From PERFORM to PERFORM2Scale: Lessons from scaling-up a health management strengthening intervention to support Universal Health Coverage in three African countries.

Strengthening management and leadership competencies among district and local health managers has emerged as a common approach for health systems strengthening and to achieve Universal Health Coverage (UHC). While the literature is rich with localised examples of initiatives that aim to strengthen the capacity of district or local health managers, particularly in sub-Saharan Africa, considerably less attention is paid to the science of how to scale-up these initiatives. The aim of this paper is thus to examine the process of scaling-up a management strengthening intervention (MSI) and identify new knowledge and key lessons learned that can be used to inform the scale-up process of other complex health interventions, in support of UHC. Qualitative methods were used to identify lessons learned from scaling-up the MSI in Ghana, Malawi and Uganda. We conducted 14 interviews with district health management team members, three scale-up assessments with 20 scale-up stakeholders, and three reflection discussions with 11 research team members. We also kept records of activities throughout MSI and scale-up implementation. Data was recorded, transcribed, and analysed against the Theory of Change to identify both scale-up outcomes and the factors affecting these outcomes. The MSI was ultimately scaled-up across 27 districts. Repeated MSI cycles over time were found to foster greater feelings of autonomy among district health management teams (DHMTs) to address longstanding local problems, a more innovative use of existing resources without relying on additional funding, and improved teamwork. The use of 'resource teams' and the emergence of MSI 'champions', were both instrumental in supporting scale-up efforts. Challenges to the sustainability of the MSI include limited government buy-in and lack of sustained financial investment.

Identification of Src Family Kinases as Potential Therapeutic Targets for Chemotherapy-Resistant Triple Negative Breast Cancer.

Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC.

Above the Matrix: Functional Roles for Apically Localized Integrins.

Integrins are transmembrane proteins that are most typically thought of as integrating adhesion to the extracellular matrix with intracellular signaling and cell regulation. Traditionally, integrins are found at basolateral and lateral cell surfaces where they facilitate binding to the ECM and intercellular adhesion through cytosolic binding partners that regulate organization of actin microfilaments. However, evidence is accumulating that integrins also are apically localized, either endogenously or due to an exogenous stimulus. Apically localized integrins have been shown to regulate several processes by interacting with proteins such as connexins, tight junction proteins, and polarity complex proteins. Integrins can also act as receptors to mediate endocytosis. Here we review these newly appreciated roles for integrins localized to the apical cell surface.

Sphingomyelinase decreases transepithelial anion secretion in airway epithelial cells in part by inhibiting CFTR-mediated apical conductance.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel whose dysfunction causes cystic fibrosis (CF). The loss of CFTR function in pulmonary epithelial cells causes surface dehydration, mucus build-up, inflammation, and bacterial infections that lead to lung failure. Little has been done to evaluate the effects of lipid perturbation on CFTR activity, despite CFTR residing in the plasma membrane. This work focuses on the acute effects of sphingomyelinase (SMase), a bacterial virulence factor secreted by CF relevant airway bacteria which degrades sphingomyelin into ceramide and phosphocholine, on the electrical circuitry of pulmonary epithelial monolayers. We report that basolateral SMase decreases CFTR-mediated transepithelial anion secretion in both primary bronchial and tracheal epithelial cells from explant tissue, with current CFTR modulators unable to rescue this effect. Focusing on primary cells, we took a holistic ion homeostasis approach to determine a cause for reduced anion secretion following SMase treatment. Using impedance analysis, we determined that basolateral SMase inhibits apical and basolateral conductance in non-CF primary cells without affecting paracellular permeability. In CF primary airway cells, correction with clinically relevant CFTR modulators did not prevent SMase-mediated inhibition of CFTR currents. Furthermore, SMase was found to inhibit only apical conductance in these cells. Future work should determine the mechanism for SMase-mediated inhibition of CFTR currents, and further explore the clinical relevance of SMase and sphingolipid imbalances.

Evaluation of serum calcium differences in hypertensive crises and control patients: A randomly matched case-control study.

The role of calcium in blood pressure has been widely studied among hypertensive patients; however, no study has explored the role of calcium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum calcium levels between hypertensive crises patients and a 1:1 random matched controls (age-, sex-, race-, diabetes, and body mass index matched). This study is a single-center, retrospective, chart review, case-control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented calcium level. The control group patients were required to be 18 years of age or older, have a documented calcium level, and have no diagnosis of hypertensive crises. The primary outcome of the study was to compare the mean serum calcium in patients with hypertensive crises vs patients without hypertensive crises. Five hundred and sixty-six patients were included in the study: 283 patients in both the case group and control group. The primary outcome results showed that serum calcium concentration was not significantly different between the case group (8.99 ± 0.78 mg/dL) and control group (8.96 ± 0.75 mg/dL) (P = .606). This study found no significant difference in serum calcium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of calcium on blood pressure in hypertensive crises.

We need to address ableism in science.

In science, technology, engineering, and mathematics (STEM) fields, disabled people remain a significantly underrepresented part of the workforce. Recent data suggests that about 20% of undergraduates in the United States have disabilities, but representation in STEM fields is consistently lower than in the general population. Of those earning STEM degrees, only about 10% of undergraduates, 6% of graduate students, and 2% of doctoral students identify as disabled. This suggests that STEM fields have difficulty recruiting and retaining disabled students, which ultimately hurts the field, because disabled scientists bring unique problem-solving perspectives and input. This essay briefly explores the ways in which ableism-prejudice against disabled people based on the assumption that they are "less than" their nondisabled peers-in research contributes to the exclusion of disabled scientists and suggests ways in which the scientific community can improve accessibility and promote the inclusion of disabled scientists in academic science.

Ruffles and spikes: Control of tight junction morphology and permeability by claudins.

Epithelial barrier function is regulated by a family of transmembrane proteins known as claudins. Functional tight junctions are formed when claudins interact with other transmembrane proteins, cytosolic scaffold proteins and the actin cytoskeleton. The predominant scaffold protein, zonula occludens-1 (ZO-1), directly binds to most claudin C-terminal domains, crosslinking them to the actin cytoskeleton. When imaged by immunofluorescence microscopy, tight junctions most frequently are linear structures that form between tricellular junctions. However, tight junctions also adapt non-linear architectures exhibiting either a ruffled or spiked morphology, which both are responses to changes in claudin engagement of actin filaments. Other terms for ruffled tight junctions include wavy, tortuous, undulating, serpentine or zig-zag junctions. Ruffling is under the control of hypoxia induced factor (HIF) and integrin-mediated signaling, as well as direct mechanical stimulation. Tight junction ruffling is specifically enhanced by claudin-2, antagonized by claudin-1 and requires claudin binding to ZO-1. Tight junction spikes are sites of active vesicle budding and fusion that appear as perpendicular projections oriented towards the nucleus. Spikes share molecular features with focal adherens junctions and tubulobulbar complexes found in Sertoli cells. Lung epithelial cells under stress form spikes due to an increase in claudin-5 expression that directly disrupts claudin-18/ZO-1 interactions. Together this suggests that claudins are not simply passive cargoes controlled by scaffold proteins. We propose a model where claudins specifically influence tight junction scaffold proteins to control interactions with the cytoskeleton as a mechanism that regulates tight junction assembly and function.

Implementation research to assess a health workers performance-based management system in Nepal.

AIM: To test and refine a performance-based management system to improve health worker performance in Nepal. METHODS: A mixed-methods implementation research in three districts. The study assessed health workers' job satisfaction at the start and end of the study. Qualitative techniques were used to document processes, and routine health service data were analysed to measure outcomes. RESULTS: Job satisfaction significantly increased in six of nine key areas, and the proportion of staff absenteeism significantly declined in the study districts. It demonstrated an increase in immunisation coverage, the proportion of women who had a first antenatal check-up also having a fourth check-up and the proportion of childbirth in a health facility. The greatest perceived strengths of the system were its robust approach to performance planning and evaluation, supportive supervision, outcome-based job descriptions and a transparent reward system. A functional health facility environment, leadership and community engagement support successful implementation. CONCLUSION: The performance-based management system has the potential to increase health workers' job satisfaction, and it offers a tool to link facility-wide human resource management. A collaborative approach, ownership and commitment of the health system are critical to success. Considering the Nepal context, a management system that demonstrates a positive improvement has potential for improved health care delivery.

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma.

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.

Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance.

Approximately 10% of non-small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry-based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572-85. ©2017 AACR.

Oceanic protists with different forms of acquired phototrophy display contrasting biogeographies and abundance.

This first comprehensive analysis of the global biogeography of marine protistan plankton with acquired phototrophy shows these mixotrophic organisms to be ubiquitous and abundant; however, their biogeography differs markedly between different functional groups. These mixotrophs, lacking a constitutive capacity for photosynthesis (i.e. non-constitutive mixotrophs, NCMs), acquire their phototrophic potential through either integration of prey-plastids or through endosymbiotic associations with photosynthetic microbes. Analysis of field data reveals that 40-60% of plankton traditionally labelled as (non-phototrophic) microzooplankton are actually NCMs, employing acquired phototrophy in addition to phagotrophy. Specialist NCMs acquire chloroplasts or endosymbionts from specific prey, while generalist NCMs obtain chloroplasts from a variety of prey. These contrasting functional types of NCMs exhibit distinct seasonal and spatial global distribution patterns. Mixotrophs reliant on 'stolen' chloroplasts, controlled by prey diversity and abundance, dominate in high-biomass areas. Mixotrophs harbouring intact symbionts are present in all waters and dominate particularly in oligotrophic open ocean systems. The contrasting temporal and spatial patterns of distribution of different mixotroph functional types across the oceanic provinces, as revealed in this study, challenges traditional interpretations of marine food web structures. Mixotrophs with acquired phototrophy (NCMs) warrant greater recognition in marine research.

Early signaling dynamics of the epidermal growth factor receptor.

Despite extensive study of the EGF receptor (EGFR) signaling network, the immediate posttranslational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10-s resolution in the 80 s after stimulation in response to a range of eight growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 s after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Src homology 2 domain containing transforming protein (Shc) and phosphoinositol 3-kinase (PI3K) phosphorylation levels increase rapidly, but equilibrate within 20 s, whereas proteins such as Grb2-associated binder-1 (Gab1) and SH2-containing tyrosine phosphatase (SHP2) show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms and also uncovers primed activating components in the network, including Src family kinases, whose inhibition affects only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation and provide a window into exploring mechanistic hypotheses about receptor tyrosine kinase (RTK) biology.

Measurement of Phosphorylated Peptides with Absolute Quantification.

Mass spectrometry, when coupled to on-line separation such as liquid chromatography or capillary electrophoresis, enables the identification and quantification of protein expression and post-translational modification changes under diverse conditions. To date most of the methods for mass spectrometry-based quantification have either provided relative quantification information (e.g., comparison to a selected condition) or utilized one-point calibration curves, or calibration curves in a different biological matrix. Although these quantitative methods have been used to generate insight into the differences between biological samples, additional biological insight could be gained by accurately measuring the absolute quantity of selected proteins and protein modifications. To address this challenge, we have developed the MARQUIS (Multiplex Absolute Regressed Quantification with Internal Standards) method, designed to provide absolute quantification for potentially hundreds of peptides across multiple samples in a single analysis, using a multi-point internal calibration curve derived from synthetic, isotopically distinct standard peptides.

Vascular endothelial growth factor (VEGF) and platelet (PF-4) factor 4 inputs modulate human microvascular endothelial signaling in a three-dimensional matrix migration context.

The process of angiogenesis is under complex regulation in adult organisms, particularly as it often occurs in an inflammatory post-wound environment. As such, there are many impacting factors that will regulate the generation of new blood vessels which include not only pro-angiogenic growth factors such as vascular endothelial growth factor, but also angiostatic factors. During initial postwound hemostasis, a large initial bolus of platelet factor 4 is released into localized areas of damage before progression of wound healing toward tissue homeostasis. Because of its early presence and high concentration, the angiostatic chemokine platelet factor 4, which can induce endothelial anoikis, can strongly affect angiogenesis. In our work, we explored signaling crosstalk interactions between vascular endothelial growth factor and platelet factor 4 using phosphotyrosine-enriched mass spectrometry methods on human dermal microvascular endothelial cells cultured under conditions facilitating migratory sprouting into collagen gel matrices. We developed new methods to enable mass spectrometry-based phosphorylation analysis of primary cells cultured on collagen gels, and quantified signaling pathways over the first 48 h of treatment with vascular endothelial growth factor in the presence or absence of platelet factor 4. By observing early and late signaling dynamics in tandem with correlation network modeling, we found that platelet factor 4 has significant crosstalk with vascular endothelial growth factor by modulating cell migration and polarization pathways, centered around P38α MAPK, Src family kinases Fyn and Lyn, along with FAK. Interestingly, we found EphA2 correlational topology to strongly involve key migration-related signaling nodes after introduction of platelet factor 4, indicating an influence of the angiostatic factor on this ambiguous but generally angiogenic signal in this complex environment.

Can action research strengthen district health management and improve health workforce performance? A research protocol.

INTRODUCTION: The single biggest barrier for countries in sub-Saharan Africa (SSA) to scale up the necessary health services for addressing the three health-related Millennium Development Goals and achieving Universal Health Coverage is the lack of an adequate and well-performing health workforce. This deficit needs to be addressed both by training more new health personnel and by improving the performance of the existing and future health workforce. However, efforts have mostly been focused on training new staff and less on improving the performance of the existing health workforce. The purpose of this paper is to disseminate the protocol for the PERFORM project and reflect on the key challenges encountered during the development of this methodology and how they are being overcome. METHODS: The overall aim of the PERFORM project is to identify ways of strengthening district management in order to address health workforce inadequacies by improving health workforce performance in SSA. The study will take place in three districts each in Ghana, Tanzania and Uganda using an action research approach. With the support of the country research teams, the district health management teams (DHMTs) will lead on planning, implementation, observation, reflection and redefinition of the activities in the study. Taking into account the national and local human resource (HR) and health systems (HS) policies and practices already in place, 'bundles' of HR/HS strategies that are feasible within the context and affordable within the districts' budget will be developed by the DHMTs to strengthen priority areas of health workforce performance. A comparative analysis of the findings from the three districts in each country will add new knowledge on the effects of these HR/HS bundles on DHMT management and workforce performance and the impact of an action research approach on improving the effectiveness of the DHMTs in implementing these interventions. DISCUSSION: Different challenges were faced during the development of the methodology. These include the changing context in the study districts, competing with other projects and duties for the time of district managers, complexity of the study design, maintaining the anonymity and confidentiality of study participants as well as how to record the processes during the study. We also discuss how these challenges are being addressed. The dissemination of this research protocol is intended to generate interest in the PERFORM project and also stimulate discussion on the use of action research in complex studies such as this on strengthening district health management to improve health workforce performance.

Neural and humoral changes associated with the adjustable gastric band: insights from a rodent model.

BACKGROUND: Bariatric surgical procedures, including the laparoscopic adjustable gastric band (LAGB), are currently the only effective treatments for morbid obesity, however, there is no clear understanding of the mechanisms underpinning the efficacy of LAGB. The aim of this study is to examine changes in activation of the sensory neuronal pathways and levels of circulating gut hormones associated with inflation of an AGB. DESIGN AND RESULTS: The trajectory within the central nervous system of polysynaptic projections of sensory neurons innervating the stomach was determined using the transsynaptically transported herpes simplex virus (HSV). Populations of HSV-infected neurons were present in the brainstem, hypothalamus and cortical regions associated with energy balance. An elevation of Fos protein was present within the nucleus of the solitary tract, a region of the brainstem involved in the control of food intake, following acute and chronic band inflation. Two approaches were used to test (1) the impact of inflation of the band alone (on a standard caloric background) or (2) the impact of a standard caloric meal (on the background of the inflated band) on circulating gut hormones. Importantly, there was a significant elevation of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) following oral gavage of a liquid meal in animals with pre-inflated bands. There was no impact of inflation of the band alone on circulating GLP-1, PYY or ghrelin in animals on a standard caloric background. CONCLUSION: These data are consistent with the notion that the LAGB exerts its effects on satiety, reduced food intake and reduced body weight by the modulation of both neural and hormonal responses with the latter involving an elevation of meal-related levels of GLP-1 and PYY. These data are contrary to the view that the surgery is purely 'restrictive'.

Life and light: exotic photosynthesis in binary and multiple-star systems.

The potential for Earth-like planets within binary/multiple-star systems to host photosynthetic life was evaluated by modeling the levels of photosynthetically active radiation (PAR) such planets receive. Combinations of M and G stars in (i) close-binary systems; (ii) wide-binary systems, and (iii) three-star systems were investigated, and a range of stable radiation environments were found to be possible. These environmental conditions allow for the possibility of familiar, but also more exotic, forms of photosynthetic life, such as IR photosynthesizers and organisms that are specialized for specific spectral niches.

The 'Making it Happen' programme in India and Bangladesh.

A training package designed to train health care providers in the management of common obstetric and newborn complications using a competency based 'skills and drills' approach is used in Bangladesh and India as one of the interventions under the 'Making it Happen' programme. The programme was commenced in 2009 and aims to reduce maternal and newborn mortality and morbidity by improving health care providers' capacity to deliver Essential (Emergency) Obstetric and Newborn Care (EOC&NC) thus increasing the availability and quality of these services. Preliminary results indicate that the training package has improved knowledge and skills of trained health care providers and ensures more signal functions of EOC are provided.

Stomatal vs. genome size in angiosperms: the somatic tail wagging the genomic dog?

BACKGROUND AND AIMS: Genome size is a function, and the product, of cell volume. As such it is contingent on ecological circumstance. The nature of 'this ecological circumstance' is, however, hotly debated. Here, we investigate for angiosperms whether stomatal size may be this 'missing link': the primary determinant of genome size. Stomata are crucial for photosynthesis and their size affects functional efficiency. METHODS: Stomatal and leaf characteristics were measured for 1442 species from Argentina, Iran, Spain and the UK and, using PCA, some emergent ecological and taxonomic patterns identified. Subsequently, an assessment of the relationship between genome-size values obtained from the Plant DNA C-values database and measurements of stomatal size was carried out. KEY RESULTS: Stomatal size is an ecologically important attribute. It varies with life-history (woody species < herbaceous species < vernal geophytes) and contributes to ecologically and physiologically important axes of leaf specialization. Moreover, it is positively correlated with genome size across a wide range of major taxa. CONCLUSIONS: Stomatal size predicts genome size within angiosperms. Correlation is not, however, proof of causality and here our interpretation is hampered by unexpected deficiencies in the scientific literature. Firstly, there are discrepancies between our own observations and established ideas about the ecological significance of stomatal size; very large stomata, theoretically facilitating photosynthesis in deep shade, were, in this study (and in other studies), primarily associated with vernal geophytes of unshaded habitats. Secondly, the lower size limit at which stomata can function efficiently, and the ecological circumstances under which these minute stomata might occur, have not been satisfactorally resolved. Thus, our hypothesis, that the optimization of stomatal size for functional efficiency is a major ecological determinant of genome size, remains unproven.

Darwin--a mission to detect and search for life on extrasolar planets.

The discovery of extrasolar planets is one of the greatest achievements of modern astronomy. The detection of planets that vary widely in mass demonstrates that extrasolar planets of low mass exist. In this paper, we describe a mission, called Darwin, whose primary goal is the search for, and characterization of, terrestrial extrasolar planets and the search for life. Accomplishing the mission objectives will require collaborative science across disciplines, including astrophysics, planetary sciences, chemistry, and microbiology. Darwin is designed to detect rocky planets similar to Earth and perform spectroscopic analysis at mid-infrared wavelengths (6-20 mum), where an advantageous contrast ratio between star and planet occurs. The baseline mission is projected to last 5 years and consists of approximately 200 individual target stars. Among these, 25-50 planetary systems can be studied spectroscopically, which will include the search for gases such as CO(2), H(2)O, CH(4), and O(3). Many of the key technologies required for the construction of Darwin have already been demonstrated, and the remainder are estimated to be mature in the near future. Darwin is a mission that will ignite intense interest in both the research community and the wider public.