How have smallholder farmers used digital extension tools? Developer and user voices from Sub-Saharan Africa, South Asia and Southeast Asia

Digital extension tools (DETs) include phone calls, WhatsApp groups and specialised smartphone applications used for agricultural knowledge brokering. We researched processes through which DETs have (and have not) been used by farmers and other extension actors in low- and middle-income countries. We interviewed 40 DET developers across 21 countries and 101 DET users in Bihar, India. We found DET use is commonly constrained by fifteen pitfalls (unawareness of DET, inaccessible device, inaccessible electricity, inaccessible mobile network, insensitive to digital illiteracy, insensitive to illiteracy, unfamiliar language, slow to access, hard to interpret, unengaging, insensitive to user's knowledge, insensitive to priorities, insensitive to socio-economic constraints, irrelevant to farm, distrust). These pitfalls partially explain why women, less educated and less wealthy farmers often use DETs less, as well as why user-driven DETs (e.g. phone calls and chat apps) are often used more than externally-driven DETs (e.g. specialised smartphone apps). Our second key finding was that users often made - not just found - DETs useful for themselves and others. This suggests the word ‘appropriation’ conceptualises DET use more accurately and helpfully than the word ‘adoption’. Our final key finding was that developers and users advocated almost ubiquitously for involving desired users in DET provision. We synthesise these findings in a one-page framework to help funders and developers facilitate more useable, useful and positively impactful DETs. Overall, we conclude developers increase DET use by recognizing users as fellow developers – either through collaborative design or by designing adaptable DETs that create room for user innovation

Artificial escape from XCI by DNA methylation editing of the CDKL5 gene.

A significant number of X-linked genes escape from X chromosome inactivation and are associated with a distinct epigenetic signature. One epigenetic modification that strongly correlates with X-escape is reduced DNA methylation in promoter regions. Here, we created an artificial escape by editing DNA methylation on the promoter of CDKL5, a gene causative for an infantile epilepsy, from the silenced X-chromosomal allele in human neuronal-like cells. We identify that a fusion of the catalytic domain of TET1 to dCas9 targeted to the CDKL5 promoter using three guide RNAs causes significant reactivation of the inactive allele in combination with removal of methyl groups from CpG dinucleotides. Strikingly, we demonstrate that co-expression of TET1 and a VP64 transactivator have a synergistic effect on the reactivation of the inactive allele to levels >60% of the active allele. We further used a multi-omics assessment to determine potential off-targets on the transcriptome and methylome. We find that synergistic delivery of dCas9 effectors is highly selective for the target site. Our findings further elucidate a causal role for reduced DNA methylation associated with escape from X chromosome inactivation. Understanding the epigenetics associated with escape from X chromosome inactivation has potential for those suffering from X-linked disorders

A validated numerical model for the growth and resorption of bubbles in magma

The rate and timing of bubble growth in magma is an important control on eruption style, determining whether or not magma fragments to produce an explosive eruption. Bubbles nucleate, grow, shrink, and de-nucleate in magma in response to changes in pressure and temperature, and these changes may be recorded in the spatial distribution and speciation of water 'frozen into' the glass in eruptive products. Accurate modelling of growth and resorption is therefore essential both for forward modelling of eruptive processes, and for inverse modelling to reconstruct pre-eruptive history. We present the first experimentally-validated numerical model for bubble growth and resorption in magma. The model includes the kinetics of speciation, allows for arbitrary temperature and pressure pathways, and accounts for the impact of spatial variations in water content on diffusivity and viscosity. We validate the model against three sets of data. (1) Continuous vesicularity-time data collected using optical dilatometry and in-situ synchrotron-source x-ray tomography of natural and synthetic magma during thermally-induced vesiculation and resorption at magmatic temperatures and ambient pressure. This represents approximately isobaric bubble growth and resorption under disequilibrium conditions. (2) Final vesicularity data from decompression experiments at magmatic temperatures and pressures. This represents isothermal, decompression-driven bubble growth from equilibrium to strongly disequilibrium conditions. (3) Speciation data from diffusion-couple experiments on synthetic haplogranites at magmatic temperatures and pressures. The numerical model closely reproduces all experimental data, providing validation against equilibrium and disequilibrium bubble growth/resorption and speciation scenarios. The validated model can be used to predict the growth and resorption of bubbles, and associated changes in magma properties, for arbitrary eruption pathways. It can also be used to reconstruct pressure-temperature-time pathways from textures and volatile contents of eruptive products. This will open up new ways of accessing the dynamics of magma ascent and eruption in unobserved volcanic eruptions

Viewing scenes of the history of chemistry through the opera glass

Artistic creation has always reflected the spirit of the moment and opera has not been an exception. There are several examples of operas which appeared at key moments of the development of science, portraying them. Additionally there are also operas that emerged after scientific events or the lifetime of the scientists they were inspired on. In what concerns chemistry, the first category could be exemplified by the apothecary operas (already discussed by the author in a previous paper of this journal) while the others could be illustrated by recent operas such as Dr. Atomic or Madame Curie. Continuing our endeavor of establishing relations between opera and chemistry, and considering that history of science plays an important role in the process of teaching and learning sciences, some milestones of the history of chemistry are here revisited through the opera glass. The operas analyzed have been grouped in the following categories: Operas of Fire and Metallurgy, Operas of the Philosophers of Antiquity, Operas of Alchemy, Operas of the Age of Enlightenment, Operas of the Revolutions and Operas of Entropy.Thanks are due to the Foundation for Science and Technology (FCT–Portugal) and FEDER (European Fund for Regional Development)-COMPETE/QREN/EU for financial support through the research unity PEst-C/QUI/UI686/2013.

Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML

Increasing the Effectiveness of Vaginal Microbicides: A Biophysical Framework to Rethink Behavioral Acceptability

Microbicide candidates delivered via gel vehicles are intended to coat the vaginal epithelium after application. The coating process depends on intrinsic biophysical properties of the gel texture, which restricts the potential choices for an effective product: the gel first must be physically synthesizable, then acceptable to the user, and finally applied in a manner promoting timely adequate coating, so that the user adherence is optimized. We present a conceptual framework anchoring microbicide behavioral acceptability within the fulfillment of the product biophysical requirements.We conducted a semi-qualitative/quantitative study targeting women aged 18-55 in Northern California to assess user preferences for microbicide gel attributes. Attributes included: (i) the wait time between application and intercourse, (ii) the gel texture and (iii) the trade-off between wait time and gel texture. Wait times were assessed using a mathematical model determining coating rates depending upon the gel's physical attributes.71 women participated. Results suggest that women would independently prefer a gel spreading rapidly, in 2 to 15 minutes (P<0.0001), as well as one that is thick or slippery (P<0.02). Clearly, thick gels do not spread rapidly; hence the motivation to study the trade-off. When asked the same question 'constrained' by the biophysical reality, women indicated no significant preference for a particular gel thickness (and therefore waiting time) (P>0.10) for use with a steady partner, a preference for a watery gel spreading rapidly rather than one having intermediate properties for use with a casual partner (P = 0.024).Biophysical constraints alter women's preferences regarding acceptable microbicide attributes. Product developers should offer a range of formulations in order to address all preferences. We designed a conceptual framework to rethink behavioral acceptability in terms of biophysical requirements that can help improve adherence in microbicide use ultimately enhancing microbicide effectiveness

After-hours colorectal surgery: a risk factor for anastomotic leakage

__Purpose:__ This study aims to increase knowledge of colorectal anastomotic leakage by performing an incidence study and risk factor analysis with new potential risk factors in a Dutch tertiary referral center. __Methods:__ All patients whom received a primary colorectal anastomosis between 1997 and 2007 were selected by means of operation codes. Patient records were studied for population description and risk factor analysis. __Results:__ In total 739 patients were included. Anastomotic leakage (AL) occurred in 64 (8.7%) patients of whom nine (14.1%) died. Median interval between operation and diagnosis was 8 days. The risk for AL was higher as the anastomoses were constructed more distally (p = 0.019). Univariate analysis showed duration of surgery (p = 0.038), BMI (p = 0.001), time of surgery (p = 0.029), prophylactic drainage (p = 0.006) and time under anesthesia (p = 0.012) to be associated to AL. Multivariate analysis showed BMI greater than 30 kg/m2(p = 0.006; OR 2.6 CI 1.3-5.2) and "after hours" construction of an anastomosis (p = 0.030; OR 2.2 CI 1.1-4.5) to be independent risk factors. __Conclusion:__ BMI greater than 30 kg/m2and "after hours" construction of an anastomosis were independent risk factors for colorectal anastomotic leakage

A Synaptic Mechanism for Temporal Filtering of Visual Signals

The visual system transmits information about fast and slow changes in light intensity through separate neural pathways. We used in vivo imaging to investigate how bipolar cells transmit these signals to the inner retina. We found that the volume of the synaptic terminal is an intrinsic property that contributes to different temporal filters. Individual cells transmit through multiple terminals varying in size, but smaller terminals generate faster and larger calcium transients to trigger vesicle release with higher initial gain, followed by more profound adaptation. Smaller terminals transmitted higher stimulus frequencies more effectively. Modeling global calcium dynamics triggering vesicle release indicated that variations in the volume of presynaptic compartments contribute directly to all these differences in response dynamics. These results indicate how one neuron can transmit different temporal components in the visual signal through synaptic terminals of varying geometries with different adaptational properties

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations