quality traits that were genetically related to lipid deposition. Increasing harvest weight was genetically related to high fillet lipid% (r(G) = 0.59 ± 0.14), lighter fillet color (0.61 ± 0.25), and to greater condition factor (0.60 ± 0.12). All other genetic correlations of harvest weights with the quality traits were nonsignificant, indicating that rapid growth was not genetically related to gaping and softer flesh. Fourth, none of the genetic correlations of carcass%, fillet%, maturity, and survival with the quality traits were significant, implying weak genetic integration between the traits. Yet, marginally significant genetic correlations were found for fillet lipid% with maturity score (r(G) = -0.46 ± 0.24) and survival (0.36 ± 0.19). These results provide the genetic basis for assessing the potential to improve product quality via selective breeding.
Asunto(s)
Carne/análisis , Salmonidae/genética , Animales , Composición Corporal , Peso Corporal , Femenino , Masculino , Fenotipo , Carácter Cuantitativo Heredable , Salmonidae/crecimiento & desarrollo , Salmonidae/fisiologíaRESUMEN
OBJECTIVE: Cardiac repolarization is regulated, in part, by the KCNH2 gene, which encodes a rapidly activating component of the delayed rectifier potassium channel. The gene expresses a functional single nucleotide polymorphism, K897T, which changes the biophysical properties of the channel. The objective of this study was to evaluate whether this polymorphism influences two indices of repolarization--the QT interval and T-wave alternans (TWA)--during different phases of a physical exercise test. MATERIAL AND METHODS: The cohort consisted of 1,975 patients undergoing an exercise test during which on-line electrocardiographic data were registered. Information on coronary risk factors and medication was recorded. The 2690A>C nucleotide variation in the KCNH2 gene corresponding to the K897T amino acid change was analysed after polymerase chain reaction with allele-specific TaqMan probes. RESULTS: Among all subjects, the QTc intervals did not differ between the three genotype groups (p> or =0.31, RANOVA). Women with the CC genotype tended to have longer QT intervals during the exercise test, but the difference was statistically significant only at rest (p = 0.011, ANOVA). This difference was also detected when the analysis was adjusted for several factors influencing the QT interval. No statistically significant effects of the K897T polymorphism on TWA were observed among all subjects (p = 0.16, RANOVA), nor in men and women separately. CONCLUSIONS: The K897T polymorphism of the KCNH2 gene may not be a major genetic determinant for the TWA, but the influence of the CC genotype on QT interval deserves further research among women.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/genética , Corazón/fisiología , Miocardio/metabolismo , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Presión Sanguínea/fisiología , Estudios de Cohortes , Canal de Potasio ERG1 , Electrocardiografía , Prueba de Esfuerzo , Femenino , Finlandia , Frecuencia de los Genes , Genotipo , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
Body composition traits have potential use in fish breeding programs as indicator traits for selective improvement of feed efficiency. Moreover, feed companies are increasingly replacing traditional fish meal (FM) based ingredients in feeds for carnivorous farmed fish with plant protein ingredients. Therefore, genetic relationships of composition and feed utilization traits need to be quantified for both current FM-based and future plant-based aquaculture feeds. Individual whole-body lipid% and protein%, daily gain (DG), ADFI, and G:F (daily gain/daily feed intake) were measured on 1,505 European whitefish (Coregonus lavaretus) from 70 half/full-sib families reared in a split-family design with either a typical FM or a novel soybean meal (SBM) based diet. Diet-specific genetic parameters were estimated with multiple-trait animal models. Lipid% was significantly greater in the FM diet group than in the SBM group, even independent of final BW or total feed intake. In both diets, lipid% showed moderate heritability (0.12 to 0.22) and had positive phenotypic and genetic correlations with DG (0.37 to 0.82) and ADFI (0.36 to 0.88). Therefore, selection against lipid% can be used to indirectly select for lower feed intake. Protein% showed low heritability (0.05 to 0.07), and generally very weak or zero correlations with DG and ADFI. In contrast to many previous studies on terrestrial livestock, lipid% showed zero or very weak phenotypic and genetic correlations with G:F. However, selection index calculations demonstrated that simultaneous selection for high DG and reduced lipid% could be used to indirectly increase G:F; this strategy increased absolute genetic response in G:F by a factor of 1.5 to 1.6 compared with selection on DG alone. Lipid% and protein% were not greatly affected by genotype-diet environment interactions, and therefore, selection strategies for improving body composition within current FM diets should also improve populations for future SBM diets.
Asunto(s)
Alimentación Animal , Composición Corporal/genética , Cruzamiento/métodos , Ingestión de Alimentos , Salmonidae/genética , Selección Genética , Tejido Adiposo/crecimiento & desarrollo , Alimentación Animal/análisis , Alimentación Animal/normas , Fenómenos Fisiológicos Nutricionales de los Animales/genética , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Ambiente , Femenino , Productos Pesqueros , Genotipo , Masculino , Músculo Esquelético/crecimiento & desarrollo , Fenotipo , Salmonidae/crecimiento & desarrollo , Glycine max , Aumento de Peso/genéticaRESUMEN
A Self-Organizing Map (SOM) is typically trained in unsupervised mode, using a large batch of training data. If the data contain semantically related object groupings or classes, subsets of vectors belonging to such user-defined classes can be mapped on the SOM by finding the best matching unit for each vector in the set. The distribution of the data vectors over the map forms a two-dimensional discrete probability density. Even from the same data, qualitatively different distributions can be obtained by using different feature extraction techniques. We used such feature distributions for comparing different classes and different feature representations of the data in the context of our content-based image retrieval system PicSOM. The information-theoretic measures of entropy and mutual information are suggested to evaluate the compactness of a distribution and the independence of two distributions. Also, the effect of low-pass filtering the SOM surfaces prior to the calculation of the entropy is studied.
Asunto(s)
Inteligencia Artificial , Redes Neurales de la Computación , Reconocimiento Visual de Modelos , Teorema de Bayes , Entropía , Aprendizaje por ProbabilidadRESUMEN
Low phosphorous (P) feeds in aquaculture are recommended to reduce eutrophication of water systems. However, the feed should be adequate for normal growth and intact immune defence. Influence of low dietary P supply on non-specific and specific immune defence of European whitefish (Coregonus lavaretus) was studied in two trials. For Trial 1, a semi-purified, low-P diet was formulated and supplied with 0, 2.5, 5.0, 7.5, or 10.0 g P kg(-1)to obtain a P gradient of 4.4-14.9 g kg(-1)diet. Diets were fed to four replicate groups of fingerling whitefish for 42 days in a flow-through, freshwater system maintained at 15 degrees C. Fish fed with the P-unsupplemented diet had significantly lower plasma immunoglobulin M (IgM) levels than fish fed with the P-fortified diets (means 2.53 vs. 3.19 mg ml(-1); P=0.047). Plasma lysozyme activity did not differ between fish fed with the P-unsupplemented diet and fish fed with the P-fortified diets (means 21.8 vs. 25.5 U ml(-1); P=0.107). For Trial 2, fish were acclimated for 49 days by feeding the lowest or highest dietary P contents, and thereafter immunised with a single intraperitoneal injection of a novel antigen, bovine gamma globulin (BGG). A clear antibody response against BGG was elicited but the antibody levels did not differ between fish fed low-P or high-P contents. Similar to Trial 1, plasma IgM was lower in fish fed low-P diets, and low-P diet did not influence plasma lysozyme activity. In both trials the growth of fish, having received low-P diet, was significantly lowered. It is concluded that P deficiency has only minor effects on the immune parameters in whitefish, and the practical aquafeed with P contents sufficient for normal growth does not compromise immune functions of this species.
Asunto(s)
Fósforo Dietético/inmunología , Salmonidae/inmunología , Animales , Formación de Anticuerpos , Acuicultura , Peso Corporal , Europa (Continente) , Inmunoglobulina M/sangre , Muramidasa/sangre , Fósforo Dietético/administración & dosificación , Fósforo Dietético/metabolismo , Salmonidae/crecimiento & desarrollo , Salmonidae/metabolismo , gammaglobulinas/inmunologíaRESUMEN
OBJECTIVES: To evaluate the effectiveness of mammography service screening. SETTING: Helsinki (population 0.5 million), the capital of Finland, the breast cancer service screening programme was started gradually in 1986. MATERIALS AND METHODS: The study was based on the data from the breast cancer screening programme in Helsinki. All incident cases of breast cancer and rates in the female population in Helsinki during the period 1970-97, and information on the subsequent breast cancer mortality were derived from the files of the Finnish Cancer Registry. To estimate the sensitivity of the programme, the number of screen detected cancers were compared with the overall number of breast cancers at the targeted age groups. Effects of screening were estimated for cumulative incidence and for the refined mortalities among the birth cohorts screened. RESULTS: Altogether 144 400 invitations had been sent during 1986-97 among the 50-9 year old women as targeted in Helsinki. The average attendance rate was 82%; and 545 breast cancers were detected by screening, with a detection rate of 0.46%. In the birth cohort of women born between the start of 1935 and the end of 1939-namely, those subjected to most complete screening and long follow up time since the onset of the programme-there was an increase in the cumulative incidence of breast cancer (relative risk (RR) 1.18, 95% confidence interval (95% CI) 1.09 to 1.27). The estimated sensitivity of the screening programme was 58%; and 53% if corrected for overdiagnosis. There was also a decrease of 19% (RR 0.81, 95% CI 0.62 to 1.05) in the refined mortality within this screened birth cohort, compared with the death rate of women of comparable ages in the non-screened reference cohort. CONCLUSION: The study provides further support to the hypothesis that service screening with mammography reduces the risk of breast cancer mortality.
Asunto(s)
Neoplasias de la Mama/epidemiología , Mamografía/estadística & datos numéricos , Tamizaje Masivo/métodos , Evaluación de Programas y Proyectos de Salud , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Finlandia/epidemiología , Humanos , Incidencia , Persona de Mediana Edad , MortalidadRESUMEN
Surface acoustic wave (SAW) impedance element antenna duplexers provide compact, high performance, front-end components apt for industrial fabrication. We describe investigations on the design and modeling of a compact ISM antenna duplexer fabricated on a 36 degrees YX-cut LiTaO3 substrate based on SAW impedance elements. In particular, we have performed 3-D modeling of the inductive and capacitive electromagnetic couplings caused by the package parasitics for the duplexer. The use of a 1:3 IDT structure for the reduction of the passband width is discussed. The frequency response of the duplexer is predicted with the help of circuit simulation; the modeling is refined by optimization of the model parameters to improve the fit between the measured and simulated responses. We also report scanning optical imaging of the acoustic field within the resonator structures with the help of laser interferometry; this provides insight into the loss mechanisms beyond that attainable in mere electric measurements.
RESUMEN
We discuss acoustic losses in synchronous leaky surface acoustic wave (LSAW) resonators on rotated Y-cut lithium tantalate (LiTaO3) substrates. Laser probe measurements and theoretical models are employed to identify and characterize the radiation of leaky waves into the busbars of the resonator and the excitation of bulk acoustic waves. Escaping LSAWs lead to a significant increase in the conductance, typically occurring in the vicinity of the resonance and in the stopband, but they do not explain the experimentally observed deterioration of the electrical response at the antiresonance. At frequencies above the stop-band, the generation of fast shear bulk acoustic waves is the dominant loss mechanism.
RESUMEN
An analytic approach is developed for simulating synchronous resonators employing shear horizontally polarized surface acoustic waves, such as surface transverse waves, and leaky surface acoustic waves on LiTaO/sub 3/ and LiNbO/sub 3/ substrates. The approach, based on a simplified parametrized Green's function theory, allows the description of the localization of the wave and the interaction with bulk acoustic waves. An analytic expression is found for the harmonic admittance of an infinite periodic electrode array, and approximate corrections for finite structures are presented. The model enables fast computation of the admittance of synchronous resonators, and it compares favorably with experiments and numerical simulations.
Asunto(s)
Absorciometría de Fotón , Fracturas Espontáneas/diagnóstico por imagen , Fracturas de la Tibia/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Levantamiento de Peso/lesiones , Adulto , Densidad Ósea , Fracturas Espontáneas/diagnóstico , Humanos , Masculino , Fracturas de la Tibia/diagnósticoRESUMEN
A novel numerical method for determining the surface acoustic wave and the leaky surface acoustic wave characteristics is proposed. The Green's function method is used to simulate an infinite periodic transducer driven by a periodic voltage. We show that the coupling of modes parameters and the dispersion relation can be extracted from the change in the admittance as the periodicity of the driving voltage is slightly shifted. The method first introduced here leads to significant savings in computing time.
RESUMEN
We discuss effects on the propagation of surface acoustic waves (SAW) due to heavy mass loading on Y-cut lithium niobate and lithium tantalate substrates. An abrupt reduction in the leaky-SAW (LSAW) attenuation is observed in the measured admittance of a long resonator test structure on 64 degrees -YX-cut lithium niobate for aluminum electrodes of thickness h/lambda(0) beyond 9-10%. This experimental fact is explained theoretically as the slowing down of the leaky wave below the velocity of the slow shear surface-skimming bulk wave (SSBW), such that energy dissipation into bulk-wave emission becomes inhibited. An infinite transducer structure is modeled using the periodic Green's function and the boundary-element method (BEM); the computed theoretical properties well explain for the experimental findings. The model is further employed to quantify the leaky surface-wave attenuation characteristics as functions of the crystal-cut angle and the thickness of the electrodes. The resonance and antiresonance frequencies and the corresponding Q values are investigated to facilitate the selection of crystal cuts and electrode thicknesses. The transformation of the leaky SAW into a SAW-type nonleaky wave is also predicted to occur for gold electrodes, with considerably thinner finger structures.
RESUMEN
A new haemoglobin, Hb Helsinki, in which beta 82-Lys (EF6) is replaced by Met, was found in a Finnish family. It was associated with familial erythrocytosis, and the oxygen affinity of the blood was higher than normal. The oxygen equilibrium curves of purified Hb Helsinki and HbA from the same haemolysate have been determined under vaious conditions. "Stripped' Hb Helsinki was found to show normal cooperativity, slightly low oxygen affinity and a reduced Bohr effect at physiological pH. However, the organic phosphates, 2,3-diphosphoglycerate (2,3-DPG) and inositol hexaphosphate (IHP) had a very small effect on Hb Helsinki, and the 2,3-DPG binding constant of deoxygenated Hb Helsinki is close to that of oxyhaemoglobin A. Thus, the replacement of Lys by Met at position 82 dramatically changes the nature of the central cavity of the tetramer and the effect of 2,3-DPG on the respiratory function of the molecule.