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Control over the orientation of metal nanorods is important for both fundamental and applied research. We show that gold nanorods (GNRs) can be aligned in a single direction by adsorbing positively charged GNRs onto a double-strand DNA-grafted substrate through electrostatic interaction. The ordered structure can be optimized by controlling the density of the positive charges on the surface of the GNRs. We found, in agreement with the results of theoretical simulation, that the resultant structure exhibits plasmonic properties that are dependent on the GNR orientation relative to the direction of an oscillating electric field. Our approach provides new insights into the polymer-assisted self-assembly of rod-shaped nanoparticles utilizing electrostatic interactions., Competing Interests: The authors declare no competing financial interest.

Poly(styrene)-block-poly(dimethylsiloxane) (PS-b-PDMS) is an excellent block copolymer (BCP) system for self-assembly and inorganic template fabrication because of its high Flory-Huggins parameter (χ ∼ 0.26) at room temperature in comparison to other BCPs, and high selective etch contrast between PS and PDMS block for nanopatterning. In this work, self-assembly in PS-b-PDMS BCP is achieved by combining hydroxyl-terminated poly(dimethylsiloxane) (PDMS-OH) brush surfaces with solvent vapor annealing. As an alternative to standard brush chemistry, we report a simple method based on the use of surfaces functionalized with silane-based self-assembled monolayers (SAMs). A solution-based approach to SAM formation was adopted in this investigation. The influence of the SAM-modified surfaces upon BCP films was compared with polymer brush-based surfaces. The cylinder forming PS-b-PDMS BCP and PDMS-OH polymer brush were synthesized by sequential living anionic polymerization. It was observed that silane SAMs provided the appropriate surface chemistry which, when combined with solvent annealing, led to microphase segregation in the BCP. It was also demonstrated that orientation of the PDMS cylinders may be controlled by judicious choice of the appropriate silane. The PDMS patterns were successfully used as an on-chip etch mask to transfer the BCP pattern to underlying silicon substrate with sub-25 nm silicon nanoscale features. This alternative SAM/BCP approach to nanopattern formation shows promising results, pertinent in the field of nanotechnology, and with much potential for application, such as in the fabrication of nanoimprint lithography stamps, nanofluidic devices or in narrow and multilevel interconnected lines.

Predicting species responses to climate change is a central challenge in ecology. These predictions are often based on lab-derived phenomenological relationships between temperature and fitness metrics. We tested one of these relationships using the embryonic stage of a Chinook salmon population. We parameterised the model with laboratory data, applied it to predict survival in the field, and found that it significantly underestimated field-derived estimates of thermal mortality. We used a biophysical model based on mass transfer theory to show that the discrepancy was due to the differences in water flow velocities between the lab and the field. This mechanistic approach provides testable predictions for how the thermal tolerance of embryos depends on egg size and flow velocity of the surrounding water. We found support for these predictions across more than 180 fish species, suggesting that flow and temperature mediated oxygen limitation is a general mechanism underlying the thermal tolerance of embryos., (© 2016 John Wiley & Sons Ltd/CNRS.)

Psychological interventions for chronic pain and its consequences have been shown to improve mood, disability, pain, and catastrophic thinking, but there has been no systematic review specifically of their effects on health care use or time lost from work as treatment outcomes in mixed chronic pain. We conducted a systematic review and meta-analysis to evaluate the effectiveness of psychological therapies for chronic pain (excluding headache) in adults for these outcomes. We used searches from 2 previous systematic reviews and updated them. Eighteen randomized controlled trials were found that reported health care use (15 studies) and work loss (9 studies) as outcomes. Fourteen studies provided data for meta-analysis. There were moderate effects for psychological interventions compared with active controls, treatment as usual and waiting list controls in reducing health care use, with confidence in the findings. No benefits were found for medication reduction, but with less confidence in this result. Analysis of work loss showed no significant effects of psychological interventions over comparisons, but the use of many different metrics necessitated fragmenting the planned analyses, making summary difficult. The results are encouraging for the potential of routine psychological intervention to reduce posttreatment health care use, with associated cost savings, but it is likely that the range and complexity of problems affecting work necessitate additional intervention over standard group psychological intervention.

Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼ 702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immune-deficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods.

Mosquitoes possess an innate immune system that is capable of limiting infection by a variety of pathogens, including the Plasmodium spp. parasites responsible for human malaria. The Anopheles immune deficiency (IMD) innate immune signaling pathway confers resistance to Plasmodium falciparum. While some previously identified Anopheles anti-Plasmodium effectors are regulated through signaling by Rel2, the transcription factor of the IMD pathway, many components of this defense system remain uncharacterized. To begin to better understand the regulation of immune effector proteins by the IMD pathway, we used oligonucleotide microarrays and iTRAQ to analyze differences in mRNA and protein expression, respectively, between transgenic Anopheles stephensi mosquitoes exhibiting blood meal-inducible overexpression of an active recombinant Rel2 and their wild-type conspecifics. Numerous genes were differentially regulated at both the mRNA and protein levels following induction of Rel2. While multiple immune genes were up-regulated, a majority of the differentially expressed genes have no known immune function in mosquitoes. Selected up-regulated genes from multiple functional categories were tested for both anti-Plasmodium and anti-bacterial action using RNA interference (RNAi). Based on our experimental findings, we conclude that increased expression of the IMD immune pathway-controlled transcription factor Rel2 affects the expression of numerous genes with diverse functions, suggesting a broader physiological impact of immune activation and possible functional versatility of Rel2. Our study has also identified multiple novel genes implicated in anti-Plasmodium defense., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A strategy for recovering endangered species during climate change is to restore ecosystem processes that moderate effects of climate shifts. In mid-latitudes, storm patterns may shift their intensity, duration, and frequency. These shifts threaten flooding in human communities and reduce migration windows (conditions suitable for migration after a storm) for fish. Rehabilitation of historic floodplains can in principle reduce these threats via transient storage of storm water, but no one has quantified the benefit of floodplain rehabilitation for migrating fish, a widespread biota with conservation and economic value. We used simple models to quantify migration opportunity for a threatened migratory fish, steelhead (Oncorhynchus mykiss), in an episodic rain-fed river system, the Pajaro River in central California. We combined flow models, bioenergetic models, and existing climate projections to estimate the sensitivity of migration windows to altered storm patterns under alternate scenarios of floodplain rehabilitation. Generally, migration opportunities were insensitive to warming, weakly sensitive to duration or intensity of storms, and proportionately sensitive to frequency of storms. The rehabilitation strategy expanded migration windows by 16-28% regardless of climate outcomes. Warmer conditions raised the energy cost of migrating, but not enough to matter biologically. Novel findings were that fewer storms appeared to pose a bigger threat to migrating steelhead than warmer or smaller storms and that floodplain rehabilitation lessened the risk from fewer or smaller storms across all plausible hydroclimatic outcomes. It follows that statistical downscaling methods may mischaracterize risk, depending on how they resolve overall precipitation shifts into changes of storm frequency as opposed to storm size. Moreover, anticipating effects of climate shifts that are irreducibly uncertain (here, rainfall) may be more important than anticipating effects of relatively predictable changes such as warming. This highlights a need to credibly identify strategies of ecosystem rehabilitation that are robust to uncertainty. Rehabilitación de Planicies Inundables como Cerco contra la Incertidumbre Hidroclimática en un Corredor Migratorio de Oncorhynchus mykiss, Especie Amenazada., (© 2013 Society for Conservation Biology No claim to original US government works.)

The functionalization of silicon as elemental crystalline wafer, nanoporous layers, or nanocrystalline particles with DNA oligonucleotides using automated solid phase synthesis is described. The procedures provide semiconductor surfaces covalently modified with oligomers suitable for capturing complementary oligonucleotide strands.

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.

The in vivo occupancy of brain benzodiazepine binding sites by compounds A and B was measured using a [(3)H]Ro 15-1788 binding assay and related to plasma and brain drug concentrations. The plasma concentration associated with 50% occupancy was higher for compound A than compound B (73 and 3.7 nM, respectively), however, there was little difference in the brain concentrations required (73 and 63 nM). Both compounds showed a non-linear relationship between plasma and brain concentrations such that above brain concentrations of approximately 100 nM increasing plasma concentrations did not result in a concomitant increase in brain concentrations. This is consistent with brain concentrations being dependent on a saturable compartment which was postulated to be the benzodiazepine binding site-containing GABA(A) receptors. This hypothesis was tested in alpha1H101R mice, in which the alpha1 subunit of the GABA(A) receptor is rendered insensitive to benzodiazepine binding resulting in an approximate 50% reduction in the total benzodiazepine-containing GABA(A) receptor population. It was shown that the Occ(50) brain concentrations in the alpha1H101R animals was lower (17 nM) than in wild type mice (63 nM), as was the plateau concentration in the brain (105 and 195 nM, respectively). These data suggest measured concentrations of compounds A and B in brain tissue are dependent on receptor expression with a minimal contribution from unbound and non-specifically bound compound.

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.

Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.

The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.

There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.

The ferrocenyl-nucleoside, 5-ethynylferrocenyl-2'-deoxycytidine (1) has been prepared by Pd-catalyzed cross-coupling between ethynylferrocene and 5-iodo-2'-deoxycytidine and incorporated into oligonucleotides by using automated solid-phase synthesis at both silica supports (CPG) and modified single-crystal silicon electrodes. Analysis of DNA oligonucleotides prepared and cleaved from conventional solid supports confirms that the ferrocenyl-nucleoside remains intact during synthesis and deprotection and that the resulting strands may be oxidised and reduced in a chemically reversible manner. Melting curve data show that the ferrocenyl-modified oligonucleotides form duplex structures with native complementary strands. The redox potential of fully solvated ferrocenyl 12-mers, 350 mV versus SCE, was shifted by +40 mV to a more positive potential upon treatment with the complement contrary to the anticipated negative shift based on a simple electrostatic basis. Automated solid-phase methods were also used to synthesise 12-mer ferrocenyl-containing oligonucleotides directly at chemically modified silicon <111> electrodes. Hybridisation to the surface-bound ferrocenyl-DNA caused a shift in the reduction potential of +34 mV to more positive values, indicating that, even when a ferrocenyl nucleoside is contained in a film, the increased density of anions from the phosphate backbone of the complement is still dominated by other factors, for example, the hydrophobic environment of the ferrocene moiety in the duplex or changes in the ferrocene-phosphate distances. The reduction potential is shifted >100 mV after hybridisation when the aqueous electrolyte is replaced by THF/LiClO(4), a solvent of much lower dielectric constant; this is consistent with an explanation based on conformation-induced changes in ferrocene-phosphate distances.

Ferrocenylthymidine derivatives have been prepared by Pd-catalysed cross-coupling between ethynylferrocene or vinylferrocene and 5-iodo-2'-deoxyuridine. In the latter case a mixture of trans (2a) and gem (2b) isomers was obtained. The cis-vinylferrocenyl (2c), and ethylferrocenyl (3) derivatives were obtained by catalytic hydrogenation of ethynylferrocenyl-dT (1a), and 2c respectively. Single-crystal X-ray data for 1a, the ferrocenyl-2'furano-pyrimidone 1b, and 2a show that the nucleobase is essentially co-planar with the substituted Cp ring of the metallocene. The selective reduction of the linkage between the ferrocenyl and thymidine moieties, from -C identical to C- to -CH2CH2-, causes a shift in the reduction potential of -124 mV. DFT calculations for the one-electron oxidised species indicate that the diminished conjugation reduces the spin transfer onto the bridging C2 group, but has less effect on the extent transferred to the nucleobase from the ferrocenyl group. Compound 1a was incorporated site-specifically into DNA oligonucleotides by using automated solid-phase methods. However, some interconversion of 1a-->1b occurs, even under rapid mild conditions of deprotection.

A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.