Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.

The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High-content screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.This is the author's accepted manuscript. The final version was published in Nature Communications here: http://www.nature.com/ncomms/2014/140117/ncomms4155/full/ncomms4155.html#affil-auth

What do aquaporin knockout studies tell us about fluid transport in epithelia?

The investigation of near-isosmotic water transport in epithelia goes back over 100 years; however, debates over mechanism and pathway remain. Aquaporin (AQP) knockouts have been used by various research groups to test the hypothesis of an osmotic mechanism as well as to explore the paracellular versus transcellular pathway debate. Nonproportional reductions in the water permeability of a water-transporting epithelial cell (e.g., a reduction of around 80–90 %) compared to the reduction in overall water transport rate in the knockout animal (e.g., a reduction of 50–60 %) are commonly found. This nonproportionality has led to controversy over whether AQP knockout studies support or contradict the osmotic mechanism. Arguments raised for and against an interpretation supporting the osmotic mechanism typically have partially specified, implicit, or incorrect assumptions. We present a simple mathematical model of the osmotic mechanism with clear assumptions and, for models based on this mechanism, establish a baseline prediction of AQP knockout studies. We allow for deviations from isotonic/isosmotic conditions and utilize dimensional analysis to reduce the number of parameters that must be considered independently. This enables a single prediction curve to be used for multiple epithelial systems. We find that a simple, transcellular-only osmotic mechanism sufficiently predicts the results of knockout studies and find criticisms of this mechanism to be overstated. We note, however, that AQP knockout studies do not give sufficient information to definitively rule out an additional paracellular pathway

Testing foundations of quantum mechanics with photons

The foundational ideas of quantum mechanics continue to give rise to counterintuitive theories and physical effects that are in conflict with a classical description of Nature. Experiments with light at the single photon level have historically been at the forefront of tests of fundamental quantum theory and new developments in photonics engineering continue to enable new experiments. Here we review recent photonic experiments to test two foundational themes in quantum mechanics: wave-particle duality, central to recent complementarity and delayed-choice experiments; and Bell nonlocality where recent theoretical and technological advances have allowed all controversial loopholes to be separately addressed in different photonics experiments.Comment: 10 pages, 5 figures, published as a Nature Physics Insight review articl

Histological and biochemical criteria for objective and early selection of grapevine cultivars resistant to Plasmopara viticola

Grapevine breeding is the most effective way to create cultivars resistant to downy mildew (Plasmopara viticola), and to reduce the number of fungicide applications. Four criteria, including histological and biochemical analyses, based on the level of different mechanisms of resistance to grapevine downy mildew, were tested on 42 different cultivars. Plantlets were artificially inoculated with downy mildew and the sporangia density was measured spectrophotometrically 6 d after infection. Callose synthesis in stomata and δ- and ε-viniferin levels at the site of infection were recorded 48 h after inoculation. These observations have allowed the 42 cultivars to be divided into 5 groups: very resistant (VR), resistant (R), less susceptible (LS), susceptible (S) and highly susceptible (HS). All 4 criteria have to be applied to assign the resistance level closer to field conditions. This method allows to rapidly evaluate the level of resistance of seedlings to downy mildew thereby leading to a reduction in duration  of the breeding program by several years.

Moral hazard in marriage: the use of domestic labor as an incentive device

This paper argues that some women in developing countries use domestic labor as a tool to incentivize husbands. A theoretical model is derived based on the traditions of rural Malawi, where men often supplement farm income with wage labor. As wage labor is not observed by the wife, this creates moral hazard: husbands may not make enough effort to bring home wages. The model predicts that women overcome this by using domestic labor as an incentive device: they increase their domestic labor and reduce their leisure in response to good consumption outcomes, but only if they cannot rely on divorce threat as an alternative source of incentives. This prediction is confirmed using survey data from Malawi. Identification is based on the fact that Malawi's kinship traditions exogenously determine women's accessibility to divorce. Where divorce is not an option, women make inefficient labor choices in order to provide incentives

Interim heterogeneity changes measured using entropy texture features on T2- weighted MRI at 3.0 T predict pathological response to neoadjuvant chemotherapy in primary breast cancer

Objectives: This study investigated whether interim changes in hetereogeneity (measured using entropy features) on magnetic resonance images (MRI) were associated with pathological residual cancer burden (RCB) at final surgery in patients receiving neoadjuvant chemotherapy (NAC) for primary breast cancer.Methods: Institutional review board approval was waived for this retrospective study of 88 consenting women (age:30-79). Scanning was performed on a 3.0T MRI scanner prior to NAC (baseline) and after 2-3 cycles of treatment (interim). Entropy was derived from the grey-level co-occurrence matrix, on slice-matched baseline/interim T2- weighted images. Response, assessed using RCB score on surgically resected specimens, was compared statistically with entropy/heterogeneity changes and ROC analysis performed. Prediction of pCR within each tumour immunophenotype was evaluated.Results: Mean entropy percent differences between examinations, by response category, were: pCR:32.8%, RCB-I:10.5%, RCB-II:9.7% and RCB-III:3.0%. Prediction of ultimate pCR from coarse entropy changes between baseline/interim MRI across all lesions yielded 85.2% accuracy (area under ROC curve:0.845). Excellent sensitivity/specificity was obtained for pCR prediction within each immunophenotype: ER+: 100%/100%; HER2+: 83.3%/95.7%, TNBC: 87.5%/80.0%.Conclusions: Lesion T2 heterogeneity changes are associated with response to NAC using RCB scores, particularly for pCR, and can be useful in prediction across all immunophenotypes with good diagnostic accuracy

The benefits and challenges of multiple health behavior change in research and in practice

Objective: The major chronic diseases are caused by multiple risks, yet the science of multiple health behavior change (MHBC) is at an early stage, and factors that facilitate or impede scientists\u27 involvement in MHBC research are unknown. Benefits and challenges of MHBC interventions were investigated to strengthen researchers\u27 commitment and prepare them for challenges. Method: An online anonymous survey was e-mailed to listservs of the Society of Behavioral Medicine between May 2006 and 2007. Respondents (N = 69) were 83% female; 94% held a doctoral degree; 64% were psychologists, 24% were in public health; and 83% targeted MHBC in their work. Results: A sample majority rated 23 of the 24 benefits, but only 1 of 31 challenge items, as very to extremely important. Those engaged in MHBC rated the total benefits significantly higher than respondents focused on single behaviors, F(1,69) = 4.21, p \u3c .05, and rated the benefits significantly higher than the challenges: paired t(57) = 7.50, p \u3c .001. The two groups did not differ in ratings of challenges. Conclusion: It appears that individuals focused solely on single behaviors do not fully appreciate the benefits that impress MHBC researchers; it is not that substantial barriers are holding them back. Benefits of MHBC interventions need emphasizing more broadly to advance this research area

Carbohydrate reserves in grapevine (Vitis vinifera L. 'Chasselas'): the influence of the leaf to fruit ratio

Seasonal dynamics of total non-structural carbohydrates (TNC) in relation to the leaf-fruit ratio were measured over five years at different grapevine phenological stages in one- and two-year-old canes, trunks and roots of the cultivar 'Chasselas' (Vitis vinifera L.). Carbohydrates were mainly stored as starch in different parts of the grapevine during the growing season. Soluble carbohydrates represented only a small part (< 7 % of dry weight, DW) of the TNC. In the roots and trunks, the starch content fluctuated during the growing season, reaching the lowest values between budbreak and flowering depending on the year, and the highest values between harvest and leaf fall. The soluble sugar content increased in the trunks and the two-year-old canes during the winter period with the decrease in temperatures. A negative correlation was established between the average air temperature recorded during the seven days before sample collection for carbohydrate analysis, and soluble carbohydrate content in the trunks and two-year-old canes. The leaffruit ratio (source-sink), expressed by the “light-exposed leaf area∙kg-1 fruit”, not only substantially influenced the soluble sugar content in berries but also the starch and TNC concentrations in the trunks and roots at harvest. Higher leaf-fruit ratios resulted in increased starch and TNC concentrations in the trunks and roots, which attained the maximum values when the leaf-fruit ratio neared 2.0 m2 of light-exposed leaf area∙kg-1 fruit. Canopy height and leaf area had no predominant influence on the soluble sugars, starch contents, or TNC in the permanent vine parts. 

Bridging the gap between robotic technology and health care

Although technology and computation power have become more and more present in our daily lives, we have yet to see the same tendency in robotics applied to health care. In this work we focused on the study of four distinct applications of robotic technology to health care, named Robotic Assisted Surgery, Robotics in Rehabilitation, Prosthetics and Companion Robotic Systems. We identified the main roadblocks that are limiting the progress of such applications by an extensive examination of recent reports. Based on the limitations of the practical use of current robotic technology for health care we proposed a general modularization approach for the conception and implementation of specific robotic devices. The main conclusions of this review are: (i) there is a clear need of the adaptation of robotic technology (closed loop) to the user, so that robotics can be widely accepted and used in the context of heath care; (ii) for all studied robotic technologies cost is still prohibitive and limits their wide use. The reduction of costs influences technology acceptability; thus innovation by using cheaper computer systems and sensors is relevant and should be taken into account in the implementation of robotic systems