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Background: In Western countries, age at pubertal development has declined during the last century in girls, and probably also in boys. No studies have investigated whether nitrate, a widespread environmental exposure with teratogenic and hormone disrupting properties, might affect timing of puberty. Objectives: We investigated if prenatal exposure to nitrate from drinking water and diet was associated with timing of puberty. Methods: This cohort study included 15,819 children born from 2000 to 2003 within the Danish National Birth Cohort. Self-reported information on current status of various pubertal milestones was provided every six months by a questionnaire from 11 years of age until 18 years or full maturity, whichever came first. Maternal nitrate intake from diet (mg/day) was derived from a mid-pregnancy food frequency questionnaire and individual level nitrate exposure from drinking water (mg/L) was derived using measurements from Danish public waterworks. Adjusted average differences in months in age at attaining several pubertal milestones as well as the average age difference in age at attaining all the milestones were estimated separately for diet and water using a regression model for interval-censored data. C- and E-vitamin, red meat and processed meat intake were explored as potential effect modifiers in sub-analyses. Results: No strong associations were observed between prenatal exposure to nitrate and timing of puberty in children. However, sons born of mothers with a nitrate concentration in drinking water at their residential address of > 25 mg/L (half of the World Health Organisation (WHO) guideline value) compared with ≤ 1 mg/L showed a tendency towards earlier age at pubertal development with an average age difference of −1.2 months (95 % confidence interval,−3.0;0.6) for all the pubertal milestones combined. Discussion: Studies including more highly exposed children are needed before the current WHO drinking water guideline value for nitrate can be considered safe concerning pubertal development.

Exposure to exogenous sex hormones with estrogenic or anti-androgen properties may influence intrauterine development of male genitals. This population-based cohort study based on data from 44,408 live-born singleton sons in the Danish National Birth Cohort (DNBC) aimed to investigate whether maternal use of oral contraceptives prior to or during early pregnancy increase the risk of cryptorchidism or hypospadias. We found no consistent association between use of oral contraceptives and cryptorchidism or hypospadias, neither in those exposed any time four months prior to conception [cryptorchidism: adjusted Odds Ratio (aOR): 1.06 (95% CI: 0.91; 1.23), hypospadias: 0.74 (95% CI: 0.53; 1.03)] nor in those exposed any time during the first trimester of pregnancy [cryptorchidism: aOR: 0.93 (95% CI: 0.53; 1.62), hypospadias: 1.02 (95% CI: 0.32; 3.23)]. Despite relatively strong exposure levels from oral contraceptive use in pregnancy, this study revealed no evidence of an increased risk of either two genital malformations.

BACKGROUND: Hypospadias surgery undertaken in early life often continues to impose challenges as patients age. Little is known about the natural history of uncorrected hypospadias persisting into adulthood.OBJECTIVE: To describe presenting symptoms and management strategies in men with uncorrected hypospadias referred to our national tertiary transitional clinic for congenital urological conditions.MATERIALS AND METHODS: Patients with uncorrected hypospadias older than 16 years at the time of referral were identified by searching the electronic patient record system for ICD-10 hypospadias codes. Data were extracted over a 10-year period according to a predefined protocol.RESULTS: Among 201 referrals, 65 men with hypospadias (glanular n = 12, coronal n = 26, subcoronal n = 9, corporal n = 4, penoscrotal n = 2 and MIP n = 12) had never previously had reconstructive surgery undertaken. Obstructive symptoms predominated (n = 30) and the risk of symptoms increased with advancing age (Figure). Presenting complaints varied across the age span; cosmetic issues (n = 11) and coital pain (n = 5) were primarily seen in youth as opposed to urinary obstructive symptoms that were increasingly more frequent with age (p = 0.002) (Figure). Management included reconstructive surgery (n = 24), minor procedures (preputioplasty, circumcision, meatoplasty, dilatation/urethrotomy, total n = 28) as well as counselling (n = 12). The management strategies were independent of age and hypospadias type.DISCUSSION: The current cohort delineates the dynamic nature of hypospadias in itself. We speculate that the distinction in the primary complaint leading to referral between the extremes of age may relate to the vanity and insecurity of youth while older patients first come forward when other symptoms arise. Dissatisfaction with genital appearance is uncommon in previous smaller studies on men with uncorrected hypospadias unlike in our study, where 11 patients were assessed mainly for cosmetic concerns. Obstruction is the main symptom encountered in adult hypospadias patients operated in early life, and a similar picture was observed in our cohort of unoperated cases. Urethral dilatation and internal urethrotomy are temporizing procedures but were successful in immediate alleviation of obstructive symptoms in patients not willing to consign themselves to formal surgery. The study is limited by its retrospective design, and our symptomatic cohort may also represent the extreme end of the hypospadias spectrum.CONCLUSION: Medical issues vary across the age span in men with unrepaired hypospadias. Minor surgical procedures as well as counselling play an equally important role as reconstructive hypospadias surgery in the management of unrepaired hypospadias in adulthood.

Background Children with congenital heart defects (CHD) have an increased risk of developmental delay. It remains sparsely investigated if these patients also have a delayed pubertal development. In this nationwide cohort study, we evaluated if CHD was associated with timing of puberty using longitudinally collected data on pubertal milestones. Methods and Results We used data from the Danish nationwide Puberty Cohort. Information on CHD was obtained from the Danish National Patient Register. Information on pubertal development was obtained from 15 780 children through questionnaires answered half‐yearly from 11 years until 18 years or full maturity. Using a multivariable regression model for censored time‐to‐event data, mean difference in age at attaining each pubertal milestone was estimated, including a combined pubertal marker. Compared with children without CHD, analyses were performed for both CHD overall and subdivided into simple and complex CHD. In a subanalysis, analyses were repeated in children born at term. In total, 137 children (62 boys and 75 girls) had a CHD diagnosis. Overall, no difference in age at pubertal timing was observed for children with CHD compared with unaffected children. The average differences were small for both boys (1.6 [95% CI, −2.6 to 5.7] months) and girls (1.0 [95% CI, −2.5 to 4.4] months). The same differences were observed when subdividing into simple or complex CHD and when restricting to children born at term. Conclusions We found no association between CHD and pubertal timing. For the group of children with complex CHD, we were unable to exclude a later pubertal timing.

OBJECTIVE: To study the association between maternal diabetes and timing of pubertal development in daughters and sons.DESIGN: Prospective cohort study.SETTING: Not applicable.PATIENT(S): A total of 15,822 mother-child pairs included in the Danish National Birth Cohort and the Puberty Cohort with prospectively collected, register-based and self-reported information on maternal diabetes and self-reported information on pubertal development.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Adjusted mean monthly difference in age at attaining pubertal milestones in children born of mothers with diabetes compared with children born of mothers without diabetes.RESULT(S): A total of 502 children were born of mothers with diabetes during pregnancy. In daughters exposed to gestational diabetes mellitus, we observed advanced onset in all pubertal milestones. The associations were statistically significant with regard to pubic hair Tanner stage 2 (-4.8 months) (95% confidence interval [CI] -7.7, -2.0), pubic hair Tanner stage 3 (-2.2 months) (95 % CI -4.4, 0.0), pubic hair Tanner stage 5 (-6.0 months) (95% CI -10.8, -1.2), and menarche (-2.5 months) (95 % CI -4.9, 0.0). We observed no tendencies between maternal type 1 or type 2 diabetes mellitus and pubertal development in daughters. We observed no associations between maternal diabetes and pubertal development in sons.CONCLUSION(S): Our findings suggest that gestational diabetes mellitus may accelerate the pubertal development in daughters. Our results did not support an association between type 1 or type 2 diabetes mellitus and daughters' pubertal development, as well as between any type of maternal diabetes and sons' pubertal development.

Green energy, i.e. electricity stemming from renewable resources, can help mitigate climate change. This paper presents a social simulation (or agent-based model) that aims going one step in validating a dynamic psychological decision micro-theory that has been developed to include goals, deliberative decisions as well as status quo bias, social milieus, communication over personal networks, and sensitivity towards external events such as price changes or messages from the media. We show how the simulation replicates a set of customer data from a German green energy provider, reproducing the temporal and spatial diffusion of adoption of their product. The building of the simulation is supported by a survey (N = 778) investigating the psychological variables relating to the adoption of green energy and lifestyles (milieus), and online experiments about personal networks and information processing style. A scenario, i.e. an experiment run within the simulation, introduces more frequent communication between households that is interpreted as the effect of an information campaign. The frequency of personal communication and a salient event reported in the media interact to foster green energy adoption. We argue that social simulation proves being an appropriate tool to develop and test dynamic psychological theories.

Climate change impacts and adaptation measures are subject to various uncertainties. In communication and decision-making, these uncertainties need to be adequately considered. However, uncertainty is a conceptually multifaceted issue, a plethora of connotations and meanings surround the term, and most of that is not explicit but only implicit. We examined the notions of climate-change-related uncertainties actually held by stakeholders – from government and administration, water management, agriculture, tourism, nature conservation, education, and the insurance industry – in the coastal region of Krummhorn, East Frisia, Germany. We employed qualitative, semi-structured in-depth interviews, covering general as well as context-specific aspects of uncertainty. To analyze the interviews, we employed qualitative content analysis, using MAXQDA software and deductively and inductively formed codes. One main finding was the large heterogeneity in the responses: different stakeholders hold widely differing notions of uncertainty – across and even within sectors. Most stakeholders do not normally employ one of the established scientific concepts of uncertainty, but hold a normative perspective on uncertainty which is strongly based on subjective valuation. When dealing with objective information on the quantification of uncertainty, such as probabilities, most stakeholders are inconsistent. The particular perspective on uncertainty is strongly related to the specific topic. On a meta-level, we found that all stakeholders were unfamiliar with talking about uncertainty and had difficulties expressing their ideas in language. Overall, our study confirmed that uncertainty is a contested, pluralistic, and complex phenomenon, which is looked at from different perspectives by different stakeholders. We conclude that the communication of uncertainty at the science–society interface requires particular attention, as the notions of uncertainty held by stakeholders are not always in line with the established scientific concepts of uncertainty.

This paper reports on a single-use pressure sensor for medical applications. The sensor principle makes use of the radial expansion of a silicone tube which occurs when there is a pressure difference between the inside and the outside of the tube. The change in outer diameter is detected by a capacitive measurement method, whereas the amplification electronics can be separated from the tube being in contact with the fluid. This enables a cross-contamination-free measurement system for patient near application as e.g. within infusion systems. The sensor includes a novel highly sensitive and fast analog amplification circuit in combination with gold electrodes fabricated in PCB technology. This circuit enables to amplify even highly dynamic pressure changes, in the range of a few milliseconds causing capacitive changes on the electrodes in the fF range to a readable voltage level. A functional model is developed based on flex board technology which allows for studying the influence of the electrode geometry as well as the material properties of the silicone tube with respect to the sensitivity of the sensor. The best performing electrode geometry determined by experiments features a sensitivity of 0.195 fF/kPa at a mean coefficient of variation (CV) of 6.4%, considering three individual sensor assemblies. A sensor prototype is designed and fabricated based on the results of the investigated functional model. The performance of the prototype is investigated experimentally in a pressure range from 0 to 40 kPa. As a result a sensitivity of 0.135 V/kPa for DI water as measurement liquid could be achieved and a good linearity of the signal (R2 = 0.996) was observed up to 35 kPa.

Protein-protein interactions (PPIs) govern intracellular life, and identification of PPI inhibitors is challenging. Roadblocks in assay development stemming from weak binding affinities of natural PPIs impede progress in this field. We postulated that enhancing binding affinity of natural PPIs via protein engineering will aid assay development and hit discovery. This proof-of-principle study targets PPI between linear ubiquitin chains and NEMO UBAN domain, which activates NF-κB signaling. Using phage display, we generated ubiquitin variants that bind to the functional UBAN epitope with high affinity, act as competitive inhibitors, and structurally maintain the existing PPI interface. When utilized in assay development, variants enable generation of robust cell-based assays for chemical screening. Top compounds identified using this approach directly bind to UBAN and dampen NF-κB signaling. This study illustrates advantages of integrating protein engineering and chemical screening in hit identification, a development that we anticipate will have wide application in drug discovery.

In the past two decades, research on so-called climate engineering approaches has increased. These technologies are considered to be potential substitutes for mitigation strategies in combating climate change. The ongoing process of layperson acceptance and resultant opinion formation can be expected to play a crucial role in future public debate about field experiments or the actual deployment of climate engineering. In July 2017, we assessed public reactions from the German population in a representative online survey. Participants were given a brief text informing them about climate change and one of four different scenarios in a between-subject design (N = 678). Two of the scenarios described the use of climate engineering technologies - stratospheric aerosol injection (SAI) and bio-energy with carbon capture and storage (BECCS) - one of them covered conventional mitigation strategies and the fourth group was given an outline of the business-as-usual (BAU) approach. The mitigation scenario (willingness for individual behaviour changes) showed the highest acceptance rate (M = 74.23), which was significantly higher than acceptance of the other scenarios (p

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptor(s) remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. Therefore, we investigated cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38-knockout (IL-38 KO) mice showed delayed disease resolution due to exacerbated IL-17-mediated inflammation, which was reversed by administration of mature IL-38. Mechanistically, IL-38 antagonized X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1), which was upregulated upon γδ T cell activation to feed-forward amplify IL-17 production. Heightened activation of tumor-infiltrating γδ T cells was also observed in IL-38 KO oncogene-driven mammary carcinoma, accompanied by attenuated tumor growth. Our findings, which are supported by clinical data, highlight the connection between auto-inflammation and anti-tumor immunity and indicate IL-38 as a potential therapeutic target under these conditions.

OBJECTIVE: To study the associations between exposure to oral contraceptives before conception and early in pregnancy and pubertal timing in boys and girls.DESIGN: Population-based cohort study.SETTING: Not applicable.PATIENT(S): Overall, 15,800 children (70%) born during 2000-2003 into the Danish National Birth Cohort were categorized according to maternal use of combined oral contraceptive pills or progestin-only pills reported around gestational week 17: no exposure (reference), exposure 4 months before conception, and exposure in early pregnancy. Children self-assessed pubertal status using Web-based questionnaires from 11 years and biannually throughout puberty.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Adjusted mean age differences (months) for attaining individual pubertal milestones and overall pubertal timing. Proportion mediated by prepubertal body mass index.RESULT(S): In boys, intrauterine exposure to oral contraceptives showed a tendency toward slightly earlier mean age for voice break (months, -3.8; 95% confidence interval [CI] -6.5, -1.0) and first ejaculation (months, -2.9; 95% CI -5.9, 0.1) and a mean difference of -1.4 months (95% CI -3.3, 0.4) for overall pubertal timing. Girls with intrauterine exposure tended to have slightly earlier age at menarche (months, -1.9; 95% CI -4.0, 0.3) and Tanner breast stages and had a mean difference of -0.9 months (95% CI -2.7, 1.0) for overall pubertal timing. Exposure before conception was not associated with pubertal timing. Prepubertal body mass index did not play a mediating role.CONCLUSION(S): This study shows some evidence that intrauterine exposure to oral contraceptives might slightly affect pubertal timing.

Summary Purpose The ventral aspect of the penis in boys with hypospadias is composed of dysplastic tissue of the skin and the urethra. The aim of this study was to assess the pre-operative size and biomechanical properties of urethrae in boys with and without hypospadias using a more objective catheter-based system. Materials & methods In this non-blinded clinical observation study, the study population consisted of 19 boys with hypospadias—the case group (median age 13.9 months [range: 12.2–21.3])—and seven boys without hypospadias—the control group (median age 8.5 months [range: 3.8–18.1]). Modified measurements of impedance were used to assess the size, compliance and viscoelasticity of the urethrae under stepwise increased pressures (between 0, 40 and 60 cmH2O) using a customised Endolumenal Functional Lumen Imaging probe (EndoFLIP®). Results The sizes of the urethrae in boys with hypospadias are variable but tend towards being narrower and less compliant than those of the control subjects i.e. median diameter for meatus urethra was 3.2 mm (range: 2.98–3.92) in the hypospadias group compared with 3.64 (range: 3.22–4.44) in the control group at 40 cmH2O, and the median change in diameter at meatus urethra was 0.08 mm (range: −0.02 to 0.52) in the hypospadias group compared with 0.23 mm (range: −0.02 to 0.34) when the pressure was increased from 40 to 60 cmH2O. This biomechanical analysis found that there was no significant viscoelasticity of the urethral meatus in both the groups, whereas the remainder of the urethral structure generally had viscoelastic properties in the control group, seen as a creep on the time/diameter curves (Figure). In the group of boys with hypospadias, evaluations of the urethrae revealed varying viscoelastic abilities, ranging from abilities that were comparable with those of the control subjects to no sign of viscoelasticity at all. Conclusions This study is the first to measure the biomechanical properties of the urethra in children, which might help to provide an understanding as to the structural and functional changes associated with hypospadias. The urethrae in the subjects with hypospadias were variable in diameter but tended to be narrower overall, especially in the distal portion of the urethra. Furthermore, the urethrae in boys with hypospadias were frequently less viscoelastic than those of controls. Clinical relevance The EndoFLIP® system may be a future way of objectively estimating the severity of a urethral obstruction and could potentially be included in the postoperative assessment of patients with signs of hampered voiding. Download : Download high-res image (169KB) Download : Download full-size image Figure . Time/diameter curves showing the diameter change in MU (meatus urethra) and 5, 10 and 15 mm proximally from MU in urethra in two control patients (a, b) and two hypospadias patients (c, d). The arrow indicates the time of pressure increase. Figures (a) and (b) show no viscoelasticity in MU but a creep in urethra indicating viscoelasticity. Figures (c) and (d) show no viscoelasticity in MU and also no viscoelasticity in urethra after pressure increase.

This paper presents a novel method for nanoliter droplet characterization using a polymer coated sensor of a low-cost quartz crystal microbalance (QCM). The gold electrode of the crystal sensor was coated by a surface-attached polymer hydrogel film of about 2µm thickness using simple spin casting and photocrosslinking procedure [1,2]. The resonance frequency of the coated crystal sensor was continuously recorded at the sample rate of 2 Hz over 90 seconds before and after loading a micro droplet of filtered double-distilled water. Good repeatability (max. CV = 3.8%) and good linearity (r(x,y)= 0.995) of the maximum resonance frequency shift have been observed during 144 dispenses for 6 different droplet volumes in the range from 3 nl to 13 nl. A calibration line for the measured domain of the maximum frequency shift in relation to droplet mass was established according to the gravimetric calibration of the used dispenser with an ultra-microbalance. © 2012 Published by Elsevier Ltd.

This paper reports on a non-contact optical sensor for the detection of single droplets in flight. The sensor allows for online process control of non-contact dispensing systems delivering droplets in the nanolitre range. A dispensed liquid droplet, which passes through the optical transducer, leads to a change of the light intensity caused by absorption, reflection and diffraction. The change in light intensity measured by a photo transistor provides information about, e.g. droplet size, velocity and shape. This information is encoded in the time dependent signal shape that yields a characteristic “fingerprint”-signal for each droplet. The fabrication of the sensor is achieved by standard printing circuit board (PCB) technology. Therefore, an easy adaption of the sensor to different kinds of contactless dispensing system and furthermore a very cost efficient production is granted.

This paper reports on a sensor for the detection of microdroplets in flight. The presented sensor is based on a capacitive principle, which allows for non-contact monitoring of a complete droplet dispensing process. In the presented experiments the change in capacity caused by liquid droplets in the range of a few nanoliters passing through the electric field of the sensor is studied. From the capacitive change the droplet presence can be deduced with a reliability of 100%, which means that every single droplet dispensed within the experiments caused a significant signal change. In addition, the sensor signal is sensitive to the droplet’s volume V, dielectric constant er (epsilon) and velocity v. It turns out that every specific droplet exhibits a characteristic “fingerprint” signal depending on these parameters. Especially the droplet volume correlates very well with the peak value of the extracted signal. Therefore, the calibrated sensor is able to determine the volume of dispensed droplets in the range from 20 to 65 nl with a resolution of less than 2 nl. Furthermore, the printed circuit board (PCB) technology applied for fabrication of the sensor enables a very cost efficient and flexible realisation of the whole sensor unit. The non-contact capacitive principle prevents contamination and loss of media. Therefore, the proposed approach is well suited for high precision droplet presence detection and low cost online monitoring of liquid volumes in

This paper presents an agent-based model of the diffusion of water-saving innovations. The empirical foundation of this model is a study, which was carried out for that specific purpose. As an example case, the diffusion of three water-related innovations in Southern Germany was chosen. The model represents a real geographic area and simulates the diffusion of showerheads, toilet flushes, and rain-harvesting systems. Agents are households of certain lifestyles, as represented by the Sinus-Milieus® from commercial marketing. Agents use two different kinds of decision rules to decide upon adoption or rejection of the modeled innovations: A cognitively demanding deliberate decision rule and a very simple decision heuristic. Thus, the model integrates concepts of bounded rationality. The overall framework for decision-making is the Theory of Planned Behavior, which has been elaborated using innovation characteristics from diffusion research. The model was calibrated with empirical data stemming from a questionnaire survey and validated against independent data. Scenarios for the nearer future show that water-saving innovations will diffuse even without further promotion, and different promotion strategies that relate specifically to both innovations and lifestyles can be pointed out.

We present the combination of an illumination invariant approach to face detection combined with a tracking mechanism used for improving speed and accuracy of the system. We introduce illumination invariant local structure features for object detection. For an efficient computation we propose a modified census transform, which enhances the original work of Zabih and Woodfill [19] [Ramin Zabih, John Woodfill. A non-parametric approach to visual correspondence. IEEE Transactions on Pattern Analysis and Machine Intelligence, 1996.]. The tracking is performed by means of continuous detection. We show that the advent of new rapid detection algorithms may change the need for traditional tracking. Furthermore the mentioned problems have a natural solution within the presented tracking by continuous detection approach. The only assumption on the object to track is its maximal speed in the image plane, which can be set very generously. From this assumption we derive three conditions for a valid state sequence in time. To estimate the optimal state of a tracked face from the detection results a Kalman filter is used. This leads to an instant smoothing of the face trajectory. It can be shown experimentally that smoothing the face trajectories leads to a significant reduction of false detections compared to the static detector without the presented tracking extension. We further show how to exploit the highly redundant information in a natural video sequence to speed-up the execution of the static detector by a temporal scanning procedure which we call 'slicing'. A demo program showing the outcomes of our work can be found in the internet under http://www.iis.fraunhofer.de/bv/biometrie/ for download.

The versatility of a titanium-induced reductive oxo-amide coupling reaction is illustrated by the syntheses of the alkaloids secofascaplysin 8 and indolopyridocoline 14 as well as by an efficient and flexible approach to the arylated indole-2-carboxylic acid 4 , which has recently been disclosed as a promising endothelin-receptor-antagonist. Depending on the particular substitution pattern in the substrates, either pre-formed titanium on graphite or low-valent titanium formed in situ (“instant conditions”) are the preferred coupling agents for reductive heterocycle syntheses of this type.

A short synthetic route to the phytoalexin camalexin 7 and a convergent approach to the alkaloids indolopyridocoline 8 , 6,7-dihydroflavopereirine 15 and flavopereirine 9 are presented. Starting from well accessible precursors, these total syntheses highlight the preparative potential of a new method for indole synthesis based on the formation of the C2C3 bond by low-valent titanium induced reductive coupling of oxo-amides.

Nocturnal plasma delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) was determined serially in seven healthy male subjects. Time courses during nocturnal sleep (2300-0800 h), nocturnal sleep deprivation (2300-0500 h), and morning recovery sleep (0500-0800 h) after sleep deprivation were compared. A significant decrease in plasma DSIP-LI was found at the transition from wakefulness to sleep in both evening sleep (2300 h) and morning recovery sleep (0500 h). Time courses were accompanied by physiological changes in sleep electroencephalographic slow-wave activity, and in plasma concentrations of cortisol and human growth hormone. No sleep stage specificity was found. It is concluded that DSIP is influenced by the initiation of sleep.

This paper develops a decision framework for environmental philanthropy in search of achieving sustainability on a crowded planet. Many of the world's most pressing global challenges are environmental in nature (or have stark environmental implications) and require long-term efforts. Asking what and how environmental philanthropy can contribute to address the sustainability challenges, the paper first reviews the history of environmental philanthropy and analyzes its role in a world in which humanity is de facto tasked to actively manage nature. The paper maps the current landscape of environmental philanthropy, and applies the concepts of manufactured and external risks to the field. Subsequently, the paper develops a decision framework suggesting a portfolio approach that classifies actions based on knowledge about outcomes and probabilities under the categories of risk, uncertainty and ignorance. The framework is applied to the area deforestation.

This case study was developed in 2003 as a blueprint for case studies on leading social entrepreneurs. It explores the tension between scaling up and scaling deep, analyzing the case of Association pour le Soutien et l'Appui' la Femme Entrepreneur (ASAFE) in Cameroon and its leader Gisele Yitamben from 1987-2003. Since its creation, ASAFE had successfully addressed many challenges and was well known in the national and international development community. Its very existence gave hope to hardened expatriate development workers in the field, disillusioned by the omnipresence of corruption in Africa. Expectations ran high. As an attache at a major embassy interviewed by the authors put it, "only half a per cent of the local NGOs are reliable and transparent. Combine that with their expertise and a fifteen year track record, and you will agree that ASAFE is unique." But this also created challenges. ASAFE's reliability and transparency almost had international donors chasing the organization to secure its involvement in a diverse array of activities. Balancing donors' needs and sticking to one's mission was not always easy. ASAFE had entered new fields three times in a decade - business education, microfinance and e-commerce - always driven by the importance of its constituency's newly arising needs. But a lot remained to be done to promote large-scale e-readiness. The case study thus poses the following management dilemma: Had the time come to take ASAFE's proven track record on education into the domain of public health and accept funds readily available for an HIV/AIDS project? Or should it focus on the core competences established so far?

Ecological knowledge is analyzed under psychological and educational aspects. In empirical studies three experimental settings were used to investigate this type of knowledge: (1) a computer simulation of an ecological system, (2) an environmental game as a new variant of the Commons Dilemma, and (3) a computerized text base on various aspects of an actual environmental problem. The subjects had to acquire and to apply this knowledge in making predictions, planning intervention, deciding about environmental measures etc. The results show which conditions impair the acquisition and correct utilization of ecological knowledge and how it is possible to provide well-structured learning environments for this content domain.

In the reaction of manganese(III) acetate with carboxylic acids and alkenes, three distinct processes have been identified which involve the alkene and two processes which are independent of alkene. A combination of product studies, rearrangements, dilution experiments and literature kinetic data allow the proposal of a unified mechanistic picture to describe these processes. Specifically, the role of α-H acidity of the carboxylic acid component, electron deficient radical additions, metal complexed organic radicals, and the importance of an oxo-centered manganese(III) triangle are discussed as they relate to the lactone annulation reaction. Single electron transfer oxidation of alkenes is described as a route toward 1,2-diacetates of alkenes within the 8.1-7.5 eV I.P. range. Three less common modes of Mn(III) reaction are discussed and compared with the two primary processes of lactone annulation and 1,2-diacetate formation.

Comment in : A Billion Ubiquitin Variants to Probe and Modulate the UPS. [Mol Cell. 2016]; International audience; HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.