A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge)

GABA levels in left and right sensorimotor cortex correlate across individuals

Differences in -aminobutyric acid (GABA) levels measured with Magnetic Resonance Spectroscopy have been shown to correlate with behavioral performance over a number of tasks and cortical regions. These correlations appear to be regionally and functionally specific. In this study, we test the hypothesis that GABA levels will be correlated within individuals for functionally related regions—the left and right sensorimotor cortex. In addition, we investigate whether this is driven by bulk tissue composition. GABA measurements using edited MRS data were acquired from the left and right sensorimotor cortex in 24 participants. T1-weighted MR images were also acquired and segmented to determine the tissue composition of the voxel. GABA level is shown to correlate significantly between the left and right regions (r = 0.64, p < 0.03). Tissue composition is highly correlated between sides, but does not explain significant variance in the bilateral correlation. In conclusion, individual differences in GABA level, which have previously been described as functionally and regionally specific, are correlated between homologous sensorimotor regions. This correlation is not driven by bulk differences in voxel tissue composition

Organizing research data

Research relies on ever larger amounts of data from experiments, automated production equipment, questionnaries, times series such as weather records, and so on. A major task in science is to combine, process and analyse such data to obtain evidence of patterns and correlations

Dissolved organic matter characteristics of deciduous and coniferous forests with variable management: different at the source, aligned in the soil

This dataset contains the data to the article: "Dissolved organic matter characteristics of deciduous and coniferous forests with variable management: different at the source, aligned in the soil" published in BiogeosciencesDFG/108154260/Elementkreisläufe in Grünland- und Waldökosystemen der Biodiversitätsexploratorien in Abhängigkeit von Landnutzungsintensität und damit verknüpfter Biodiversität/BECycle

Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease

Background:Extensive prostate specific antigen screening for prostate cancer generates a high number of unnecessary biopsies and over-treatment due to insufficient differentiation between indolent and aggressive tumours. We hypothesized that seminal plasma is a robust source of novel prostate cancer (PCa) biomarkers with the potential to improve primary diagnosis of and to distinguish advanced from indolent disease. &lt;br&gt;Methodology/Principal Findings: In an open-label case/control study 125 patients (70 PCa, 21 benign prostate hyperplasia, 25 chronic prostatitis, 9 healthy controls) were enrolled in 3 centres. Biomarker panels a) for PCa diagnosis (comparison of PCa patients versus benign controls) and b) for advanced disease (comparison of patients with post surgery Gleason score &#60;7 versus Gleason score &#62;&gt;7) were sought. Independent cohorts were used for proteomic biomarker discovery and testing the performance of the identified biomarker profiles. Seminal plasma was profiled using capillary electrophoresis mass spectrometry. Pre-analytical stability and analytical precision of the proteome analysis were determined. Support vector machine learning was used for classification. Stepwise application of two biomarker signatures with 21 and 5 biomarkers provided 83% sensitivity and 67% specificity for PCa detection in a test set of samples. A panel of 11 biomarkers for advanced disease discriminated between patients with Gleason score 7 and organ-confined (&#60;pT3a) or advanced (&#8805;pT3a) disease with 80% sensitivity and 82% specificity in a preliminary validation setting. Seminal profiles showed excellent pre-analytical stability. Eight biomarkers were identified as fragments of N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase​,prostatic acid phosphatase, stabilin-2, GTPase IMAP family member 6, semenogelin-1 and -2. Restricted sample size was the major limitation of the study.&lt;/br&gt; &lt;br&gt;Conclusions/Significance: Seminal plasma represents a robust source of potential peptide makers for primary PCa diagnosis. Our findings warrant further prospective validation to confirm the diagnostic potential of identified seminal biomarker candidates.&lt;/br&gt

Early cortical surface plasticity relates to basic mathematical learning

Children lay the foundation for later academic achievement by acquiring core mathematical abilities in the first school years. Neural reorganization processes associated with individual differences in early mathematical learning, however, are still poorly understood. To fill this research gap, we followed a sample of 5-6-year-old children longitudinally to the end of second grade in school (age 7–8 years) combining magnetic resonance imaging (MRI) with comprehensive behavioral assessments. We report significant links between the rate of neuroplastic change of cortical surface anatomy, and children's early mathematical skills. In particular, most of the behavioral variance (about 73%) of children's visuospatial abilities was explained by the change in cortical thickness in the right superior parietal cortex. Moreover, half of the behavioral variance (about 55%) of children's arithmetic abilities was explained by the change in cortical folding in the right intraparietal sulcus. Additional associations for arithmetic abilities were found for cortical thickness change of the right temporal lobe, and the left middle occipital gyrus. Visuospatial abilities were related to right precentral and supramarginal thickness, as well as right medial frontal gyrus folding plasticity. These effects were independent of other individual differences in IQ, literacy and maternal education. Our findings highlight the critical role of cortical plasticity during the acquisition of fundamental mathematical abilities

Does plant diversity affect the water balance of established grassland systems like in manipulative biodiversity experiments?

Land-use intensification and biodiversity loss are known drivers of the water cycle but their interactions are unclear. We investigated how evapotranspiration (ETa), downward water flux (DF), and capillary rise (CR) in topsoil and subsoil are related to land-use and plant diversity in established, commercially managed grassland and compared these results to findings from an experiment in which plant diversity was manipulated. In three Central European regions (“Biodiversity Exploratories”), we studied 29 grassland plots (50 m x 50 m; 9-11 plots per region). Land-use intensity increases in the order, pasture &lt; mown pasture &lt; meadow. In 2010-2015, we measured soil moisture, meteorological conditions, plant species richness, number of species in the functional groups of grasses, herbs, and legumes, and root biomass. ETa, DF, and CR were calculated for two soil layers with a soil water balance model. Land-use and biodiversity effects on water fluxes were analyzed with repeated-measures analysis of variance. Land-use intensity did not affect water fluxes. Species richness did not influence DF and CR. ETa from topsoil decreased with increasing species richness while ETa from subsoil increased. Opposing effects on ETa in the two soil layers were also observed for the number of herbs and legumes. In manipulative biodiversity experiments, such opposing effects were explained by higher biomass in species-rich mixtures, which increases shading of topsoil and reduces evaporation. In subsoil, deeper roots in species-rich mixtures increased transpiration. In the commercially managed grasslands, biomass and species richness correlated negatively because fertilizer application increased biomass and decreased species richness. Thus, similar effects of biodiversity on water fluxes in commercially managed and experimentally manipulated grassland had different reasons. We speculate that improved infiltration and enhanced bioturbation in species-rich grassland explained our observations

Cascade testing in Familial Hypercholesterolaemia: how should family members be contacted?

Cascade testing or screening provides an important mechanism for identifying people at risk of a genetic condition. For some autosomal dominant conditions, such as Familial Hpercholesterolaemia (FH), identifying relatives allows for significant health-affecting interventions to be administered, which can extend a person’s life expectancy significantly. However, cascade screening is not without ethical implications. In this paper, we examine one ethically contentious aspect of cascade screening programmes, namely the alternative methods by which relatives of a proband can be contacted. Should the proband be responsible for contacting his or her family members, or should the screening programme contact family members directly? We argue that direct contact is an ethically justifiable method of contact tracing in cascade screening for FH. Not only has this method of contact already been utilised without adverse effects, an examination of the ethical arguments against it shows these are unsubstantiated. We describe several criteria which, if met, will allow an appropriate balance to be struck between maximising the efficiency of family tracing and respecting the interests of probands and their relatives. Keywords Cascade genetic screening; cascade testing; confidentiality; autonomy; genetics; ethics; guidelines; familial hypercholesterolaemi

Isotopic Scaling of Heavy Projectile Residues from the collisions of 25 MeV/nucleon 86Kr with 124Sn, 112Sn and 64Ni, 58Ni

The scaling of the yields of heavy projectile residues from the reactions of 25 MeV/nucleon 86Kr projectiles with 124Sn,112Sn and 64Ni, 58Nitargets is studied. Isotopically resolved yield distributions of projectile fragments in the range Z=10-36 from these reaction pairs were measured with the MARS recoil separator in the angular range 2.7-5.3 degrees. The velocities of the residues, monotonically decreasing with Z down to Z~26-28, are employed to characterize the excitation energy. The yield ratios R21(N,Z) for each pair of systems are found to exhibit isotopic scaling (isoscaling), namely, an exponential dependence on the fragment atomic number Z and neutron number N. The isoscaling is found to occur in the residue Z range corresponding to the maximum observed excitation energies. The corresponding isoscaling parameters are alpha=0.43 and beta=-0.50 for the Kr+Sn system and alpha=0.27 and beta=-0.34 for the Kr+Ni system. For the Kr+Sn system, for which the experimental angular acceptance range lies inside the grazing angle, isoscaling was found to occur for Z<26 and N<34. For heavier fragments from Kr+Sn, the parameters vary monotonically, alpha decreasing with Z and beta increasing with N. This variation is found to be related to the evolution towards isospin equilibration and, as such, it can serve as a tracer of the N/Z equilibration process. The present heavy-residue data extend the observation of isotopic scaling from the intermediate mass fragment region to the heavy-residue region. Such high-resolution mass spectrometric data can provide important information on the role of isospin in peripheral and mid-peripheral collisions, complementary to that accessible from modern large-acceptance multidetector devices.Comment: 8 pages, 6 figures, submitted to Phys. Rev.