Photoelectron jets and interference structures in ionization beyond dipole approximation: carrier- envelope phase effects and vortex streets.

We have analyzed photoelectron jet formation in strong-field ionization using the hydrodynamic picture of quantum mechanics. We showed that von-Kármán-like vortex streets emerge in between jets in photoelectron momentum distributions. The spatial orientation of the jets can be controlled by tailoring the carrier-envelope phase of the driving laser pulse. This indicates that it is possible to experimentally measure emitted photoelectrons off the optical axis, which opens up new possibilities for high-frequency laser pulse diagnostics.

Carrier-envelope-phase and helicity control of electron vortices and spirals in photodetachment.

Formation of electron vortices and spirals in photodetachment from the H- anion driven by isolated ultrashort laser pulses of circular polarization or by pairs of such pulses (of either co-rotating or counter-rotating polarizations) are analyzed under the scope of the strong-field approximation. It is demonstrated that the carrier-envelope phase (CEP) and helicity of each individual pulse can be used to actively manipulate and control the vortical and spiral patterns in the probability amplitude of photodetachment. Specifically, we show that the vortical patterns can be rotated in momentum space by the CEP of the driving pulse (or, of two identical pulses); thus, offering a tool of pulse characterization. For co-rotating pulses of arbitrary CEPs, a novel type of structured vortices is discovered. Also, we demonstrate that the momentum spirals are formed when photodetachment is driven by two pulses of time-reversal symmetry, which is accompanied by absolute disappearance of vortical structures. Hence, we attribute the spiral formation to annihilation of vortices with antivortices, which are generated by time-reversed pulses comprising the train. Finally, the CEP and helicity control of spiral structures is demonstrated, leading to their rotation in momentum space.

"Seeing Rain": Integrating phenomenological and Bayesian predictive coding approaches to visual hallucinations and self-disturbances (Ichstörungen) in schizophrenia.

We present a schizophrenia patient who reports "seeing rain" with attendant somatosensory features which separate him from his surroundings. Because visual/multimodal hallucinations are understudied in schizophrenia, we examine a case history to determine the role of these hallucinations in self-disturbances (Ichstörungen). Developed by the early Heidelberg School, self-disturbances comprise two components: 1. The self experiences its own automatic processing as alien to self in a split-off, "doubled-I." 2. In "I-paralysis," the disruption to automatic processing is now outside the self in omnipotent agents. Self-disturbances (as indicated by visual/multimodal hallucinations) involve impairment in the ability to predict moment-to-moment experiences in the ongoing perception-action cycle. The phenomenological approach to subjective experience of self-disturbances complements efforts to model psychosis using the computational framework of hierarchical predictive coding. We conclude that self-disturbances play an adaptive, compensatory role following the uncoupling of perception and action, and possibly, other low-level perceptual anomalies.

Supporting the improvement of air quality management practices: The "FAIRMODE pilot" activity.

This paper presents the first outcomes of the "FAIRMODE pilot" activity, aiming at improving the way in which air quality models are used in the frame of the European "Air Quality Directive". Member States may use modelling, combined with measurements, to "assess" current levels of air quality and estimate future air quality under different scenarios. In case of current and potential exceedances of the Directive limit values, it is also requested that they "plan" and implement emission reductions measures to avoid future exceedances. In both "assessment" and "planning", air quality models can and should be used; but to do so, the used modelling chain has to be fit-for-purpose and properly checked and verified. FAIRMODE has developed in the recent years a suite of methodologies and tools to check if emission inventories, model performance, source apportionment techniques and planning activities are fit-for-purpose. Within the "FAIRMODE pilot", these tools are used and tested by regional/local authorities, with the two-fold objective of improving management practices at regional/local scale, and providing valuable feedback to the FAIRMODE community. Results and lessons learnt from this activity are presented in this paper, as a showcase that can potentially benefit other authorities in charge of air quality assessment and planning.

Increasing experience of ligation of the intersphincteric fistula tract for patients with Crohn's disease: what have we learned?

AIM: Ligation of the intersphincteric fistula tract (LIFT) has been proposed as a treatment of trans-sphincteric fistula in perianal Crohn's disease (CD). The aim of this study was to look at our experience of the LIFT procedure in CD patients on long-term follow-up. Specifically, we aimed to determine the fistula healing rate after the LIFT procedure after more than 12 months follow-up and to identify any prognostic factors. METHOD: Retrospective study of patients with trans-sphincteric Crohn's fistula tracts treated with the LIFT procedure between January 2011 and October 2015. Complete fistula healing as well as clinical outcomes were analysed. RESULTS: Data were available for 23 patients. After a median follow-up of 23 months, LIFT site healing was 48%. Patients with healed LIFT had a median follow-up time of 10.5 months, while patients with failed LIFT had a median follow-up time of 31 months (P = 0.04). Median time to failure was 9 months for patients with follow-up > 1 year. Most patients failed within 1 year (9/12; 75%) of the procedure. In multi-site CD, the LIFT procedure was more likely to be successful in those with small bowel disease (P = 0.04) compared with colonic disease (P = 0.02). Other factors such as preoperative use of biological therapies, presence of a seton, previous repair attempts, fistula position, type or number of fistulas, multiple fistula tracts, smoking status and other associated perianal disease did not appear to influence LIFT healing rates. CONCLUSION: The LIFT procedure offers reasonable long-term success in the treatment of perianal trans-sphincteric fistulas associated with CD. LIFT is more likely to fail in patients with concurrent colonic CD than in patients with small bowel CD.

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

BACKGROUND & AIMS: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB. METHODS AND RESULTS: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat. We calculated the homeostasis model assessment index (HOMA-IR) and whole body insulin sensitivity from oral glucose tolerance tests and measured intramyocellular fat by magnetic resonance spectroscopy. BCAAs and 3-HIB plasma concentrations were inversely related to insulin sensitivity but not to intramyocellular fat content at baseline. With 7.4 ± 4.5% weight loss mean BCAA and 3-HIB plasma concentrations did not change, irrespective of dietary macronutrient content. Individual changes in 3-HIB with 6-month diet but not BCAAs were correlated to the change in whole body insulin sensitivity and HOMA-IR independently of BMI changes. CONCLUSIONS: 3-HIB relates to insulin sensitivity but is not associated with intramyocellular fat content in overweight to obese individuals. Moreover, changes in 3-HIB rather than changes in BCAAs are associated with metabolic improvements with weight loss. Registration number for clinical trials: ClinicalTrials.gov Identifier: NCT00956566.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects.

BACKGROUND & AIMS: Amino acids may interfere with insulin action, particularly in obese individuals. We hypothesized that increased circulating branched-chain and aromatic amino acids herald insulin resistance and ectopic fat storage, particularly hepatic fat accumulation. METHODS AND RESULTS: We measured fasting branched-chain and aromatic amino acids (tryptophan, tyrosine, and phenylalanine) by mass spectrometry in 111 overweight to obese subjects. We applied abdominal magnetic resonance imaging and spectroscopy to assess adipose tissue distribution and ectopic fat storage, respectively. Plasma branched-chain amino acids concentrations were related to insulin sensitivity and intrahepatic fat independent from adiposity, age and gender, but not to abdominal adipose tissue or intramyocellular fat. CONCLUSIONS: In weight stable overweight and obese individuals, branched-chain amino acid concentrations are specifically associated with hepatic fat storage and insulin resistance.

Search for Dark Matter Axions with CAST-CAPP.

The CAST-CAPP axion haloscope, operating at CERN inside the CAST dipole magnet, has searched for axions in the 19.74 µeV to 22.47 µeV mass range. The detection concept follows the Sikivie haloscope principle, where Dark Matter axions convert into photons within a resonator immersed in a magnetic field. The CAST-CAPP resonator is an array of four individual rectangular cavities inserted in a strong dipole magnet, phase-matched to maximize the detection sensitivity. Here we report on the data acquired for 4124 h from 2019 to 2021. Each cavity is equipped with a fast frequency tuning mechanism of 10 MHz/ min between 4.774 GHz and 5.434 GHz. In the present work, we exclude axion-photon couplings for virialized galactic axions down to gaγγ = 8 × 10-14 GeV-1 at the 90% confidence level. The here implemented phase-matching technique also allows for future large-scale upgrades.

Development and validation of a weather-based warning system to advise fungicide applications to control dollar spot on turfgrass.

Dollar spot is one of the most common diseases of golf course turfgrass and numerous fungicide applications are often required to provide adequate control. Weather-based disease warning systems have been developed to more accurately time fungicide applications; however, they tend to be ineffective and are not currently in widespread use. The primary objective of this research was to develop a new weather-based disease warning system to more accurately advise fungicide applications to control dollar spot activity across a broad geographic and climactic range. The new dollar spot warning system was developed from data collected at field sites in Madison, WI and Stillwater, OK in 2008 and warning system validation sites were established in Madison, WI, Stillwater, OK, Knoxville, TN, State College, PA, Starkville, MS, and Storrs, CT between 2011 and 2016. A meta-analysis of all site-years was conducted and the most effective warning system for dollar spot development consisted of a five-day moving average of relative humidity and average daily temperature. Using this model the highest effective probability that provided dollar spot control similar to that of a calendar-based program across the numerous sites and years was 20%. Additional analysis found that the 20% spray threshold provided comparable control to the calendar-based program while reducing fungicide usage by up to 30%, though further refinement may be needed as practitioners implement this warning system in a range of environments not tested here. The weather-based dollar spot warning system presented here will likely become an important tool for implementing precision disease management strategies for future turfgrass managers, especially as financial and regulatory pressures increase the need to reduce pesticide usage on golf course turfgrass.

Chimeric Mos1 and piggyBac transposases result in site-directed integration.

Genetic transformation systems based on Mos1 and piggyBac transposable elements are used to achieve stable chromosomal integration. However, integration sites are randomly distributed in the genome and transgene expression can be influenced by position effects. We developed a novel technology that utilizes chimeric transposases to direct integration into specific sites on a target DNA molecule. The Gal4 DNA binding domain was fused to the NH(2) terminus of the Mos1 and piggyBac transposases and a target plasmid was created that contained upstream activating sequences (UAS), to which the Gal4 DBD binds with high affinity. The transpositional activity of the Gal4-Mos1 transposase was 12.7-fold higher compared to controls where the Gal4-UAS interaction was absent and 96% of the recovered transposition products were identical, with integration occurring at the same TA site. In a parallel experiment, a Gal4-piggyBac transposase resulted in an 11.6-fold increase in transpositional activity compared to controls, with 67% of the integrations occurring at a single TTAA site. This technology has the potential to minimize nonspecific integration events that may result in insertional mutagenesis and reduced fitness. Site-directed integration will be advantageous to the manipulation of genomes, study of gene function, and for the development of gene therapy techniques.

First Report of Ophiosphaerella agrostis Infecting Creeping Bentgrass in Canada.

Dead spot, also known as bentgrass dead spot or bermudagrass dead spot, is a relatively new disease of golf course putting greens and is caused by the pathogen Ophiosphaerella agrostis (1). The disease first was reported on a creeping bentgrass (Agrostis stolonifera) putting green in Maryland (2) and since has been identified on putting greens of creeping bentgrass and hybrid bermudagrass (Cynodon dactylon × C. transvaalensis) in the eastern and southern United States (3,4). In June 2004, disease symptoms resembling dead spot were observed on a golf course in southern Ontario. Small (≤3 cm) spots first appeared approximately 14 months after establishment of the sand-based, 'L-93' creeping bentgrass putting greens. The disease became more severe during the summer months and patches increased in size to as much as 5 to 8 cm in diameter. Dead spot infection centers remained visible throughout the winter months and the disease again became active during the spring of 2005. Bentgrass tissues growing adjacent to the periphery of active infection centers were orange-red to reddish-brown. Although dark brown ectotrophic hyphae were observed on bentgrass stolons, none were found on the roots. Few new infection centers occurred in 2005 and pseudothecia embedded within necrotic tissue only were observed in small numbers. No mature ascospores were observed when samples were collected during September 2005. A single fungal morphotype consistently was isolated from leaves and stolons with a rose-quartz color when grown for several days on potato dextrose agar. To demonstrate pathogenicity, 'L-93' creeping bentgrass seedlings were grown for 28 days in 10-cm-diameter pots containing an autoclaved greens-mix with a mechanical analysis of 94% sand, 5% silt, and 1% clay. Inoculum was prepared by placing mycelia from a hyphal-tipped isolate on an autoclaved mix of seed of tall fescue (Festuca arundinacea) and wheat (Triticum aestivum) bran (50% [vol/vol]), and grown at 24°C for 14 days. The inoculum (5 g) was embedded a few milliliters into the sand in the center of each pot (n = 5), and uninfested inoculum served as the untreated control. Pots were placed in enclosed plastic containers and incubated at room temperature (13 to 26°C) under natural light (replication 1) or under 14 h of light per day from fluorescent lights (replication 2). After 7 days, tissue along the periphery of each inoculation point became covered in a pink mycelium, and newly infected leaves appeared tan or brownish-red. Most plants were dead after 22 to 28 days of incubation. Reisolation of the pathogen from necrotic leaves produced fungal colonies similar in color, morphology, and growth rate to the original isolates. Few pseudothecia developed on infected tissue but were present in large numbers on infested tall fescue seed. Bitunicate asci containing spirally twisted filiform ascospores were observed. Light brown ascospores (n = 50) were 7 to 15 septate and measured 1.9 to 3.6 µm × 60.7 to 147.9 µm. On the basis of field symptoms, morphological characteristics, and pathogenicity tests, the pathogen was identified as O. agrostis. To our knowledge, this is the first report of dead spot on creeping bentgrass in Canada and of O. agrostis outside the United States. References: (1) M. P. S. Câmara et al. Mycologia 92:317, 2000. (2) P. H. Dernoeden et al. Plant Dis. 83:397, 1999. (3) J. E. Kaminski and P. H. Dernoeden. Plant Dis. 86:1253, 2002. (4) J. P. Krausz et al. Plant Dis. 85:1286, 2001.

Prostate cancer gene therapy and the role of radiation.

Even though prostate cancer is detected earlier than in the pre-PSA era, prostate cancer is the second leading cause of cancer mortality in the American male. Prostate cancer therapy is not ideal, especially for high-risk localized and metastatic cancer; therefore, investigators have sought new therapeutic modalities such as angiogenesis inhibitors, inhibitors of the cell signaling pathway, vaccines, and gene therapy. Gene therapy has emerged as potential therapy for both localized and systemic prostate cancer. Gene therapy has been shown to work supra-additively with radiation in controlling prostate cancer in vivo. With further technological advances in radiation therapy, gene therapy, and the understanding of prostate cancer biology, gene therapy will potentially have an important role in prostate cancer therapy.

Defining a future role for radiogenic therapy.

The goal of cancer therapy is to eliminate the cancer and/or to arrest further growth while decreasing normal tissue toxicity, i.e. to increase the therapeutic ratio. This review focuses on a group of therapeutics that are either (1) directly stimulated by radiation to produce either directly or indirectly cytotoxic agents (i.e. genes under the control of a radiation inducible promoter that produce a cytotoxic protein or an enzyme that converts a prodrug to an active form, respectively); (2) auger-electron emitting radiolabelled oligonucleotides, antibodies, nucleotide analogues, or other small molecules that are internalized; (3) radiation inducible genes that produce a ligand or transporter (or the like) which then can be targeted by cytotoxic agents (e.g. radiolabelled substance). We have termed this group of therapeutics radiogenic therapy.

Antiulcer agents. 6. Analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2-a]pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies.

A number of substituted imidazo[1,2-a]pyridines and related analogues were selected for analysis of their in vitro biochemical and in vivo gastric antisecretory activity using comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL) methodologies. The training set of compounds selected included those that were also chosen for an extensive molecular modeling study initiated, using the active analog approach, to define the pharmacophore by means of which 1 and its analogues interact with the gastric proton pump enzyme, H+/K(+)-ATPase. Using either CoMFA or HASL, it was possible to identify an optimal alignment paradigm of the proposed bioactive conformation for this series to reasonably predict the in vitro H+/K(+)-ATPase inhibitory potency in the purified enzyme model and the in vivo intravenous gastric antisecretory activity for compounds outside of the training set. Furthermore, the steric and electrostatic effects suggested by these two independent methods and their influence on determining biological activity were consistent and complementary to each other.

Soft drugs. 2. Soft alkylating compounds as potential antitumor agents.

A class of soft alkylating compounds as potential anticancer agents was developed. The first examples include alpha-halo esters of various carboxylic acids. A new method for quantitative evaluation of the alkylating reactivity was developed, using a competitive alkylation reactivity was developed, using a competitive alkylation reaction, followed by NMR analysis of the reaction mixture. The method is sensitive and reproducible. One of the two selected soft alkylating agents, chloromethyl hexanoate, was found to have anticancer activity.

Soft drugs. 1. Labile quaternary ammonium salts as soft antimicrobials.

Strategies for the design of safer drugs are discussed. The various classes of "soft drugs" are designed to avoid undesired metabolic disposition (primarily various oxidative routes, occurring via possible toxic intermediates) and to be metabolized by a predictable manner with controlled rates. As a first example for the "soft analogue" type drugs, a new class of antimicrobial, surface-active quaternary salts of the type RCOOCHR1--N+ comes from X- was developed. These "soft" quaternary salts are isosteric analogues of known "hard" quaternary surfactants and are characterized by predictable and controllable cleavage (metabolism) to nontoxic components, while showing good activity against a wide range of bacteria. Due to their soft nature (low toxicity), the new antimicrobials are much safer than the conventional, hard analogues.

Electronic structures of some antimicrobial N-chloramines. Possible existence of intramolecular hydrogen bonding and its effect on germicidal efficiency.

The photoelectron spectra of eight N-chloramines and N,N-dichloramines derived from either alpha-aminoisobutyric acid or 2-amino-2-methylpropanol have been measured. The lone-pair ionization potentials obtained from the photoelectron spectra have been interpreted to indicate that a substantial intramolecular interaction exists between tne N-H function and the various oxygen lone pairs of the N-chloramines. Such an intramolecular interaction for the N-chloramines can explain at least in part why these molecules are less potent as antimicrobial agents than are the N,N-cichloramine analogues for which a similar intramolecular interaction is impossible.

Stereochemical considerations and the antiinflammatory activity of 6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols and related derivatives.

The antiinflammatory activity of a series of 6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols and related derivatives was examined using the reverse passive Arthus reaction (RPAR). The antiinflammatory activity of these compounds was markedly influenced by the stereochemistry of the amino alcohol moiety. The threo diastereomer exhibited activity in the RPAR, while the erythro diastereomer was devoid of any significant antiinflammatory activity. The antiinflammatory activity of the amino alcohols was also significantly influenced by the position and nature of the aromatic substituent. Latentiation of the amino alcohol function resulted in analogues exhibiting antiinflammatory activity equivalent to their amino alcohol precursors. Masking the amino alcohol function as a more stable derivative led to analogues exhibiting an antiinflammatory profile unique to their structural class.

Soft drugs. 3. A new class of anticholinergic agents.

A new class of antimuscarinic drugs was designed and synthesized. The compounds are "soft" quaternary ammonium esters in which there is only one carbon atom separating the ester oxygen and the quaternary head. The compounds are potent anticholinergics when derived from hindered "umbrella" acids and cholinergics when derivatives of simple aliphatic acids. The more potent anticholinergics have up to 10 times higher acetylcholine antagonist activity than atropine, but they have a much shorter duration of action. The compounds cleave hydrolytically with simultaneous destruction of the quaternary head. The compounds are promising as selective, local agents, particularly as inhibitors of eccrine sweating.