Exceptionally Long Lifetimes of Strongly Entangled Acyl-Trityl Radical Pairs Photochemically Generated in Crystalline Trityl Ketones.

Triplet acyl-alkyl radical pairs generated by pulsed laser excitation within the constraints of their nanocrystalline ketone precursors were recently introduced as a potential platform for the robust and repeated instantiation of spin qubit pairs for applications in quantum information science. Here, we report the transient spectroscopy of a series of nanocrystalline trityl-alkyl and trityl-aryl ketones capable of generating correlated triplet radical pairs with persistent triphenylmethyl radicals forced to remain within bonding distances of highly reactive acyl radicals. Whereas triplet trityl-acyl radical pairs decay by competing product-forming decarbonylation and intersystem crossing, triplet trityl-benzoyl radical pairs have lifetimes of up to ca. 4 ms and exclusively regenerate the starting ketone. We propose that these long lifetimes are the result of the short inter-radical distances and the colinear orientation of the two singly occupied orbitals, which are expected to result in large singlet-triplet energy gaps, large zero-field splitting parameters, and a poor geometry for spin-obit coupling. Ketones generating trityl-benzoyl radical pairs demonstrate promising performance along multiple dimensions that are crucial for quantum information science.

Strongly Entangled Triplet Acyl-Alkyl Radical Pairs in Crystals of Photostable Diphenylmethyl Adamantyl Ketones.

Radical pairs generated in crystalline solids by bond cleavage reactions of triplet ketones offer the unique opportunity to explore a frontier of spin dynamics where rigid radicals are highly entangled as the result of short inter-radical distances, large singlet-triplet energy gaps (ΔEST), and limited spin-lattice relaxation mechanisms. Here we report the pulsed laser generation and detection of strongly entangled triplet acyl-alkyl radical pairs generated in nanocrystalline suspensions of 1,1-diphenylmethyl 2-ketones with various 3-admantyl substituents. The sought-after triplet acyl-alkyl radical pairs could be studied for the first time in the solid state by taking advantage of the efficient triplet excited state α-cleavage reactions of 1,1-diphenylmethyl ketones and the slow rate of CO loss from the acyl radicals, which would have to generate highly unstable phenyl and primary alkyl radicals or relatively unstable secondary and tertiary alkyl radicals. With the loss of CO prevented, the lifetime of the triplet acyl-alkyl radical pair intermediates is determined by intersystem crossing to the singlet radical pair state, which is followed by immediate bond formation to the ground state starting ketone. Experimental results revealed biexponential kinetics with long-lived components that account for ca. 87-92% of the transient population and lifetimes that extend to the range of 53-63 µs, the longest reported so far for this type of radical pair. Structural information inferred from the starting ketone will make it possible to analyze the affects of proximity and orientation of the singly occupied orbitals and potentially help set a path for the use of triplet radical pairs as qubits in quantum information technologies.

Taming Radical Pairs in the Crystalline Solid State: Discovery and Total Synthesis of Psychotriadine.

Solid-state photodecarbonylation is an attractive but underutilized methodology to forge hindered C-C bonds in complex molecules. This study discloses the use of this reaction to assemble the vicinal quaternary stereocenter motif present in bis(cyclotryptamine) alkaloids. Our strategy was enabled by experimental and computational investigations of the role of substrate conformation on the success or failure of the solid-state photodecarbonylation reaction. This informed a crystal engineering strategy to optimize the key step of the total synthesis. Ultimately, this endeavor culminated in the successful synthesis of the bis(cyclotryptamine) alkaloid "psychotriadine," which features the elusive piperidinoindoline framework. Psychotriadine, a previously unknown compound, was identified in the extracts of the flower Psychotria colorata, suggesting it is a naturally occurring metabolite.

Mechanistic Studies of Adamantylacetophenones with Competing Reaction Pathways in Solution and in the Crystalline Solid State.

Photochemical reactions in crystals occur under conditions of highly restricted molecular mobility such that only one product is generally obtained, even when there are many others that can be observed in the gas phase or in solution. A series of 2-(1-adamantyl)-o-alkyl-acetophenones with γ-hydrogen atoms on both the adamantyl and ortho aromatic groups was selected to determine whether one can engineer and observe competing Norrish type II reaction pathways in the crystalline state. It was shown that excited state competition for hydrogen abstraction between secondary adamantyl and benzylic hydrogens is affected not only by the relative bond dissociation energies but also by the molecular conformation in the crystal. The subsequent fate of the resulting biradical species is determined by competition between radical recombination to form the photoproduct and reverse hydrogen atom transfer to regenerate the starting ketone. Crystallographic information, photoproduct distributions in solution and in the solid state, and the results of multiple mechanistic experiments, including transient absorption spectroscopy in acetonitrile and with nanocrystals suspended in water, are reported. The results demonstrate that it is possible to engineer competing reactions in crystals and that consideration of all of the aforementioned factors is necessary to account for the observed photoproduct selectivity.

Patient Blood Management Program Improves Blood Use and Clinical Outcomes in Orthopedic Surgery.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although randomized trials show that patients do well when given less blood, there remains a persistent impression that orthopedic surgery patients require a higher hemoglobin transfusion threshold than other patient populations (8 g/dl vs. 7 g/dl). The authors tested the hypothesis in orthopedic patients that implementation of a patient blood management program encouraging a hemoglobin threshold less than 7 g/dl results in decreased blood use with no change in clinical outcomes. METHODS: After launching a multifaceted patient blood management program, the authors retrospectively evaluated all adult orthopedic patients, comparing transfusion practices and clinical outcomes in the pre- and post-blood management cohorts. Risk adjustment accounted for age, sex, surgical procedure, and case mix index. RESULTS: After patient blood management implementation, the mean hemoglobin threshold decreased from 7.8 ± 1.0 g/dl to 6.8 ± 1.0 g/dl (P < 0.0001). Erythrocyte use decreased by 32.5% (from 338 to 228 erythrocyte units per 1,000 patients; P = 0.0007). Clinical outcomes improved, with decreased morbidity (from 1.3% to 0.54%; P = 0.01), composite morbidity or mortality (from 1.5% to 0.75%; P = 0.035), and 30-day readmissions (from 9.0% to 5.8%; P = 0.0002). Improved outcomes were primarily recognized in patients 65 yr of age and older. After risk adjustment, patient blood management was independently associated with decreased composite morbidity or mortality (odds ratio, 0.44; 95% CI, 0.22 to 0.86; P = 0.016). CONCLUSIONS: In a retrospective study, patient blood management was associated with reduced blood use with similar or improved clinical outcomes in orthopedic surgery. A hemoglobin threshold of 7 g/dl appears to be safe for many orthopedic patients.

Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration.

The synthesis of a 2-methyl-substituted analogue of the natural product, neopeltolide, is reported in an effort to analyze the importance of molecular conformation and ligand-target interactions in relation to biological activity. The methyl substitution was incorporated via highly diastereoselective ester enolate alkylation of a late-stage intermediate. Coupling of the oxazole sidechain provided 2-methyl-neopeltolide and synthetic neopeltolide via total synthesis. The substitution was shown to maintain the conformational preferences of its biologically active parent compound through computer modeling and NMR studies. Both compounds were shown to be potential antimalarial compounds through the inhibition of mitochondrial respiration in P. falciparum parasites.

Transient Kinetics and Quantum Yield Studies of Nanocrystalline α-Phenyl-Substituted Ketones: Sorting Out Reactions from Singlet and Triplet Excited States.

Recent work has shown that diarylmethyl radicals generated by pulsed laser excitation in nanocrystalline (NC) suspensions of tetraarylacetones constitute a valuable probe for the detailed mechanistic analysis of the solid-state photodecarbonylation reaction. Using a combination of reaction quantum yields and laser flash photolysis in nanocrystalline suspensions of ketones with different substituents on one of the α-carbons, we are able to suggest with confidence that a significant fraction of the initial α-cleavage reaction takes place from the ketone singlet excited state, that the originally formed diarylmethyl-acyl radical pair loses CO in the crystal with time constants in the sub-nanosecond regime, and that the secondary bis(diarylmethyl) triplet radical pair has a lifetime limited by the rate of intersystem crossing of ca. 70 ns.

Impact of atrazine prohibition on the sustainability of weed management in Wisconsin maize production.

BACKGROUND: Controversy has surrounded atrazine owing to its susceptibility to leaching and run-off, with regular calls for a ban or restrictions on its use. In the context of a decreasing trend in the percentage of US maize using no-till since 2008, coinciding with the trend of glyphosate-resistant weeds becoming problematic in the Midwestern United States, we empirically examine how atrazine use restrictions have impacted the diversity of weed management practices used by Wisconsin maize farmers. RESULTS: Using survey data from farms inside and outside atrazine prohibition areas, we found that prohibiting atrazine did not directly impact tillage practices, but rather it increased the adoption of herbicide-resistant seed, which then increased adoption of conservation tillage systems. We also found that prohibiting atrazine and using herbicide-resistant seed reduced the number of herbicide sites of action used. CONCLUSIONS: The results indicate that prohibiting atrazine reduced the diversity of weed management practices, which increased the risk of herbicide resistance. Our concern is that a regulatory policy to address one issue (atrazine in groundwater) has induced farmer responses that increase problems with another issue (herbicide-resistant weeds) that longer term will contribute to water quality problems from increased soil erosion and offset the initial benefits. © 2016 Society of Chemical Industry.

Chiral amine enantiomeric excess determination using self-assembled octahedral Fe(II)-imine complexes.

A receptor assembly composed of iron(II) triflate and pyridine-2,6-dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha-chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha-chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay.

Effect of Glyphosate Application on Sudden Death Syndrome of Glyphosate-Resistant Soybean Under Field Conditions.

Sudden death syndrome (SDS), caused by Fusarium virguliforme, is an important yield limiting disease of soybean. Glyphosate is used to control weeds in soybean; however, its effect on SDS is not clearly understood. The objective of this study was to examine the impact of glyphosate on SDS, yield, and plant nutrition under field conditions. Fourteen field experiments were conducted in Iowa, Illinois, Indiana, Michigan, Wisconsin, and Ontario, Canada during 2011 to 2013. The experiment consisted of six treatment combinations of glyphosate and herbicides not containing glyphosate. Disease index was significantly different across the location-years, ranging from 0 to 65. The highest disease was noted in locations with irrigation, indicating that high soil moisture favors development of SDS. There were no effects of herbicide treatments or interactions on disease. The foliar disease index among the treatments over all years ranged from 9 to 13. Glyphosate-treatments also tended to yield more than treatments of herbicides not containing glyphosate. There were no interactions between glyphosate-treatments and total manganese in plant tissue. The interaction of glyphosate with other nutrients in plant tissue was inconclusive. This 14 location-year study demonstrated that glyphosate application did not increase SDS severity or adversely affect soybean yield under field conditions.

A tandem isomerization/prins strategy: iridium(III)/Brønsted acid cooperative catalysis.

Working together: A mild and efficient isomerization/protonation sequence generates pyran-fused indoles by cooperative catalysis between cationic iridium(III) and Bi(OTf)3 . Three distinct cyclization manifolds lead to the corresponding bioactive scaffolds in good yields. In addition, N-substituted indoles can be synthesized enantioselectively in the presence of a chiral phosphate.

New structural motif for carboxylic acid perhydrolases.

Some serine hydrolases also catalyze a promiscuous reaction--reversible perhydrolysis of carboxylic acids to make peroxycarboxylic acids. Five X-ray crystal structures of these carboxylic acid perhydrolases show a proline in the oxyanion loop. Here, we test whether this proline is essential for high perhydrolysis activity using Pseudomonas fluorescens esterase (PFE). The L29P variant of this esterase catalyzes perhydrolysis 43-fold faster (k(cat) comparison) than the wild type. Surprisingly, saturation mutagenesis at the 29 position of PFE identified six other amino acid substitutions that increase perhydrolysis of acetic acid at least fourfold over the wild type. The best variant, L29I PFE, catalyzed perhydrolysis 83-times faster (k(cat) comparison) than wild-type PFE and twice as fast as L29P PFE. Despite the different amino acid in the oxyanion loop, L29I PFE shows a similar selectivity for hydrogen peroxide over water as L29P PFE (ß(0)=170 vs. 160 M(-1)), and a similar fast formation of acetyl-enzyme (140 vs. 62 U mg(-1)). X-ray crystal structures of L29I PFE with and without bound acetate show an unusual mixture of two different oxyanion loop conformations. The type II ß-turn conformation resembles the wild-type structure and is unlikely to increase perhydrolysis, but the type I ß-turn conformation creates a binding site for a second acetate. Modeling suggests that a previously proposed mechanism for L29P PFE can be extended to include L29I PFE, so that an acetate accepts a hydrogen bond to promote faster formation of the acetyl-enzyme.

Cross-resistance of horseweed (Conyza canadensis) populations with three different ALS mutations.

BACKGROUND: Horseweed is a weed commonly found in agronomic crops, waste areas and roadsides. Resistance to ALS-inhibiting herbicides in horseweed was first reported in 1993 in a population from Israel. Resistance to ALS-inhibiting herbicides in horseweed is now widespread, but, as of now, the resistance mechanism has not been reported. RESULTS: Two of three populations evaluated (P116 and P13) were found to be uniform for resistance (>98% of individuals survived 8.8 g AI ha(-1) of cloransulam), whereas a third population, P525, contained about 85% resistant individuals. Cross-resistance to cloransulam, chlorimuron, imazethapyr and bispyribac was observed in the P116 population. P525 and P13 were both sensitive to imazethapyr but resistant to chlorimuron, imazethapyr and bispyribac. Enzyme activity assays indicated that resistance in P13 was due to an altered target site. Southern blot analysis indicated that the ALS target site is encoded by a single copy gene. Overlapping ALS gene regions were amplified and sequenced from each population. Amino acid substitutions of Ser for Pro at position 197 (P197S) was detected from P13, Ala for Pro (P197A) was identified from P525 and substitution of Glu for Asp (D376E) at position 376 was found in P116. Molecular markers were developed to differentiate between wild-type and resistant codons at positions 197 and 376 of horseweed ALS. CONCLUSION: Resistance to ALS-inhibiting herbicides in horseweed is conferred by target-site mutations that have also been identified in other weed species. Identification of the mutations within horseweed ALS gene sequence enables molecular assays for rapid detection and resistance diagnosis.

Tumour necrosis factor alpha is not an essential component of verotoxin 1-induced toxicity in mice.

Previous studies have shown that tumour necrosis factor alpha (TNF-alpha) gene transcription is induced in the mouse kidney in response to Shiga-like toxin 1 (Stx 1, or Verotoxin 1, VT1) administration, suggesting that local TNF-alpha expression plays a role in renal pathogenesis caused by the toxin. Further, TNF-alpha neutralizing antibody pretreatment of mice orally infected with VT-producing Escherichia coli (VTEC) protected the animals from disease development and death. We examined the role of TNF-alpha release in response to parenteral challenge with purified VT1. Mice injected with 10- and 100-fold the 50% lethal dose (LD(50)) of VT1 showed a weak, transient elevation of serum TNF-alpha only at the higher toxin dose. TNF-alpha was not detected in the urine of mice at either dose. Treatment of BALB/c mice with a neutralizing anti-TNF-alpha antibody prior to administration of 3 LD(50) of toxin failed to protect the mice from VT1-mediated toxicity. Further, TNF-alpha knock-out mice administered 3 LD(50) of VT1 were not protected against the lethal effects of the toxin relative to the wild-type animals. These findings suggest that VT1 is a poor inducer of TNF-alpha in vivo and that the low levels of the cytokine released in response to toxin challenge do not play a direct role in potentiating the toxicity of VT1 in mice. Strong toxin accumulation in the kidney but not in the brain was demonstrated by immunohistochemistry after intraperitoneal administration of VT1. Tubular damage and extensive apoptosis in the kidney, together with a 10-fold increase in levels of blood urea nitrogen, suggest that mice died of acute renal failure.

A mutational analysis of the globotriaosylceramide-binding sites of verotoxin VT1.

Escherichia coli verotoxin, also known as Shiga-like toxin, binds to eukaryotic cell membranes via the glycolipid Gb(3) receptors which present the P(k) trisaccharide Galalpha(1-4)Galbeta(1-4)Glcbeta. Crystallographic studies have identified three P(k) trisaccharide (P(k)-glycoside) binding sites per verotoxin 1B subunit (VT1B) monomer while NMR studies have identified binding of P(k)-glycoside only at site 2. To understand the basis for this difference, we studied binding of wild type VT1B and VT1B mutants, defective at one or more of the three sites, to P(k)-glycoside and pentavalent P(k) trisaccharide (pentaSTARFISH) in solution and Gb(3) presented on liposomal membranes using surface plasmon resonance. Site 2 was the key site in terms of free trisaccharide binding since mutants altered at sites 1 and 3 bound this ligand with wild type affinity. However, effective binding of the pentaSTARFISH molecule also required a functional site 3, suggesting that site 3 promotes pentavalent binding of linked trisaccharides at site 1 and site 2. Optimal binding to membrane-associated Gb(3) involved all three sites. Binding of all single site mutants to liposomal Gb(3) was weaker than wild type VT1B binding. Site 3 mutants behaved as if they had reduced ability to enter into high avidity interactions with Gb(3) in the membrane context. Double mutants at site 1/site 3 and site 2/site 3 were completely inactive in terms of binding to liposomal Gb(3,) even though the site 1/site 3 mutant bound trisaccharide with almost wild type affinity. Thus site 2 alone is not sufficient to confer high avidity binding to membrane-localized Gb(3). Cytotoxic activity paralleled membrane glycolipid binding. Our data show that the interaction of verotoxin with the Gb(3) trisaccharide is highly context dependent and that a membrane environment is required for biologically relevant studies of the interaction.

Sequential hydrolysis of swine carcass samples and determination of amino acid concentrations using pre-column derivatization with phenyl isothiocyanate.

Comparing amino acid (AA) retention levels in pig carcass to true ileal digestible AA intake provides an estimate of the marginal efficiency of AA utilization. Accurate analysis of AA levels in the carcass samples is critical. However, the standard 24 h of hydrolysis does not always provide maximum AA values. A study was carried out to investigate the effect of hydrolysis time on AA measurements in pig carcass. Correction factors to standardize AA levels to 24 h of hydrolysis were also determined. Ground carcass samples were hydrolysed with 6 mol litre-1 hydrochloric acid (HCl) in a 110 °C oven for nine different time periods. Pre-column derivatization with phenyl isothiocyanate (PITC) was used to determine AA concentrations in all of the samples. Hydrolysis time significantly affected (P < 0.001) AA levels. The highest levels (P > 0.05) of valine, isoleucine, serine, glycine, threonine, alanine, arginine, proline, histidine and phenylalanine were not observed with 24 h hydrolysis. Therefore, correction factors and sequential hydrolysis curves are important for these amino acids. In conclusion, the effect of hydrolysis time should be considered in amino acids analysis. © 2000 Society of Chemical Industry.

Treatment of major depression in general practice: a double-blind comparison of paroxetine and lofepramine.

A six-week, double-blind, randomised study was used to compare the efficacy, tolerability, safety and effect on cognitive function of paroxetine with that of lofepramine in the treatment of 138 patients with major depression in general practice. Efficacy was assessed using the Montgomery and Asberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) scale. Effect on cognitive function was assessed using the paired associate learning test and the serial "E' cancellation test. The results showed that the antidepressant efficacy of paroxetine was comparable to that of lofepramine in the treatment of depressed patients. Similar improvements in mean total MADRS scores were observed in both treatment groups, but a significantly greater improvement was seen in the CGI with paroxetine at weeks 2 and 4. The effect of treatment on cognitive function did not differ significantly across the two treatment groups, nor did the number of adverse events reported nor the overall tolerability.

Paroxetine in the treatment of elderly depressed patients in general practice: a double-blind comparison with amitriptyline.

A total of 101 patients entered a double-blind, parallel-group study in general practice, comparing the efficacy and tolerability of paroxetine and amitriptyline in elderly depressed patients. All patients received placebo for 1 week followed by active therapy for a total of 6 weeks. Medication was randomly allocated, two-thirds of the patients took paroxetine (20 mg daily) and one-third received amitriptyline (50 mg daily); this dose was increased to 30 mg and 100 mg, respectively, after 1 week. Of the patients who entered the placebo run-in, 90 took active treatment and were evaluable on an intention-to-treat basis (56 paroxetine, 32 amitriptyline). The mean age of the patients was 72 years. Significant reductions in Hamilton Depression Rating Scale (HAMD) from baseline to the end of treatment were seen for both groups (p < 0.01), with no difference between treatments. The HAMD score was reduced by half, or more, for 76% of patients taking paroxetine and 86% taking amitriptyline. Significant improvement was observed in the investigators' Clinical Global Impression (CGI) score for 57% of patients taking paroxetine and 52% on amitriptyline. Improvements after treatment were also observed in the Leeds Sleep Evaluation Questionnaire (LSEQ) scores. Significantly fewer patients taking paroxetine reported adverse events (34% vs 63% taking amitriptyline, p = 0.02). Those taking paroxetine experienced significantly fewer anticholinergic side effects (7% vs 25% taking amitriptyline, p = 0.04). Overall, this study confirmed the effectiveness of paroxetine as an antidepressant drug.(ABSTRACT TRUNCATED AT 250 WORDS)