Search

Organic light-emitting diodes (OLEDs) are among the most successful organic electronic devices so far. They currently dominate the mobile display market and are expanding into a broad range of lighting, automotive and wearable device applications. Here we introduce a new class of organic light-emitting device that exhibits bistability owing to positive photonic feedback between an organic photodiode and a tandem OLED integrated in the same layer stack. These unusual devices display giant hysteresis in both their current and light emission, and respond sensitively to low-level external illumination, enabling optoelectronic upconversion with 100-fold photon-to-photon gain. Given their compatibility with existing OLED materials and manufacturing lines, these devices could find near-term use in new types of display and upconversion imaging applications, as well as offer a new platform for neuromorphic optoelectronics and image recognition.

PurposeTo determine the physical compatibility of 10% calcium chloride and 10% calcium gluconate in combination with injectable solutions, administered in the paediatric and adult intensive care unit setting during toxicological resuscitation involving calcium channel blockers and beta-blockers.MethodsForty-eight combinations were prepared at room temperature, including the following products: calcium chloride, calcium gluconate, insulin, epinephrine, norepinephrine, highly concentrated dextrose solution, sodium chloride, Plasma-Lyte A and Ringer’s lactate. A visual evaluation at times 0, 1, 4, 24, 48 and 72 hours and a particle count test with the LS-20 particle counter at times 0, 4, 24 and 72 hours were performed. The admixtures were considered incompatible if there was a precipitate, a colour change, turbidity, viscosity or a gas formation. The stability of calcium salts was also tested in empty IV bags and syringes by the particle count test.ResultsAll drug mixtures were found to be compatible by visual evaluation and using the particle counter based on United States Pharmacopoeia chapter 788 (USP<788>) specifications. Calcium salts were compatible with insulin and vasopressors in the tested combinations. The stability of 10% calcium salts in empty IV bags and polypropylene syringes was demonstrated for up to 48 hours at room temperature.ConclusionAll the combinations tested were physically compatible for up to 72 hours at room temperature. Clinical use of calcium salt infusions, at an undiluted concentration, in combination with these injectable solutions in a toxicological resuscitation context is considered clinically acceptable.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4–7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL–β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

A self-complementary graph is a graph isomorphic to its complement. A set Sof vertices in a graph Gis a restrained dominating set if every vertex in V(G) \ Sis adjacent to a vertex in Sand to a vertex in V(G) \ S. The restrained domination number of a graph Gis the minimum cardinality of a restrained dominating set of G. In this paper, we study restrained domination in self-complementary graphs. In particular, we characterize the self-complementary graphs having equal domination and restrained domination numbers.

Cruzain, an essential cysteine protease of the parasitic protozoan, Trypanosoma cruzi, is an important drug target for Chagas disease. We describe here a new series of reversible but time-dependent inhibitors of cruzain, composed of a dipeptide scaffold appended to vinyl heterocycles meant to provide replacements for the irreversible reactive “warheads” of vinyl sulfone inactivators of cruzain. Peptidomimetic vinyl heterocyclic inhibitors (PVHIs) containing Cbz-Phe-Phe/homoPhe scaffolds with vinyl-2-pyrimidine, vinyl-2-pyridine, and vinyl-2-(N-methyl)-pyridine groups conferred reversible, time-dependent inhibition of cruzain (Ki* = 0.1–0.4 μM). These cruzain inhibitors exhibited moderate to excellent selectivity versus human cathepsins B, L, and S and showed no apparent toxicity to human cells but were effective in cell cultures of Trypanosoma brucei brucei(EC50= 1–15 μM) and eliminated T. cruziin infected murine cardiomyoblasts (EC50= 5–8 μM). PVHIs represent a new class of cruzain inhibitors that could progress to viable candidate compounds to treat Chagas disease and human sleeping sickness.

Supplemental Digital Content is available in the text.

Nucleoside analogues are among the most common medications given for the treatment of viral infections and cancers. The therapeutic effectiveness of nucleoside analogues can be dramatically improved by phosphorylation. The ProTide approach was developed using a phosphorylated nucleoside that is masked by esterification with an amino acid and phenol forming a chiral phosphorus center. The biological activity of the ProTides depends, in part, on the stereochemistry at phosphorus, and thus, it is imperative that efficient methods be developed for the chemical synthesis and isolation of diastereomerically pure ProTides. Chiral ProTides are often synthesized by direct displacement of a labile phenol (p-nitrophenol or pentafluorophenol) from a chiral phosphoramidate precursor with the appropriate nucleoside analogue. The ability to produce these chiral products is dictated by the synthesis of the chiral phosphoramidate precursors. The enzyme phosphotriesterase (PTE) from Pseudomonas diminutais well-known for its high stereoselectivity and broad substrate profile. Screening PTE variants from enzyme evolution libraries enabled the identification of variants of PTE that can stereoselectively hydrolyze the chiral phosphoramidate precursors. The variant G60A-PTE exhibits a 165-fold preference for hydrolysis of the RPisomer, while the variant In1W-PTE has a 1400-fold preference for hydrolysis of the SPisomer. Using these mutants of PTE, the SPand RPisomers were isolated on a preparative scale with no detectable contamination of the opposite isomer. Combining the simplicity of the enzymatic resolution of the precursor with the latest synthetic strategy will facilitate the production of diastereometrically pure nucleotide phosphoramidate prodrugs.

This work enhances our understanding of catchment‐scale N budgets by demonstrating the modification and application of a simple method for direct in situ measurements of vadose zone nitrate leaching and attenuation. We developed a soil passive flux meter (SPFM) to measure solute leaching based on a modified design of ion‐exchange resin columns, and we tested the design in numerical simulations, laboratory experiments, plot‐scale field experiments, and a catchment‐scale field deployment. Our design minimized flow divergence around the resin column to attain nearly 100% capture of surface applied tracers in plot‐ and catchment‐scale deployments. We found that mixing resin with native soil and extending the column height 10 cm above the resin layer minimized divergence of soil water around the column, resulting in a field‐measured convergence factor (χ) of 1.3 that was consistent with numerical simulations. For catchment‐scale testing, SPFMs were used at nine sites in three dominant land uses (crop, pasture, and turf) with known N inputs in two deployments, one during the 4‐mo wet season and an additional set during the 8‐mo dry season, to obtain integral annual measures of soil nitrate fluxes. In situ measured nitrate leaching determined from the SPFMs was positively correlated with known N inputs (R2= 0.55, p< 0.05) and attenuation averaged 67% (± 24% SD) of inputs across all sites. Although N inputs explain a large portion of the variability, our results emphasize the importance of both inter‐ and intra‐land use variability in landscape‐scale N budgets. We developed a soil passive flux meter (SPFM) to measure solute leaching in situ.Our design minimized flow divergence around the resin column (nearly 100% capture).The SPFMs provided robust and accurate measurements of soil nitrate leaching.The SPFMs, together with N input data, enabled assessment of nitrate attenuation.

The bacterial enzyme phosphotriesterase (PTE) is noted for its ability to hydrolyze many organophosphate compounds, including insecticides and chemical warfare agents. PTE has been the subject of multiple enzyme evolution attempts, which have been highly successful against specific insecticides and the G-type nerve agents. Similar attempts targeting the V-type nerve agents have failed to achieve the same degree of success. Enzyme evolution is an inherently complex problem, which is complicated by synergistic effects, the need to use analogues in high-throughput screening, and a lack of quantitative data to direct future efforts. Previous evolution experiments with PTE have assumed an absence of synergy and minimally screened large libraries, which provides no quantitative information about the effects of individual mutations. Here a systemic approach has been applied to a 28800-member six-site PTE library. The library is screened against multiple V-agent analogues, and a combination of sequence and quantitative activity analysis is used to extract data about the effects of individual mutations. We demonstrate that synergistic relationships dominate the evolutionary landscape of PTE and that analogue activity profiles can be used to identify variants with high activity for substrates. Using these approaches, multiple variants with kcat/Kmvalues for the hydrolysis of VX that were improved >1500-fold were identified, including one variant that is improved 9200-fold relative to wild-type PTE and is specific for the SPenantiomer of VX. Multiple variants that were highly active for (SP)-VR were identified, the best of which has a kcat/Kmvalues that is improved 13400-fold relative to that of wild-type PTE.

A dominating set in a graph Gis a set Sof vertices such that every vertex in V(G) \ Sis adjacent to at least one vertex in S, and the domination number of Gis the minimum cardinality of a dominating set of G. Placing constraints on a dominating set yields different domination parameters, including total, connected, restrained, and clique domination numbers. In this paper, we study relationships among domination parameters of a graph and its complement.

ObjectivesProteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.DesignTrypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca2+imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.ResultsWe showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.ConclusionsIn IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.

The article focuses on the debate surrounding seawater desalination in California as a potential solution to water scarcity and climate change impacts. It discusses the driving factors for considering desalination, including the need for diversified water portfolios, the green energy transition, and the potential environmental benefits. It also highlights the challenges and public perception issues associated with desalination projects in the state.

A set S of vertices of a graph G is a dominating set if every vertex not in S is adjacent to a vertex of S and is a total dominating set if every vertex of G is adjacent to a vertex of S. The cardinality of a minimum dominating (total dominating) set of G is called the domination (total domination) number. A set that does not dominate (totally dominate) G is called a non-dominating (non-total dominating) set of G. A partition of the vertices of G into non-dominating (non-total dominating) sets is a non-dominating (non-total dominating) set partition. We show that the minimum number of sets in a non-dominating set partition of a graph G equals the total domination number of its complement G̅ and the minimum number of sets in a non-total dominating set partition of G equals the domination number of G̅ . This perspective yields new upper bounds on the domination and total domination numbers. We motivate the study of these concepts with a social network application.

The development of wearable or implantable technologies that replace center-based hemodialysis (HD) hold promise to improve outcomes and quality of life for patients with ESRD. A prerequisite for these technologies is the development of highly efficient membranes that can achieve high toxin clearance in small-device formats. Here we examine the application of the porous nanocrystalline silicon (pnc-Si) to HD. pnc-Si is a molecularly thin nanoporous membrane material that is orders of magnitude more permeable than conventional HD membranes. Material developments have allowed us to dramatically increase the amount of active membrane available for dialysis on pnc-Si chips. By controlling pore sizes during manufacturing, pnc-Si membranes can be engineered to pass middle-molecular-weight protein toxins while retaining albumin, mimicking the healthy kidney. A microfluidic dialysis device developed with pnc-Si achieves urea clearance rates that confirm that the membrane offers no resistance to urea passage. Finally, surface modifications with thin hydrophilic coatings are shown to block cell and protein adhesion.

The number of individuals infected with human immunodeficiency virus (HIV) and other pathogens causing sexually transmitted diseases (STDs) is growing dramatically worldwide. Globally, heterosexual transmission may account for as much as 85-90% of new cases of HIV infection. Latex condoms represent an effective barrier against sexually transmitted pathogens, but unfortunately, their use is not generalized. Therefore, there is an urgent need to develop safe and potent topical microbicides under the control of women to efficiently reduce the spread of sexually transmitted infections. Sodium lauryl sulfate (SLS), an anionic surfactant with protein denaturing potency, is a potent inhibitor of the infectivity of several enveloped (Herpes simplex viruses, HIV- 1, Semliki Forest virus) and nonenveloped (papillomaviruses, reovirus, rotavirus and poliovirus) viruses. The mechanism of action of SLS involves the solubilization of the viral envelope and/or the denaturation of envelope and/or capsid proteins. Studies have shown that SLS is not toxic for cultured cell lines of different origins at concentrations that inactivate HIV-1, herpes and human papillomavirus in vitro. In addition, intravaginal pretreatment of mice with a gel formulation containing SLS, completely protected animals against Herpes simplex virus type-2 infection. The gel formulation containing SLS was also well-tolerated following repeated intravaginal administrations to rabbits. Taken together, these data suggest that SLS represents a potential candidate for the use as a topical microbicide to prevent the sexual transmission of HIV-1, herpes, human papillomavirus and possibly other sexually transmitted pathogens. The impact of such a preventive tool on public health can be enormous.

A pipeline Fast Fourier Transform (FFT) switch with built-in self-test is described. The pipeline FFT, a one-dimensional systolic array, is composed of complex butterflies and FFT switches. The FFT switches are cascadeable and can support the implementation of a radix-2 pipeline FFT of up to 8192 points. The 10 000 gate ASIC device is fabricated in 1.5μm HCMOS gate array technology, and supports a throughput of 25 Mwords s−1.

A chip set for pipelined and parallel pipelined FFT applications is presented. The set consists of two cascadeable chips with built-in self-test and a chip-interconnectivity test feature. The two ASICs are a 15k gate Complex-Butterfly and a 9k gate FFT Switch. The Complex-Butterfly uses redundant binary arithmetic (RBA), a modified Booth algorithm and a Wallace tree architecture to achieve a throughput of better than 25 Msamples/sec. The cascadeable FFT Switch is designed to support the implementation of radix-2, 2Npoint, pipeline FFTs. Both devices have been fabricated in 1.5μm CMOS gate array technology.

Evaluating how nitrogen (N) sources are attenuated throughout the landscape is critical to further our understanding of catchment‐scale N budgets. We developed a catchment‐scale N budget for a mixed land use karst springshed using in situ measurements (nitrate leaching fluxes and attenuation) and long‐term records (surface N inputs and spring exports) to estimate 20‐year average landscape‐scale N loading, attenuation, and export. We introduce a conceptual model framework to compute N export that can be applied consistently for point or nonpoint sources. The model is based on the product of only four components for each N source: population density or proportion of land cover, P; specific load, L; anthropogenic attenuation, A; and natural attenuation, N. The product of these components is computed for each N source and then integrated at the basin scale. The concise PLANmodel framework predicted attenuation of 90% ± 3% of N inputs, in close agreement with the estimate based on measured spring mass discharge (87% ± 3%). Further, when this attenuation is disaggregated along the hydrological flow path, we estimate that 64% of inputs are lost in the surface soil, 20% in the vadose zone, and 6% in the aquifer. Livestock and human wastes were estimated to be the dominant contributors to spring N export, which was independently supported by isotopic data. The PLANmodel is a simple, transferable framework that supports systematically computing N export based on proportioning of load and attenuation. Identifying the main sources of N ultimately contributing to discharged N loads is a critical step toward source‐related water‐quality management. Our concise model framework predicted attenuation of 90% of N inputsWe found that 64% of surface N inputs were attenuated in the surface soilManure and septic‐treated wastewater were the largest contributors to spring N export