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Halophytes are potential future crops with a valuable nutritional profile. Produced in indoor farming, they are considered to contribute to sustainable and resilient food systems. Indoor farms operate using artificial light. In this context narrowband and low dose UVB radiation can be used to increase plant secondary metabolites, such as carotenoids, and provide an improved nutritional profile for a human diet. UVB radiation can cause eustress or distress in the plant depending on the lighting situation. The aim of this study was to identify the doses of UVB that lead to either eustress or distress and to analyze these responses in Salicornia europaea. Therefore, S. europaea plants were exposed to different UVB radiation levels, low, medium and high, and analyzed for reactive oxygen species (ROS), plant hormones, amino acids, and photosynthetic pigments. High UVB treatment was found to affect phenotype and growth, and the metabolite profile was affected in a UVB dose-dependent manner. Specifically, medium UVB radiation resulted in an increase in carotenoids, whereas high UVB resulted in a decrease. We also observed an altered oxidative stress status and increased SA and decreased ABA contents in response to UVB treatment. This was supported by the results of menadione treatment that induces oxidative stress in plants, which also indicated an altered oxidative stress status in combination with altered carotenoid content. Thus, we show that a moderate dose of UVB can increase the carotenoid content of S. europaea. Furthermore, the UVB stress-dependent response led to a better understanding of carotenoid accumulation upon UVB exposure, which can be used to improve lighting systems and in turn the nutritional profile of future crops in indoor farming., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Given its limited land and water use and the changing climate conditions, indoor farming of halophytes has a high potential to contribute significantly to global agriculture in the future. Notably, indoor farming and classical greenhouse cultivation differ in their light regime between artificial and solar lighting, which can influence plant metabolism, but how this affects the cultivation of halophytes has not yet been investigated. To address this question, we studied the yield and content of abscisic acid, carotenoids, and chlorophylls as well as chloride of three halophyte species ( Cochlearia officinalis , Atriplex hortensis , and Salicornia europaea ) differing in their salt tolerance mechanisms and following four salt treatments (no salt to 600 mM of NaCl) in two light regimes (greenhouse/indoor farming). In particular, salt treatment had a strong influence on chloride accumulation which is only slightly modified by the light regime. Moreover, fresh and dry mass was influenced by the light regime and salinity. Pigments exhibited different responses to salt treatment and light regime, reflecting their differing functions in the photosynthetic apparatus. We conclude that the interaction of light regime and salt treatment modulates the content of photosynthetic pigments. Our study highlights the potential applications of the cultivation of halophytes for indoor farming and underlines that it is a promising production system, which provides food alternatives for future diets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fitzner, Schreiner and Baldermann.)

In the face of a growing world population and limited land, there is an urgent demand for higher productivity of food crops, and cultivation systems must be adapted to future needs. Sustainable crop production should aim for not only high yields, but also high nutritional values. In particular, the consumption of bioactive compounds such as carotenoids and flavonoids is associated with a reduced incidence of non-transmissible diseases. Modulating environmental conditions by improving cultivation systems can lead to the adaption of plant metabolisms and the accumulation of bioactive compounds. The present study investigates the regulation of carotenoid and flavonoid metabolisms in lettuce ( Lactuca sativa var capitate L.) grown in a protected environment (polytunnels) compared to plants grown without polytunnels. Carotenoid, flavonoid and phytohormone (ABA) contents were determined using HPLC-MS and transcript levels of key metabolic genes were analyzed by RT- q PCR. In this study, we observed inverse contents of flavonoids and carotenoids in lettuce grown without or under polytunnels. Flavonoid contents on a total and individual level were significantly lower, while total carotenoid content was higher in lettuce plants grown under polytunnels compared to without. However, the adaptation was specific to the level of individual carotenoids. For instance, the accumulation of the main carotenoids lutein and neoxanthin was induced while the β-carotene content remained unchanged. In addition, our findings suggest that the flavonoid content of lettuce depends on transcript levels of the key biosynthetic enzyme, which is modulated by UV light. A regulatory influence can be assumed based on the relation between the concentration of the phytohormone ABA and the flavonoid content in lettuce. In contrast, the carotenoid content is not reflected in transcript levels of the key enzyme of either the biosynthetic or the degradation pathway. Nevertheless, the carotenoid metabolic flux determined using norflurazon was higher in lettuce grown under polytunnels, suggesting posttranscriptional regulation of carotenoid accumulation, which should be an integral part of future studies. Therefore, a balance needs to be found between the individual environmental factors, including light and temperature, in order to optimize the carotenoid or flavonoid contents and to obtain nutritionally highly valuable crops in protected cultivation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Harbart, Frede, Fitzner and Baldermann.)

Pd-catalyzed C-N couplings are commonplace in academia and industry. Despite their significance, finding suitable reaction conditions leading to a high yield, for instance, remains a challenging and time-consuming task which usually requires screening over many sets of conditions. To help select promising reaction conditions in the vast space of reagent combinations, machine learning is an emerging technique with a lot of promise. In this work, we assess whether the reaction yield of C-N couplings can be predicted from databases of chemical reactions. We test the generalizability of models both on challenging data splits and on a dedicated experimental test set. We find that, provided the chemical space represented by the training set is not left, the models perform well. However, the applicability domain is quickly left even for simple reactions of the same type, as, for instance, present in our plate test set. The results show that yield prediction for new reactions is possible from the algorithmic side but in practice is hindered by the available data. Most importantly, more data that cover the diversity in reagents are needed for a general-purpose prediction of reaction yields. Our findings also expose a challenge to this field in that it appears to be extremely deceiving to judge models based on literature data with test sets which are split off the same literature data, even when challenging splits are considered., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Crystal nucleation is one of the most fundamental processes in the physical sciences and almost always occurs heterogeneously with the aid of a nucleating substrate. No example of nucleation is more ubiquitous and impactful than the formation of ice, vital to fields as diverse as geology, biology, aeronautics, and climate science. However, despite considerable effort, we still cannot predict a priori the efficacy of a nucleating agent. Here we utilize deep learning methods to accurately predict nucleation ability from images of room temperature liquid water-generated from molecular dynamics simulations-on a broad range of substrates. The resulting model, named IcePic, can rapidly and accurately infer nucleation ability, eliminating the requirement for either notoriously expensive simulations or direct experimental measurement. In an online poll, IcePic was found to significantly outperform humans in predicting the ice nucleating efficacy of materials. By analyzing the typical errors made by humans, as well as the application of reverse interpretation methods, physical insights into the role the water contact layer plays in ice nucleation have been obtained. Moving forward, we suggest that IcePic can be used as an easy, cheap, and rapid way to discern the nucleation ability of substrates, also with potential for learning other properties related to interfacial water.

As a critical part of plant immunity, cells that are attacked by pathogens undergo rapid transcriptional reprogramming to minimize virulence. Many bacterial phytopathogens use type III effector (T3E) proteins to interfere with plant defense responses, including this transcriptional reprogramming. Here, we show that Xanthomonas outer protein S (XopS), a T3E of Xanthomonas campestris pv. vesicatoria (Xcv), interacts with and inhibits proteasomal degradation of WRKY40, a transcriptional regulator of defense gene expression. Virus-induced gene silencing of WRKY40 in pepper (Capsicum annuum) enhanced plant tolerance to Xcv infection, indicating that WRKY40 represses immunity. Stabilization of WRKY40 by XopS reduces the expression of its targets, which include salicylic acid-responsive genes and the jasmonic acid signaling repressor JAZ8. Xcv bacteria lacking XopS display significantly reduced virulence when surface inoculated onto susceptible pepper leaves. XopS delivery by Xcv, as well as ectopic expression of XopS in Arabidopsis thaliana or Nicotiana benthamiana, prevented stomatal closure in response to bacteria and biotic elicitors. Silencing WRKY40 in pepper or N. benthamiana abolished XopS's ability to prevent stomatal closure. This suggests that XopS interferes with both preinvasion and apoplastic defense by manipulating WRKY40 stability and downstream gene expression, eventually altering phytohormone crosstalk to promote pathogen proliferation., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

The structure of liquid water in the proximity of an interface can deviate significantly from that of bulk water, with surface-induced structural perturbations typically converging to bulk values at about ∼1 nm from the interface. While these structural changes are well established it is, in contrast, less clear how an interface perturbs the dynamics of water molecules within the liquid. Here, through an extensive set of molecular dynamics simulations of supercooled bulk and interfacial water films and nano-droplets, we observe the formation of persistent, spatially extended dynamical domains in which the average mobility varies as a function of the distance from the interface. This is in stark contrast with the dynamical heterogeneity observed in bulk water, where these domains average out spatially over time. We also find that the dynamical response of water to an interface depends critically on the nature of the interface and on the choice of interface definition. Overall these results reveal a richness in the dynamics of interfacial water that opens up the prospect of tuning the dynamical response of water through specific modifications of the interface structure or confining material.

The freezing of water into ice is one of the most important processes in the physical sciences. However, it is still not understood at the molecular level. In particular, the crystallization of cubic ice ([Formula: see text])-rather than the traditional hexagonal polytype ([Formula: see text])-has become an increasingly debated topic. Although evidence for [Formula: see text] is thought to date back almost 400 y, it is only in the last year that pure [Formula: see text] has been made in the laboratory, and these processes involved high-pressure ice phases. Since this demonstrates that pure [Formula: see text] can form, the question naturally arises if [Formula: see text] can be made from liquid water. With this in mind, we have performed a high-throughput computational screening study involving molecular dynamics simulations of nucleation on over 1,100 model substrates. From these simulations, we find that 1) many different substrates can promote the formation of pristine [Formula: see text]; 2) [Formula: see text] can be selectively nucleated for even the mildest supercooling; 3) the water contact layer's resemblance to a face of ice is the key factor determining the polytype selectivity and nucleation temperature, independent of which polytype is promoted; and 4) substrate lattice match to ice is not indicative of the polytype obtained. Through this study, we have deepened understanding of the interplay of heterogeneous nucleation and ice I polytypism and suggest routes to [Formula: see text] More broadly, the substrate design methodology presented here combined with the insight gained can be used to understand and control polymorphism and stacking disorder in materials in general., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Despite the widespread and increasing usage of Pd-catalyzed C-N cross couplings, finding good conditions for these reactions can be challenging. Practitioners mostly rely on few methodology studies or anecdotal experience. This is surprising, since the advent of data-driven experimentation and the large amount of knowledge in databases allow for data-driven insight. In this work, we address this by analyzing more than 62 000 Buchwald-Hartwig couplings gathered from CAS, Reaxys and the USPTO. Our meta-analysis of the reaction performance generates data-driven cheatsheets for reaction condition recommendation. It also provides an interactive tool to find rarer ligands with optimal performance regarding user-selected substrate properties. With this we give practitioners promising starting points. Furthermore, we study bias and diversity in the literature and summarize the current state of the reaction data, including its pitfalls. Hence, this work will also be useful for future data-driven developments such as the optimization of reaction conditions via machine learning., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Water in nature predominantly freezes with the help of foreign materials through a process known as heterogeneous ice nucleation. Although this effect was exploited more than seven decades ago in Vonnegut's pioneering cloud seeding experiments, it remains unclear what makes a material a good ice former. Here, we show through a machine learning analysis of nucleation simulations on a database of diverse model substrates that a set of physical descriptors for heterogeneous ice nucleation can be identified. Our results reveal that, beyond Vonnegut's connection with the lattice match to ice, three new microscopic factors help to predict the ice nucleating ability. These are: local ordering induced in liquid water, density reduction of liquid water near the surface and corrugation of the adsorption energy landscape felt by water. With this we take a step towards quantitative understanding of heterogeneous ice nucleation and the in silico design of materials to control ice formation.

Wet carbon interfaces are ubiquitous in the natural world and exhibit anomalous properties, which could be exploited by emerging technologies. However, progress is limited by lack of understanding at the molecular level. Remarkably, even for the most fundamental system (a single water molecule interacting with graphene), there is no consensus on the nature of the interaction. We tackle this by performing an extensive set of complementary state-of-the-art computer simulations on some of the world's largest supercomputers. From this effort a consensus on the water-graphene interaction strength has been obtained. Our results have significant impact for the physical understanding, as they indicate that the interaction is weaker than predicted previously. They also pave the way for more accurate and reliable studies of liquid water at carbon interfaces.

When an ice crystal is born from liquid water, two key changes occur: ( i ) The molecules order and ( ii ) the mobility of the molecules drops as they adopt their lattice positions. Most research on ice nucleation (and crystallization in general) has focused on understanding the former with less attention paid to the latter. However, supercooled water exhibits fascinating and complex dynamical behavior, most notably dynamical heterogeneity (DH), a phenomenon where spatially separated domains of relatively mobile and immobile particles coexist. Strikingly, the microscopic connection between the DH of water and the nucleation of ice has yet to be unraveled directly at the molecular level. Here we tackle this issue via computer simulations which reveal that ( i ) ice nucleation occurs in low-mobility regions of the liquid, ( ii ) there is a dynamical incubation period in which the mobility of the molecules drops before any ice-like ordering, and ( iii ) ice-like clusters cause arrested dynamics in surrounding water molecules. With this we establish a clear connection between dynamics and nucleation. We anticipate that our findings will pave the way for the examination of the role of dynamical heterogeneities in heterogeneous and solution-based nucleation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Ice nucleation plays a significant role in a large number of natural and technological processes, but it is challenging to investigate experimentally because of the small time scales (ns) and short length scales (nm) involved. On the other hand, conventional molecular simulations struggle to cope with the relatively long time scale required for critical ice nuclei to form. One way to tackle this issue is to take advantage of free energy or path sampling techniques. Unfortunately, these are computationally costly. Seeded molecular dynamics is a much less demanding alternative that has been successfully applied already to study the homogeneous freezing of water. However, in the case of heterogeneous ice nucleation, nature's favourite route to form ice, an array of suitable interfaces between the ice seeds and the substrate of interest has to be built, and this is no trivial task. In this paper, we present a Heterogeneous SEEDing (HSEED) approach which harnesses a random structure search framework to tackle the ice-substrate challenge, thus enabling seeded molecular dynamics simulations of heterogeneous ice nucleation on crystalline surfaces. We validate the HSEED framework by investigating the nucleation of ice on (i) model crystalline surfaces, using the coarse-grained mW model, and (ii) cholesterol crystals, employing the fully atomistic TIP4P/ice water model. We show that the HSEED technique yields results in excellent agreement with both metadynamics and forward flux sampling simulations. Because of its computational efficiency, the HSEED method allows one to rapidly assess the ice nucleation ability of whole libraries of crystalline substrates-a long-awaited computational development in, e.g., atmospheric science.

Heterogeneous crystal nucleation is ubiquitous in nature and at the heart of many industrial applications. At the molecular scale, however, major gaps in understanding this phenomenon persist. Here we investigate through molecular dynamics simulations how the formation of precritical crystalline clusters is connected to the kinetics of nucleation. Considering heterogeneous water freezing as a prototypical scenario of practical relevance, we find that precritical fluctuations connote which crystalline polymorph will form. The emergence of metastable phases can thus be promoted by templating crystal faces characteristic of specific polymorphs. As a consequence, heterogeneous classical nucleation theory cannot describe our simulation results, because the different substrates lead to the formation of different ice polytypes. We discuss how the issue of polymorphism needs to be incorporated into analysis and comparison of heterogeneous and homogeneous nucleation. Our results will help to interpret and analyze the growing number of experiments and simulations dealing with crystal polymorph selection.

Non-bonded potentials are included in most force fields and therefore widely used in classical molecular dynamics simulations of materials and interfacial phenomena. It is commonplace to truncate these potentials for computational efficiency based on the assumption that errors are negligible for reasonable cutoffs or compensated for by adjusting other interaction parameters. Arising from a metadynamics study of the wetting transition of water on a solid substrate, we find that the influence of the cutoff is unexpectedly strong and can change the character of the wetting transition from continuous to first order by creating artificial metastable wetting states. Common cutoff corrections such as the use of a force switching function, a shifted potential, or a shifted force do not avoid this. Such a qualitative difference urges caution and suggests that using truncated non-bonded potentials can induce unphysical behavior that cannot be fully accounted for by adjusting other interaction parameters.

The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P<.0001) but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence (P<.0001). However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The nucleation of crystals in liquids is one of nature's most ubiquitous phenomena, playing an important role in areas such as climate change and the production of drugs. As the early stages of nucleation involve exceedingly small time and length scales, atomistic computer simulations can provide unique insights into the microscopic aspects of crystallization. In this review, we take stock of the numerous molecular dynamics simulations that, in the past few decades, have unraveled crucial aspects of crystal nucleation in liquids. We put into context the theoretical framework of classical nucleation theory and the state-of-the-art computational methods by reviewing simulations of such processes as ice nucleation and the crystallization of molecules in solutions. We shall see that molecular dynamics simulations have provided key insights into diverse nucleation scenarios, ranging from colloidal particles to natural gas hydrates, and that, as a result, the general applicability of classical nucleation theory has been repeatedly called into question. We have attempted to identify the most pressing open questions in the field. We believe that, by improving (i) existing interatomic potentials and (ii) currently available enhanced sampling methods, the community can move toward accurate investigations of realistic systems of practical interest, thus bringing simulations a step closer to experiments.

What makes a material a good ice nucleating agent? Despite the importance of heterogeneous ice nucleation to a variety of fields, from cloud science to microbiology, major gaps in our understanding of this ubiquitous process still prevent us from answering this question. In this work, we have examined the ability of generic crystalline substrates to promote ice nucleation as a function of the hydrophobicity and the morphology of the surface. Nucleation rates have been obtained by brute-force molecular dynamics simulations of coarse-grained water on top of different surfaces of a model fcc crystal, varying the water-surface interaction and the surface lattice parameter. It turns out that the lattice mismatch of the surface with respect to ice, customarily regarded as the most important requirement for a good ice nucleating agent, is at most desirable but not a requirement. On the other hand, the balance between the morphology of the surface and its hydrophobicity can significantly alter the ice nucleation rate and can also lead to the formation of up to three different faces of ice on the same substrate. We have pinpointed three circumstances where heterogeneous ice nucleation can be promoted by the crystalline surface: (i) the formation of a water overlayer that acts as an in-plane template; (ii) the emergence of a contact layer buckled in an ice-like manner; and (iii) nucleation on compact surfaces with very high interaction strength. We hope that this extensive systematic study will foster future experimental work aimed at testing the physiochemical understanding presented herein.

Rats with implanted telemetry transponders were blood sampled by jugular puncture, periorbital puncture or tail vein puncture, or sampled by jugular puncture in carbon dioxide (CO2), isoflurane or without anaesthesia in a crossover design. Heart rate, blood pressure and body temperature were registered for three days after sampling. Initially blood pressure increased, but shortly after sampling it decreased, which led to increased heart rate. Sampling induced rapid fluctuations in body temperature, and an increase in body temperature. Generally, rats recovered from sampling within 2-3 h, except for rats sampled from the tail vein, which showed fluctuations in body temperature in excess of 30 h after sampling. Increases in heart rate and blood pressure within the first hours after sampling indicated that periorbital puncture was the method that had the largest acute impact on the rats and that it might take an extra hour to recover from it. CO2 anaesthesia seemed unable to prevent the increase in blood pressure and the fluctuations in body temperature induced by blood sampling, and up to 10 h after sampling, the rats were still affected by CO2 anaesthesia. Rats anaesthetized with isoflurane showed lower increases in blood pressure after, and fewer fluctuations in body temperature during sampling, and the post-anaesthetic effects of isoflurane, if any, seemed to disappear immediately after sampling. It is, therefore, concluded that blood sampling in rats by jugular puncture seems to be the method from which rats most rapidly recover when compared with periorbital puncture and tail vein puncture, and that for anaesthesia, isoflurane is recommended in preference to CO2.

During a cross-over study with young female volunteers, the effects of a combination of 30 micrograms ethinylestradiol (EE) and 150 micrograms desogestrel (DG) or 3-keto-desogestrel (KDG) upon lipid metabolism were investigated on day 3 of the first cycle (day 3/I) and on day 21 of the third cycle of treatment (day 21/III). As compared to the control cycle, total cholesterol (CH), low-density lipoprotein CH (LDL-CH), and the apolipoproteins A-II and B were reduced already on day 3/I, the effects being more pronounced with the DG-containing formulation. On day 21/III of treatment with EE/DG, the levels of total CH, LDL-CH and apolipoprotein B did not differ from controls, while apolipoprotein A-II was significantly increased. The effects of EE/KDG were similar, except that on LDL-CH which was still reduced on day 21/III. The serum concentrations of total triglycerides (TG), very low-density lipoprotein CH (VLDL-CH), VLDL-TG, LD-TG, high-density lipoprotein CH (HDL-CH), HDL-TG, and apolipoprotein A-I were not significantly affected on day 3/I, but elevated on day 21/III. As during treatment with EE/KDG the peak level of KDG was higher than with EE/DG, the results indicate a more pronounced antagonistic effect of EE/KDG on some EE-induced changes on lipoproteins during the first days of intake. These short-term changes possibly reflect a rapid enhancement of hepatic uptake of remnants and LDL by EE. During long-term treatment, the other effects of EE, e.g. the stimulation of hepatic synthesis of TG, VLDL, and HDL and the inhibition of hepatic lipoprotein lipase, become apparent.

The pharmacokinetics and pharmacodynamics of 150 micrograms desogestrel (DG) or 150 micrograms 3-keto-desogestrel (KDG) in combination with 30 micrograms ethinylestradiol (EE) were compared in a cross-over study. While the EE levels as well as the area under the curve (AUC) of KDG did not differ, significantly higher peak levels of KDG were observed after intake of the KDG-containing formulation. As compared to the control cycle, LH and FSH were not reduced on day 3 of the first treatment cycle (3/I), but markedly suppressed on day 21 of the third cycle (21/III), the effects being more pronounced with the DG-containing pill. The serum levels of testosterone, free testosterone, androstenedione, androstanediol glucuronide, and dehydroepiandrosterone sulfate (DHEA-S) were significantly reduced already on day 3/I, while sex hormone-binding globulin (SHBG) was unchanged and corticosteroid-binding globulin (CBG) was increased. Thereafter, both SHBG and CBG rose markedly. The progressive decrease in DHEA-S correlated best with free testosterone and androstanediol glucuronide. The results indicate that the peak level of KDG is more important for the biological effectiveness than the AUC of KDG which appears to antagonize the suppressive action of EE on gonadotropin release. The rapid decrease in the androgen levels seems to be due to a direct inhibitory action of the pill on ovarian and adrenal steroid biosynthesis.

The serum concentrations of ethinylestradiol (EE) and 3-keto-desogestrel (KDG) were compared during treatment with a combination of 20 micrograms EE + 150 micrograms DG (20EE/DG) or of 30 micrograms EE + 150 micrograms DG (30EE/DG). During intake of both preparations, the peak levels and the areas under the curve (AUC) of EE increased significantly by approximately 100% between days 1 and 10. In the steady state, the maximal EE levels were 75 +/- 34 pg/ml (20EE/DG) and 136 +/- 55 pg/ml (30EE/DG), and the AUC were 464 +/- 236 pg.h/ml and 840 +/- 492 pg.h/ml. The KDG levels, which were identical with both preparations, increased between days 1 and 21 by approximately 300% up to values of 4.5 +/- 1.6 ng/ml. There were large interindividual variations in the AUC of EE and KDG and no correlation between the levels of EE and KDG. On day 21 of intake of 30EE/DG, the serum concentrations of sex-hormone- and corticosteroid-binding globulin were higher by 16% and 12%, respectively than with 20EE/DG. Although the morning peak levels of cortisol did not differ, the decrease which occurred thereafter, according to the circadian rhythm, was slower with 30EE/DG. There was no relationship between the serum concentrations of EE and/or KDG and the occurrence of irregular bleedings, which was similar during treatment with both preparations. As most of the women who bled had bleedings both with 20EE/DG and 30EE/DG, an influence of predisposition can be assumed.(ABSTRACT TRUNCATED AT 250 WORDS)