Excited State Rotational Freedom Impacts Viscosity Sensitivity in Arylcyanoamide Fluorescent Molecular Rotor Dyes.

The microviscosity of intracellular environments plays an important role in monitoring cellular function. Thus, the capability of detecting changes in viscosity can be utilized for the detection of different disease states. Viscosity-sensitive fluorescent molecular rotors are potentially excellent probes for these applications; however, the predictable relationships between chemical structural features and viscosity sensitivity are poorly understood. Here, we investigate a set of arylcyanoamide-based fluorescent probes and the effect of small aliphatic substituents on their viscosity sensitivity. We found that the location of the substituents and the type of π-network of the fluorophore can significantly affect the viscosity sensitivity of these fluorophores. Computational analysis supported the notion that the excited state rotational energy barrier plays a dominant role in the relative viscosity sensitivity of these fluorophores. These findings provide valuable insight into the design of molecular rotor-based fluorophores for viscosity measurement.

Staff and patient experience of the implementation and delivery of a virtual health care home monitoring service for COVID-19 in Melbourne, Australia.

BACKGROUND: Provision of virtual health care (VHC) home monitoring for patients who are experiencing mild to moderate COVID-19 illness is emerging as a central strategy for reducing pressure on acute health systems. Understanding the enablers and challenges in implementation and delivery of these programs is important for future implementation and re-design. The aim of this study was to explore the perspectives of staff involved with the implementation and delivery, and the experience of patients managed by, a VHC monitoring service in Melbourne, Australia during the COVID-19 pandemic. METHODS: A descriptive qualitative approach informed by naturalist inquiry was used. Staff interviews were analysed using the Consolidated Framework for Implementation Research (CFIR). Patient experience was captured using a survey and descriptive statistics were used to describe categorical responses while content analysis was used to analyse free text responses as they related to the CFIR. Finally, data from the interviews and patient experience were triangulated to see if patient experience validated data from staff interviews. RESULTS: All 15 staff were interviewed, and 271 patients were surveyed (42%). A total of four final overarching themes emerged: service implementation enablers, service delivery benefits for patients, fragmentation of care, and workforce strengths. 19 subthemes aligned with 18 CFIR constructs from staff and patient data. CONCLUSION: Rapid implementation was enabled through shared resources, dividing implementation tasks between senior personnel, engaging furloughed healthcare staff in design and delivery, and having a flexible approach that allowed for ongoing improvements. Benefits for patients included early identification of COVID-19 deterioration, as well as provision of accurate and trustworthy information to isolate safely at home. The main challenges were the multiple agencies involved in patient monitoring, which may be addressed in the future by attributing responsibility for monitoring to a single agency.

Descriptive Analysis of a Telephone Based Community Monitoring Service for COVID-19.

The coronavirus disease (COVID-19) pandemic has required health services to rapidly respond to the needs of people diagnosed with the virus. Over 80% of people diagnosed with COVID-19 experience a mild illness and there is a need for community management to support these people in their home. In this paper we present, a telephone based COVID-19 community monitoring service developed in an Australian public health network, and we describe the rapid implementation of the service and the demographic and clinical characteristics of those enrolled. A retrospective mixed methods evaluation of the COVID-19 community monitoring service using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. Eight hundred and fifty COVID-19 positive patients were enrolled, 54% female, 45% male, mean age 34 years SD 17. Four hundred and nine (48%) patients were born outside Australia. Among the 850 patients, 305 (36%) were classified as having a high risk of serious illness from COVID-19. The most prevalent risk factors were cardiovascular disease (37%), lung disease (30%) and age over 60 years (26%). The most common reported ongoing symptoms were fatigue (55%), breathing issues (26%) and mental health issues such as low mood (19%). There were no deaths in patients that participated in the service. The process of risk stratification undertaken with telephone triage was effective in determining risk of prolonged illness from COVID-19. Telephone monitoring by trained health professionals has a strong potential in the effective management of patients with a mild COVID-19 illness.

Nutritive value, fermentation characteristics, and in situ disappearance kinetics of sorghum silage treated with inoculants.

Fibrolytic enzymes and microbial inoculants have the potential to improve the value of sorghum feedstuff and feedstock. An experiment was conducted to determine nutritive value, ensiling characteristics, and in situ disappearance kinetics of 4 sorghum (Sorghum bicolor L.) silage varieties: Dairy Master BMR (DBMR; brown midrib; Richardson Seed, Vega, TX), PS 747 (PS; photoperiod sensitive; Pogue Seed, Kenedy, TX), Silo 700D (S700D; conventional forage type; Richardson Seed), and MMR 381/73 (MMR; conventional forage type; Richardson Seed) pretreated with fibrolytic enzyme (xylanase plus cellulase, XC; 50:50 mixture of Cellulase Plus and Xylanase Plus; Dyadic, Juniper, FL) or microbial [Promote ASB (Lactobacillus buchneri and Lactobacillus plantarum); Cargill Animal Nutrition, Indianapolis, IN; PRO] inoculants. The greatest yield was for cultivar PS and the least for MMR. Neutral detergent fiber (NDF) concentration was least for XC-treated silage, and acid detergent fiber (ADF) concentration was least for XC- and PRO-treated silage. When silage was treated with XC, concentrations of NDF concentrations decreased, on average, 4.81% across all cultivars and ADF concentrations decreased, on average, 3.23% in all cultivars except MMR. Inoculant PRO reduced the NDF concentration of DBMR by 6.47%. The ADF concentrations of DBMR and PS treated with PRO were decreased by 3.25%. Treating sorghum silage with XC or PRO reduced the NDF and ADF fractions, which increased cell wall degradability. In vitro true digestibility was greatest for PRO-treated DBMR, whereas acid detergent lignin was least for PRO-treated DBMR. Aerobic stability was not improved by PRO; however, aerobic stability of XC-treated MMR was 63 h greater than that of the control. Acetate concentrations were greatest for XC-treated MMR, which explains the 63-h improvement in aerobic stability due to the inhibition of fungi. However, inoculant PRO did not improve yeast and mold counts or aerobic stability of sorghum silage compared with the control, which may be due to the lesser acetate concentrations, especially of PRO-treated S700D silage. Generally, in situ disappearance kinetics were improved with the application of XC and PRO, and XC had the greatest effect on silage with greater NDF and ADF concentrations.

Segmental allotetraploidy and allelic interactions in buffelgrass (Pennisetum ciliare (L.) Link syn. Cenchrus ciliaris L.) as revealed by genome mapping.

Linkage analyses increasingly complement cytological and traditional plant breeding techniques by providing valuable information regarding genome organization and transmission genetics of complex polyploid species. This study reports a genome map of buffelgrass (Pennisetum ciliare (L.) Link syn. Cenchrus ciliaris L.). Maternal and paternal maps were constructed with restriction fragment length polymorphisms (RFLPs) segregating in 87 F1 progeny from an intraspecific cross between two heterozygous genotypes. A survey of 862 heterologous cDNAs and gDNAs from across the Poaceae, as well as 443 buffelgrass cDNAs, yielded 100 and 360 polymorphic probes, respectively. The maternal map included 322 RFLPs, 47 linkage groups, and 3464 cM, whereas the paternal map contained 245 RFLPs, 42 linkage groups, and 2757 cM. Approximately 70 to 80% of the buffelgrass genome was covered, and the average marker spacing was 10.8 and 11.3 cM on the respective maps. Preferential pairing was indicated between many linkage groups, which supports cytological reports that buffelgrass is a segmental allotetraploid. More preferential pairing (disomy) was found in the maternal than paternal parent across linkage groups (55 vs. 38%) and loci (48 vs. 15%). Comparison of interval lengths in 15 allelic bridges indicated significantly less meiotic recombination in paternal gametes. Allelic interactions were detected in four regions of the maternal map and were absent in the paternal map.

ZD9583, an orally effective thromboxane A2 synthase inhibitor and receptor antagonist with a sustained duration of action in rat and dog.

The thromboxane A2 (TXA2) synthase inhibitory activity and the TXA2 receptor (TP-receptor) blocking action of ZD9583 ((4Z)-6-[(2S,4S,5R)-2-(1-[2-cyano-4-methylphenoxy]-1-methylethyl) -4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid) has been evaluated in-vitro by use of whole blood and platelets from man, and ex-vivo by use of platelets and whole blood from rats and dogs. ZD9583 caused concentration-dependent inhibition of human platelet microsomal TXA2 production with an IC50 of 0.017 +/- 0.003 microM; this inhibition was associated with an increase in prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) formation. ZD9583 also inhibited collagen-stimulated TXA2 synthesis in whole blood from man, rat and dog giving IC50 values of 0.027 +/- 0.005, 0.02 +/- 0.006 and 0.013 +/- 0.01 microM, respectively. The drug did not modify platelet cyclooxygenase activity as inhibition of thromboxane B2 (TXB2) formation was associated with a concomitant increased synthesis of prostaglandin D2 (PGD2), PGE2 and PGF2 alpha. ZD9583 had little effect on cultured human umbilical vein endothelial cell prostacyclin synthase giving an IC50 of 24.2 +/- 4.9 microM. In-vitro ZD9583 caused concentration-dependent inhibition of U46619-induced aggregation responses of platelets from man, rat and dog, yielding apparent log A2 values of 8.7 +/- 0.12, 8.8 +/- 0.2 and 9.3 +/- 0.2, respectively. The drug was selective; at concentrations up to 100 microM it did not affect 5-hydroxytryptamine or the primary phases of adenosine diphosphate and adrenaline-induced aggregation. ZD9583 (100 microM) did not, furthermore, modify the platelet inhibitory effects of PGD2, prostaglandin E1 (PGE1) and prostacyclin. Oral administration of ZD9583 (3-10 mg kg-1) to both rats and dogs caused dose-dependant inhibition of collagen-stimulated TXA2 production ex-vivo which persisted for up to 12 h. The drug also caused profound TXA2 receptor blockade in both species for in excess of 12-h after an oral dose of 3 mg kg-1. ZD9583 (3 mg kg-1, p.o.), when administered to dogs over a five-day period at 12 h intervals, did not cause either tachyphylaxis or an accumulation of effect. We conclude that ZD9583 is a potent, selective, orally active thromboxane synthase inhibitor and TXA2 receptor antagonist.

ZD1542, a potent thromboxane A2 synthase inhibitor and receptor antagonist in vitro.

1. The thromboxane A2 synthase (TXS) inhibitory activity and the thromboxane A2 (TP)-receptor blocking action of ZD1542 (4(Z)-6-[2S,4S,5R)-2-[1-methyl-1-(2-nitro-4-tolyloxy)ethyl]-4-(3- pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid) has been evaluated in vitro on platelets and whole blood from a range of species including man. Antagonist activity has also been investigated in vascular and pulmonary smooth muscle preparations in vitro. 2. ZD1542 caused concentration-dependent inhibition of human platelet microsomal thromboxane B2 (TXB2) production in vitro (IC50 = 0.016 microM); this inhibition was associated with an increase in prostaglandin E2 (PGE2) and PGF2 alpha formation. 3. ZD1542 also inhibited collagen-stimulated TXS in human, rat and dog whole blood giving IC50 values of 0.018, 0.009 and 0.049 microM respectively. The drug did not modify platelet cyclo-oxygenase activity as inhibition of TXB2 formation was associated with a concomitant increase in the levels of PGD2, PGE2 and PGF2 alpha. ZD1542 had little if any effect against cultured human umbilical vein endothelial cell (HUVEC) cyclo-oxygenase (IC50 > 100 microM) and prostacyclin (PGI2) synthase (IC50 = 18.0 +/- 8.6 microM). 4. ZD1542 caused concentration-dependent inhibition of U46619-induced aggregation responses of human, rat and dog platelets yielding apparent pA2 values of 8.3, 8.5 and 9.1 respectively. The drug was selective as, at concentrations up to 100 microM, it did not modify 5-hydroxytryptamine (5-HT) or the primary phases of adenosine diphosphate (ADP) and adrenaline-induced aggregation. Furthermore, ZD1542 (100 microM) modified only weakly the platelet effects of PGD2, PGE1 and PGI2. 5. ZD1542 also caused concentration-dependent inhibition of U46619-mediated contractions of rat thoracic aorta, guinea-pig trachea and lung parenchyma preparations giving apparent pA2 values of 8.6,8.3 and 8.5 respectively. At concentrations approaching three orders of magnitude greater than those required to block U46619-mediated contractions, the drug did not affect the actions of non-prostanoid agonists or exhibit agonist activity in any of the smooth muscle preparations employed; neither did it interact at EP- or FP-receptors.6. In conclusion, the present study demonstrates that ZD1542 is a drug that exhibits both potent,selective TXS inhibition and TXA2 receptor antagonism.

Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog.

1. The effects of simultaneous redirection of arachidonic acid metabolism, by inhibition of thromboxane A2 (TXA2) synthase and blockade of the platelet thromboxane A2 receptor (TP-receptor), was examined on the rate of thrombus formation in a stenosed coronary artery with damaged endothelium in an anaesthetized dog. 2. Redirection of arachidonic acid metabolism was achieved by intravenous doses of ICI D1542, a selective and potent inhibitor of TXA2 synthase and the TP-receptor. 3. Redirection of arachidonic acid metabolism was demonstrated in whole blood, stimulated ex vivo by collagen. The ED50 for inhibition of TXB2 production was 7.1 micrograms kg-1, i.v.; there were corresponding increases in the production of the eicosanoids prostaglandin D2 (PGD2), PGE2 and PGF2 alpha. 4. Thrombus formation was inhibited by D1542 (ED50 0.55 micrograms kg-1, i.v.), but could be restarted by an intravenous infusion of adrenaline (0.2-38 micrograms kg-1 min-1, i.v.). In the presence of the maximum effective dose of D1542 (1 mg kg-1, i.v.) a 190 fold increase in the infusion rate of adrenaline was required to restore thrombus formation. 5. In the presence of D1542, removal of endoperoxide metabolites by inhibition of cyclo-oxygenase with aspirin (5 mg kg-1, i.v.) caused thrombus formation to restart, indicating the ability of the endoperoxide metabolites to inhibit thrombus formation in vivo. 6. These results indicate that, in the stenosed and damaged coronary artery of the dog, redirection of arachidonic acid metabolism by D1542 is more effective at preventing thrombus formation than inhibition of cyclo-oxygenase by aspirin.

Studies in the guinea-pig with ICI 185,282: a thromboxane A2 receptor antagonist.

The effects of ICI 185,282 (5(Z)-7-([ 2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1, 3-dioxan-5-yl)heptenoic acid) have been studied on guinea-pig platelets and pulmonary smooth muscle in-vitro and in-vivo. When tested on guinea-pig lung parenchyma in-vitro. ICI 185,282 (1 x 10(-7) M) produced a significant shift in U-46619 response curves (concentration ratio of 13:3); the antagonist (1 x 10(-5) M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 x 10(-7) M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 x 10(-5) M proved less effective against contractions of PGF2 alpha, LTD4 and histamine (concentration ratios of 7.0, 1.5 and 1.6). When added to guinea-pig platelet rich plasma in-vitro, ICI 185,282 (x 10(-6), 1 x 10(-5) M) caused concentration-dependent parallel shifts to the right of U-46619 aggregation curves, yielding concentration ratios of 13.6 and 141.9, respectively. In-vitro, addition of ICI 185,282 (x 10(-5) M) to indomethacin-treated pulmonary smooth muscle did not modify resting tone, neither did it induce aggregation or swelling in platelet-rich plasma preparations. When administered orally to guinea-pigs ICI 185,282 (0.1, 0.5 mg kg-1) caused a significant inhibition of U-46619-induced platelet aggregation ex-vivo which persisted greater than or equal to 8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg-1) inhibited bronchospasm induced by U-46619, PGD2, PGF2 alpha, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605.

The synthesis and summary pharmacology of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1, 3-dioxan-cis-5-yl) hexenoic acid (3) is reported. Compound 3 was competitive and selective with pA2 values of 8.0 +/- 0.1 (rabbit) and 8.4 +/- 0.05 (rat) on smooth muscle preparations and 8.16 +/- 0.01 on human platelets. In vivo activity of 3 was demonstrated in a Konzett Rossler guinea pig model at 0.01 mg/kg p.o.

(5Z)-7-(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoi c acid: a specific thromboxane A2 receptor antagonist.

(5Z)-7-(2,2-Dimethyl-4-phenyl-1,3-dioxan-cis-5-yl)heptenoic acid (2) was found to be a specific, competitive thromboxane A2 receptor antagonist that acts at platelet, vascular, and pulmonary receptors. No antagonism was detected at receptors for prostacyclin, SRSA, norepinephrine, and serotonin. The synthesis of a series of analogues is described; activity at the thromboxane receptor was observed in cis-substituted compounds but not in their trans counterparts. Compound 2 inhibited the bronchoconstriction induced by a stable thromboxane mimetic in the anesthetized guinea pig.

Pharmacological actions of ICI 180080, a novel thromboxane receptor antagonist.

ICI 180080 (5(Z)-7-[2,2-dimethyl-4-(2-hydroxyphenyl)-1,3-dioxan-cis-5-yl] heptenoic acid) potently inhibited contractions of rat and rabbit aortae and guinea-pig trachea elicited by 11,9-epoxymethano PGH2 (U-46619). This antagonism was selective because contractions of aortae to noradrenaline and 5-hydroxytryptamine and trachea to histamine were not antagonized by ICI 180080. Schild analysis of data obtained from experiments on rabbit aortae indicated that this thromboxane receptor antagonism was competitive (pA2 = 7.50, slope = 1.07). Addition of ICI 180080 to human platelet-rich plasma caused dose-related inhibition of U-46619-induced platelet aggregation. This modification of platelet aggregation was not associated with inhibition of thromboxane synthetase, cyclo-oxygenase or lipoxygenase. ICI 180080 did not modify the primary phase of ADP-induced aggregation of human platelets neither did it affect the platelet inhibitory activity of prostacyclin. When dosed orally to anaesthetized guinea-pigs, ICI 180080 (5-50 mg kg-1) caused dose-related inhibition of U-46619-evoked bronchoconstriction. We conclude that ICI 180080 is a potent, selective, competitive, orally active thromboxane antagonist.

Effects of sorption on biological degradation rates of (2,4-dichlorophenoxy) acetic acid in soils.

Three mathematical models were proposed to describe the effects of sorption of both bacteria and the herbicide (2,4-dichlorophenoxy)acetic acid (2,4-D) on the biological degradation rates of 2,4-D in soils. Model 1 assumed that sorbed 2,4-D is not degraded, that only bacteria in solution are capable of degrading 2,4-D in solution, and that sorbed bacteria are not capable of degrading either sorbed or solution 2,4-D. Model 2 stated that only bacteria in the solution phase degrade 2,4-D in solution and that only sorbed bacteria degrade sorbed 2,4-D. Model 3 proposed that sorbed 2,4-D is completely protected from degradation and that both sorbed and solution bacteria are capable of degrading 2,4-D in solution. These models were tested by a series of controlled laboratory experiments. Models 1 and 2 did not describe the data satisfactorily and were rejected. Model 3 described the experimental results quite well, indicating that sorbed 2,4-D was completely protected from biological degradation and that sorbed- and solution-phase bacteria degraded solution-phase 2,4-D with almost equal efficiencies.