Danger in the jungle:sensible care to reduce avoidable acute kidney injury in hospitalized children

When children require hospital admission, many receive medications with nephrotoxic potential. As such, this can translate into an increased risk of acute kidney injury. In this context, acute kidney injury is hospital acquired, often iatrogenic, and portends risk of adverse outcomes. The Nephrotoxic Injury Negated by Just-in-Time Action study implemented a multicenter hospital-wide quality improvement initiative to detect and reduce nephrotoxin exposure in children aimed at decreasing the rates of potentially avoidable acute kidney injury. This commentary explores the findings and implications of the Nephrotoxic Injury Negated by Just-in-Time Action study.</p

A replicated study on nuclear proliferation shows the critical necessity of reviewing accepted scientific results.

In replicating a 2009 study on the role of asymmetric nuclear weapons possession, Mark Bell and Nicholas Miller found that a computational error led to the overestimation of the deterrent effect of nuclear weapons by a factor of several million. It is only through constant re-evaluation of scholarly findings that scholars can reach sufficiently robust conclusions that merit the attention of policymakers

Identification of a novel ß-adrenergic octopamine receptor-like gene (ßAOR-like) and increased ATP-binding cassette B10 (ABCB10) expression in a Rhipicephalus microplus cell line derived from acaricide-resistant ticks

Background: The cattle tick Rhipicephalus (Boophilus) microplus is an economically important parasite of livestock. Effective control of ticks using acaricides is threatened by the emergence of resistance to many existing compounds. Several continuous R. microplus cell lines have been established and provide an under-utilised resource for studies into acaricide targets and potential genetic mutations associated with resistance. As a first step to genetic studies using these resources, this study aimed to determine the presence or absence of two genes and their transcripts that have been linked with acaricide function in cattle ticks: β-adrenergic octopamine receptor (βAOR, associated with amitraz resistance) and ATP-binding cassette B10 (ABCB10, associated with macrocyclic lactone resistance) in six R. microplus cell lines, five other Rhipicephalus spp. cell lines and three cell lines representing other tick genera (Amblyomma variegatum, Ixodes ricinus and Hyalomma anatolicum). Methods: End-point polymerase chain reaction (PCR) was used for detection of the βAOR gene and transcripts in DNA and RNA extracted from the tick cell lines, followed by capillary sequencing of amplicons. Quantitative real-time PCR (qPCR) was performed to determine the levels of expression of ABCB10. Results: βAOR gene expression was detected in all Rhipicephalus spp. cell lines. We observed a second amplicon of approximately 220 bp for the βAOR gene in the R. microplus cell line BME/CTVM6, derived from acaricide-resistant ticks. Sequencing of this transcript variant identified a 36 bp insertion in the βAOR gene, leading to a 12-amino acid insertion (LLKTLALVTIIS) in the first transmembrane domain of the protein. In addition, nine synonymous SNPs were also discovered in R. appendiculatus, R. evertsi and R. sanguineus cell lines. Some of these SNPs appear to be unique to each species, providing potential tools for differentiating the tick species. The BME/CTVM6 cell line had significantly higher ABCB10 (P = 0.002) expression than the other R. micropluscell lines. Conclusions: The present study has identified a new βAOR gene and demonstrated a higher ABCB10 expression level in the BME/CTVM6 cell line, indicating that tick cell lines provide a useful experimental tool for acaricide resistance studies and further elucidation of tick genetics

Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores.

The simultaneous detection of a large number of different analytes is important in bionanotechnology research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, we show that highly multiplexed sensing of single molecules can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, we designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signalled by the presence or absence of multiple DNA dumbbell hairpins. We show that a 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows us to simultaneously detect four different antibodies of the same isotype at nanomolar concentration levels.N.A.W.B. and U.F.K. acknowledge funding from an ERC starting grant (Passmembrane 261101) and an ERC consolidator grant (Designerpores 647144). N.A.W.B. also acknowledges funding from an EPSRC doctoral prize award.This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/nnano.2016.5

Implementation of low-loss superinductances for quantum circuits

The simultaneous suppression of charge fluctuations and offsets is crucial for preserving quantum coherence in devices exploiting large quantum fluctuations of the superconducting phase. This requires an environment with both extremely low DC and high RF impedance. Such an environment is provided by a superinductance, defined as a zero DC resistance inductance whose impedance exceeds the resistance quantum $R_Q = h/(2e)^2 \simeq 6.5\ \mathrm{k\Omega}$ at frequencies of interest (1 - 10 GHz). In addition, the superinductance must have as little dissipation as possible, and possess a self-resonant frequency well above frequencies of interest. The kinetic inductance of an array of Josephson junctions is an ideal candidate to implement the superinductance provided its phase slip rate is sufficiently low. We successfully implemented such an array using large Josephson junctions ($E_J >> E_C$), and measured internal losses less than 20 ppm, self-resonant frequencies greater than 10 GHz, and phase slip rates less than 1 mHz

Translocation frequency of double-stranded DNA through a solid-state nanopore.

Solid-state nanopores are single-molecule sensors that measure changes in ionic current as charged polymers such as DNA pass through. Here, we present comprehensive experiments on the length, voltage, and salt dependence of the frequency of double-stranded DNA translocations through conical quartz nanopores with mean opening diameter 15 nm. We observe an entropic barrier-limited, length-dependent translocation frequency at 4M LiCl salt concentration and a drift-dominated, length-independent translocation frequency at 1M KCl salt concentration. These observations are described by a unifying convection-diffusion equation, which includes the contribution of an entropic barrier for polymer entry.This is the author accepted manuscript. The final version is available from the American Physical Society via http://dx.doi.org/10.1103/PhysRevE.93.02240

Safety, tolerability, and efficacy of fixed combination therapy with dorzolamide hydrochloride 2% and timolol maleate 0.5% in glaucoma and ocular hypertension.

Glaucoma is a collection of diseases characterized by multifactorial progressive changes leading to visual field loss and optic neuropathy most frequently due to elevated intraocular pressure (IOP). The goal of treatment is the lowering of the IOP to prevent additional optic nerve damage. Treatment usually begins with topical pharmacological agents as monotherapy, progresses to combination therapy with agents from up to 4 different classes of IOP-lowering medications, and then proceeds to laser or incisional surgical modalities for refractory cases. The fixed combination therapy with the carbonic anhydrase inhibitor dorzolamide hydrochloride 2% and the beta blocker timolol maleate 0.5% is now available in a generic formulation for the treatment of patients who have not responded sufficiently to monotherapy with beta adrenergic blockers. In pre- and postmarketing clinical studies, the fixed combination dorzolamide-timolol has been shown to be safe and efficacious, and well tolerated by patients. The fixed combination dorzolamide-timolol is convenient for patients, reduces their dosing regimen with the goal of increasing their compliance, reduces the effects of washout when instilling multiple drops, and reduces the preservative burden by reducing the number of drops administered per day

Specific protein detection using designed DNA carriers and nanopores.

Nanopores are a versatile technique for the detection and characterization of single molecules in solution. An ongoing challenge in the field is to find methods to selectively detect specific biomolecules. In this work we describe a new technique for sensing specific proteins using unmodified solid-state nanopores. We engineered a double strand of DNA by hybridizing nearly two hundred oligonucleotides to a linearized version of the m13mp18 virus genome. This engineered double strand, which we call a DNA carrier, allows positioning of protein binding sites at nanometer accurate intervals along its contour via DNA conjugation chemistry. We measure the ionic current signal of translocating DNA carriers as a function of the number of binding sites and show detection down to the single protein level. Furthermore, we use DNA carriers to develop an assay for identifying a single protein species within a protein mixture.We thank Vivek Thacker and Nadanai Laohakunakorn for critical reading of this manuscript. N.A.W.B. was supported by an EPSRC Doctoral Prize Award. U.F.K. acknowledges support by an ERC starting grant, PassMembrane 261101.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/ja512521w

Nanopore analysis of amyloid fibrils formed by lysozyme aggregation.

The measurement of single particle size distributions of amyloid fibrils is crucial for determining mechanisms of growth and toxicity. Nanopore sensing is an attractive solution for this problem since it gives information on aggregates' shapes with relatively high throughput for a single particle technology. In this paper we study the translocation of lysozyme fibrils through quartz glass nanopores. We demonstrate that, under appropriate salt and pH conditions, lysozyme fibrils translocate through bare quartz nanopores without causing significant clogging. This enables us to measure statistics on tens of thousands of translocations of lysozyme fibrils with the same nanopore and track their development over a time course of aggregation spanning 24 h. Analysis of our events shows that the statistics are consistent with a simple bulk conductivity model for the passage of rods with a fixed cross sectional area through a conical glass nanopore.N.A.W.B. acknowledges funding from the EPSRC NanoDTC program and an EPSRC doctoral prize award and U.F.K. acknowledges funding from an ERC starting grant, PassMembrane (261101).This is the final version of the article. It first appeared from RSC via http://dx.doi.org/10.1039/C5AN00530