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Introduction: Metastasis remains the major cause of death in breast cancer (BrCa) and lacks specific treatment strategies. The kynurenine pathway (KP) has been suggested as a key mechanism facilitating progression of BrCa. While KP activity has been explored in primary BrCa, its role in metastasis remains unclear. To better understand this, we examined changes in the KP of BrCa with no metastasis compared to BCa that produced local or distant metastases. Given that the cancer cell secretome plays a role in metastasis, we also investigated the relationship between changes in KP activity and serum proteins of patients with local or distant metastases., Methods: To investigate changes in the KP in BrCa, with and without metastasis, we quantified KP metabolites in blood sera collected from patients with stage 1 BrCa (n = 34), BrCa with local metastases (n = 46), BrCa with distant metastases (n = 20) and healthy controls (n = 39). The serum protein profile of the BrCa patients with local or distant metastasis was determined before correlation analyses were carried out to examine the relationship between changes in the KP and cancer serum proteins using SPSS., Results: We found that the KP was elevated in BrCa patients with local and distant metastasis compared to healthy controls and stage 1 BrCa patients. The activity of kynurenine monooxygenase (KMO) and kynureninase (KYNU) A was positively associated with disease stage and was higher compared to healthy controls. Proteome analysis in patients with local or distant metastasis revealed the dysregulation of 14 proteins, 9 of which were up-regulated and 5 down-regulated at the distant metastasis stage. Importantly, three of these proteins have not been previously linked to BrCa metastasis. In the correlation studies between the KP profile, cancer serum proteins and metastasis status, KYNU A had the greatest number of significant associations with cancer serum protein, followed by KMO., Conclusion: Our findings reveal that the KP was regulated differently at various stages of BrCa and was more dysregulated in patients with local or distant metastasis. These KP activity changes showed a significant association with cancer serum proteins in BrCa patients with local or distant metastasis, highlighting the potential role of KP in BrCa metastasis., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: The study was approved by the Macquarie University Ethics Committee (Ref: 5201600401). All analyses were conducted in accordance with the Declaration of Helsinki., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Virtual advisors (VAs) are being utilised almost in every service nowadays from entertainment to healthcare. To increase the user's trust in these VAs and encourage the users to follow their advice, they should have the capability of explaining their decisions, particularly, when the decision is vital such as health advice. However, the role of an explainable VA in health behaviour change is understudied. There is evidence that people tend to change their intentions towards health behaviour when the persuasion message is linked to their mental state. Thus, this study explores this link by introducing an explainable VA that provides explanation according to the user's mental state (beliefs and goals) rather than the agent's mental state as commonly utilised in explainable agents. It further explores the influence of different explanation patterns that refer to beliefs, goals, or beliefs&goals on the user's behaviour change. An explainable VA was designed to advise undergraduate students how to manage their study-related stress by motivating them to change certain behaviours. With 91 participants, the VA was evaluated and the results revealed that user-specific explanation could significantly encourage behaviour change intentions and build good user-agent relationship. Small differences were found between the three types of explanation patterns., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2022.)

Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa., Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively., Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA)., Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

The potential for weathered steel slag fines (D 50  < 1.6 mm) to sequester dissolved phosphorus and sulfur from fermenting biosolids was determined. Batch studies showed that sorption equilibrium between phosphates and sulfides was reached in less than 48 hr after adding basic oxygen furnace (BOF) slag grains to municipal digester sludge. When these same particles were added to pilot digesters (75 L) operating at a 30-day SRT, a classic dose-response was observed with respect to PO 4 and H 2 S sequestration, and an inhibitory performance threshold emerged above 20 g BOF/L. Only a fraction of the BOF slag solids contributed to the digester TS mass, because a substantial portion dissolved into the supernatant, some of which contributed to alkalinity. After 160 days of continuous operation, approximately 63% of the total phosphate was sequestered from the supernatant and 78% of the hydrogen sulfide from the biogas, when a steady-state BOF slag dose of 10 g BOF/L was applied. At or below this level, BOF slag fines had no significant effect on mesophilic digester performance as judged by conventional operational metrics. This study demonstrated that upcycling BOF slag directly into the anaerobic digestion process could offer wastewater resource recovery facilities a novel nutrient management tool. PRACTITIONER POINTS: Basic Oxygen Furnace (BOF) Slag fines can be engineered as a cost-effective alternative to conventional phosphorus and sulfur control strategies. A rapid phosphate and sulfide removal from anaerobic digestates occurs within hours after BOF slag addition. 63% of phosphate and 78% of hydrogen sulfide were removed when digester sludge was dosed with 10 g BOF/L, without impacting digester performance. Only a fraction of the dosed BOF slag contributed to digester TS, likely due to partial dissolution into the digestate. BOF slag can potentially increase the nutrient content of biosolids, facilitate biogas recovery, and reduce odors., (© 2019 Water Environment Federation.)

Atherosclerosis develops over a long period of time and often begins in childhood. The goal of this study was to make a cross-sectional assessment of the pattern of cardiovascular disease risk factors among Australian vegetarian (n = 49) and nonvegetarian (n = 639) 14- to 17-year-old participants from New South Wales, Australia. Vegetarians had statistically significant lower mean total (4.05 vs 4.4 mmol/L; P < .001) and low-density lipoprotein (LDL) cholesterol (2.18 vs 2.55 mmol/L; P < .001) and lower incidence of abnormal total and LDL cholesterol (31.1% vs 46.2%, P = .036, having total cholesterol ≥4.4 mmol/L and 13.3% vs 29.6%, P = .021, having LDL cholesterol ≥2.84 mmol/L). Vegetarians had a higher diastolic BP (72.0 vs 69.7 mm Hg; P = .038). No statistically significant difference was found in other risk factors including high-density lipoprotein cholesterol ( P = .83), triglycerides ( P = .601), systolic blood pressure ( P = .727), body mass index ( P = .159), plasma glucose ( P = .09), C-reactive protein ( P = .527), or homocysteine ( P = .45). The prevalence rate with 3 or more risk factors was 12.2% among vegetarians and 13.9% among nonvegetarians ( P = .156). The high percentage of abnormal total cholesterol in both diet groups and, in addition, LDL cholesterol in nonvegetarians is a cause of concern and underlines the need for lifestyle change., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2019 The Author(s).)

High protein intake and reduced levels of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) have both been independently associated with promotion of the ageing phenotype. However, it has not yet been shown whether these two independent observations are biochemically linked. To investigate this possibility, we used a cross-sectional study design of 100 apparently healthy middle-aged males (n = 48) and females, in which we assessed average dietary intakes of multiple components using a validated questionnaire. We also analysed fasting blood levels of urea, NAD+ and its metabolites, and inflammation-linked biomarkers, including interleukin-6 (IL-6), Kynurenine (Kyn), and Tryptophan (Trp). One-way ANOVA and ANCOVA were then performed for statistical analysis. Our results have shown for the first time that plasma levels of NAD+ and Total NAD(H) were lower with increasing protein intake (F (2, 92) = 4.61, P = 0.012; F (2, 92) = 4.55, P = 0.013, respectively). The associated decrease in NAD+ and NAD(H) levels was even stronger with increasing plasma levels of the protein breakdown product urea (F (2, 93) = 25.11, P≤0.001; F (2, 93) = 21.10, P≤0.001). These associations were all independent of age, gender and energy intake. However, no significant association was observed between protein intake or plasma urea, and plasma levels of NAD+ metabolites. We also observed that plasma levels of the inflammatory cytokine IL-6, and both Kyn, and Trp, but not the Kyn/Trp ratio were higher with increasing plasma urea levels (F (2, 94) = 3.30, P = 0.041; F (2, 95) = 7.41, P≤0.001; F (2, 96) = 4.23, P = 0.017, respectively). These associations were dependent on eGFR and energy intake, except for the urea and Trp association that was independent of all. In conclusion, we report for the first time, a novel association between protein intake, its metabolism, and plasma NAD+ levels with a possible link to inflammation. These findings provide further insight into how protein restriction may contribute to the anti-ageing process observed in several studies., Competing Interests: The authors have declared that no competing interests exist.

Lifestyle behaviours have been closely linked to the progressive cell damage associated with oxidative stress (OS) and the development of cardiovascular disease (CVD). Early detection of lifestyle-linked OS may therefore be useful in the early identification of prodromal disease. To test this hypothesis, this study assessed the relationship between a comprehensive redox balance lifestyle score (RBLS) and carotid intima-media thickness (CIMT), a recognized marker for CVD, and plasma biomarkers of OS. In a cross-sectional study design, 100 apparently healthy middle-aged participants were asked to complete a comprehensive lifestyle questionnaire, followed by DXA scanning, CIMT ultrasonography, and blood collection. The RBLS was composed of lifestyle components with pro- and antioxidant properties with a higher score indicative of lower oxidative activity. Multiple linear regression and logistic regression analysis were performed for statistical analysis. The RBLS was significantly associated with the risk for increased CIMT that was independent of conventional CVD risk factors ( χ 2 (9) = 35.60, P ≤ 0.001). The adjusted model explained 42.4% of the variance in CIMT. Participants with RBLS below the median were at significantly increased risk of higher CIMT compared to participants with RBLS above the median (OR = 3.60, 95% CI: 1.19-10.88, P = 0.023). Significant associations were also observed between the RBLS, plasma total antioxidant capacity (TAC) ( r (99) = 0.28, P = 0.006), hydroperoxide (HPX) ( r s (99) = -0.28, P = 0.005), TAC/HPX ratio ( r (98) = 0.41, P ≤ 0.001), γ -glutamyltransferase ( r (97) = -0.23, P = 0.024), uric acid ( r (98) = -0.20, P = 0.045), and inflammatory C-reactive protein ( r s (97) = -0.25, P = 0.012) and interleukin-1 β ( r (97) = -0.21, P = 0.040). These findings highlight the importance of identifying the collective influence of lifestyle behaviours on OS activity and its potential to remodel the vascular endothelium.

Oxidative stress has been closely linked to the progressive cell damage associated with emerging non-communicable disease (NCDs). Early detection of these biochemical abnormalities before irreversible cell damage occurs may therefore be useful in identifying disease risk at an individual level. In order to test this hypothesis, this study assessed the relationship between a simple measure of redox status and lifestyle risk factors for NCDs, and the population-based risk score of Framingham. In a cross-sectional study design, 100 apparently healthy middle-aged males (n = 48) and females (n = 52) were asked to complete a comprehensive lifestyle assessment questionnaire, followed by body fat percentage and blood pressure measurements, and blood collection. The ratio of plasma total antioxidant capacity to hydroperoxide (TAC/HPX) was used as an index of redox balance. One-way ANOVA and multiple linear regression analysis were performed to analyse the association between TAC/HPX, lifestyle components and other plasma biomarkers. The TAC/HPX ratio was higher in males compared to females (t96 = 2.34, P = 0.021). TAC/HPX was also lower in participants with poor sleep quality (t93 = 2.39, P = 0.019), with high sleep apnoea risk (t62.2 = 3.32, P = 0.002), with high caffeine (F(2, 93) = 3.97, P = 0.022) and red meat intake (F(2, 93) = 5.55, P = 0.005). These associations were independent of gender. Furthermore, the TAC/HPX ratio decreased with increasing body fat percentage (F(2, 95) = 4.74, P = 0.011) and depression score (t94 = 2.38, P = 0.019), though these associations were dependent on gender. Importantly, a negative association was observed between TAC/HPX levels and the Framingham risk score in both males (r(45) = -0.39, P = 0.008) and females (r(50) = -0.33, P = 0.019) that was independent of other Framingham risk score components. Findings from this study suggests that a relatively simple measure of redox balance such as the TAC/HPX ratio may be a sensitive indicator of redox stress, and may therefore serve as a useful biomarker for assessing an individual's specific NCD risk linked to unhealthy lifestyle practices.

Background: Uric acid (UA) has been suggested as a novel risk factor for diabetes. However, its definite role in this prevalent disease is still the subject of much discussion because it is always accompanied with other major risk factors such as obesity and high visceral adiposity. In order to clarify the role of UA in diabetes, this study aimed to investigate the associations between plasma UA and fasting plasma glucose, HbA1c, lipid profile and inflammatory markers after accounting for the contribution of other diabetes risk factors such as BMI and VAT fat mass., Methods: In the present cross-sectional study, 100 non-diabetic middle-aged males (n = 48) and females (n = 52) were recruited. Central fat distribution measures including android to gynoid fat ratio, VAT and subcutaneous adipose tissue (SAT) fat mass were determined using dual-energy X-ray absorptiometry (DXA). Biochemical analysis was done using methods well established for clinical and research laboratories. Multiple linear regression analysis was performed to analyse the association between plasma UA and the biochemical and central fat distribution measures., Results: UA was positivly associated with body mass index (BMI) (r (98) = 0.42, P ≤ 0.001), android to gynoid fat ratio (r (98) = 0.62, P ≤ 0.001) and VAT fat mass (r (96) = 0.55, P ≤ 0.001). UA was also positively associated with plasma glucose (r (98) = 0.33, P ≤ 0.001), hemoglobin A1c (r (93) = 0.25, P = 0.014), plasma triglyceride (r s (95) = 0.40, P ≤ 0.001), HDL cholesterol (r (98) = - 0.61, P ≤ 0.001) and CRP (r s (98) = 0.23, P = 0.026). However, these associations were no longer significant after accounting for BMI or/and VAT fat mass. No significant association was observed between UA and SAT fat mass (r (97) = 0.02, P ≥ 0.05), Total cholesterol (r (98) = 0.03, P ≥ 0.05), LDL cholesterol (r (98) = 0.13, P ≥ 0.05), TNF-α (r (97) = 0.12, P ≥ 0.05) and IL-6 (r (96) = -0.02, P ≥ 0.05)., Conclusion: Results from this study suggest, for the first time, that the association between plasma UA and glucose in a non-diabetic population is not direct but rather dependent on VAT fat mass.

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc., (© 2015 International Society for Autism Research, Wiley Periodicals, Inc.)

Aim: The purpose of this study was to assess the difference of removal torque values (RTV) and the bone-to-implant contact (BIC) between the sand-blasted, large grit, and acid-etched (SLA) surface-treated and the machined surface (MA) miniscrews., Material and Methods: Miniscrews used in this study were 6mm long with a diameter of 1.5mm. A total of 23 SLA miniscrews and 24 MA miniscrews were placed into the distal femoral condyle of 24 New Zealand rabbits. Removal torque test and the BIC was histologically evaluated at 0 and 8 weeks., Results: There was no statistical difference between the RTV in the MA group versus the SLA group at both 0 and 8 weeks. Comparing 0-8 weeks, there was no significant difference in RTV of the SLA group (P = 0.48), however the change in the MA group was statistically significant (P = 0.006). Histological observation showed a significant decrease in BIC comparing 0 and 8 weeks for the MA group. The BIC ratio at 8 weeks was statistically significantly higher in the SLA group compared to the MA group., Conclusion: SLA surface preparation does not increase the RTV of miniscrews. Further investigations under loading and a large sample size are required., (© The Author 2015. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR, (1)H NMR, (13)C NMR, (2)D NMR, DEPT, EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d, 1e, 2c, 2d, 2e) and the MAO-B (compounds 1a, 1b, 1c, 2a, 2b) isoforms. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The inhibition profile was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The autodock 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a, 1d, 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Excellent to good correlations between the calculated and experimental K(i) values were obtained. In the docking of the MAO-A complex, the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However, it binds slightly weaker (experimental K(i)=1.23 microM) to MAO-B than to MAO-A (experimental K(i)=4.22 nM).

In this study, the synthesis of twelve 3-(2-thienyl)pyrazoline derivatives are described. The structures of all compounds were confirmed by UV, IR, (1)H-NMR, mass spectral data, and microanalyses. In the pharmacological studies, antidepressant and anticonvulsant activities of these compounds have been screened. The antidepressant activities of the compounds were investigated by Porsolt's behavioral despair test (forced swimming) on albino mice and compared with tranylcypromine. Among the compounds examined, the compounds 9 and 12 showed significant antidepressant activity. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (metrazol) (scMet.) tests, neurotoxicities were determined by rotarod toxicity test on albino mice. Compound 8 was found to be protective against MES in the range of 30-300 mg/kg dose levels at four hours. None of the synthesized compounds showed neurotoxicity at 30-300 mg/kg dose levels.

The increasing life expectancy in our population makes Alzheimer's disease (AD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that monoamine oxidase-B (MAO-B) inhibitors and antiinflammatory agents might be effective in treating AD. Therefore, a novel series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole derivatives as promising MAO-B inhibitors was synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). Most of the synthesized compounds showed high activity against both the MAO-A (compounds 3e-3h) and the MAO-B (compounds 3i-3l) isoforms. All the synthesized compounds were also tested for their in vivo antiinflammatory activity by two different bioassays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were determined. The combined antiinflammatory data from in vivo animal models showed that compound 3k exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects. Since compound 3k exhibits both antiinflammatory-analgesic activity and MAO-B inhibition, it needs further detailed studies.

Twelve 1-phenyl-, 1-thiocarbamoyl- and 1-N-substituted thiocarbamoyl-3-(2-furyl)-5-phenyl/(2-furyl)-2-pyrazoline derivatives were synthesized. The chemical structures of the compounds were proved by IR, (1)H NMR, Mass spectrometric data and microanalyses. The antidepressant activities of the compounds were investigated by Porsolt's behavioural despair (forced swimming) test on albino mice. 1-N-Ethylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazoline (6) and 1-N-allylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (11) reduced 33.80-31.42% duration of immobility times at 10 mg kg(-1) dose level. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (metrazol) (scMet.) tests, neurotoxicities were determined by rotarod toxicity test on albino mice. 1,5-Diphenyl-3-(2-furyl)-2-pyrazoline (2), 1-N-allylthiocarbamoyl-3-(2-furyl)-5-phenyl-2-pyrazoline (7), 1-N-allylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (11) and 1-N-phenylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (12) were active at 100-300 mg kg(-1) dose levels. 1-Thiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (4), 1-N-methylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (9) and 1-N-ethylthiocarbamoyl-3,5-di(2-furyl)-2-pyrazoline (10) were found protective against MES and scMet. at 30-300 mg kg(-1) dose levels.

Elevated concentrations of sulfide in groundwater (approximately 63 mg S(2-)/L in water and 500 mg dissolved H2S/L dissipating from the wellhead) at a field site near South Lovedale (OK, USA) were inhibiting the activity of sulfate-reducing bacteria (SRB) that are known to degrade contaminants, including benzene, toluene, ethylbenzene, and xylenes. Elevated concentrations of these contaminants, except for toluene, also were present in this groundwater. Microcosms were established in the laboratory using groundwater and sediment collected from the field site and amended with various nutrient, substrate, and inhibitor treatments. All microcosms initially were amended with FeCl2 to induce FeS precipitation and, thereby, to reduce aqueous sulfide concentrations. Complete removal of benzene, ethylbenzene, and m+p-xylenes (BEX; o-xylene not detected) was observed within 39 d in treatments with various combinations of nutrient and substrate amendments, including treatments with no amendments (other than FeCl2). This indicates that the elevated concentration of sulfide is the only limiting factor to BEX biodegradation at this site under anaerobic conditions and that treating the groundwater with FeCl2 may be a simple remedy to both facilitate and enhance BEX degradation by the indigenous SRB population.

Interactions of twelve new synthesized 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-pyrolyl-2-pyrazoline derivatives with rat lung semicarbazide-sensitive amine oxidase (SSAO) were assessed. Pyrazoline derivatives were synthesized according to previous methods and SSAO was purified from the crude microsomal fractions of rat lung.Three compounds (3e, 3f, 3k) with a p-methoxy group at the phenyl ring inhibited rat lung SSAO non-competitively and irreversibly, and showed higher affinity towards SSAO when expressed in terms of IC(50) for SSAO/Monoamine oxidase B (MAO-B). Since these novel pyrazoline derivatives have been found to act as suicide inhibitors of SSAO, the semicarbazide group in these molecules may be responsible for the SSAO inhibitory action. It is suggested that these compounds cannot enter the first small active site cavity of SSAO and may interact tightly with another binding site or with some other reactive groups present in the molecule. Compound 3e showed the highest inhibitory activity on rat lung SSAO. The novel pyrazoline derivatives may be used to discriminate between Cu- and FAD-containing amine oxidases and may have promising features as anti-Parkinson agents if the SSAO-inhibitory effects can be supported by in vivo studies.

Heterotrophic respiration of ferric iron by Acidiphilium cryptum was investigated in anoxic microcosms with initial media pH values from 1.5 to 3.5. No organic carbon consumption or iron reduction was observed with an initial pH of 1.5, indicating that A. cryptum may not be capable of iron respiration at this pH. Significant iron reduction was observed at pH 2.5 and 3.5, with different effects. When the initial pH was 3.5, pH increased to 4.7-5.5 over 60 days of incubation with simultaneous production of 0.4 g L(-1) Fe2+. However, at an initial pH of 2.5, no significant change in pH was observed during iron respiration, although the accumulation of soluble ferrous iron was significantly higher, averaging 1.1 g L(-1) Fe2+. The speciation of the ferric iron electron acceptor may explain these results. At pH values of 3.5 and higher, precipitated ferric hydroxide Fe- (OH)3 would have been the primary source of ferric iron, with reduction resulting in net production of OH- ions and the significant increases in media pH observed. However at pH 2.5, soluble complexes, FeOH2+ and Fe(OH)2+, may have been the more prevalent electron acceptors, and the alkalinity generated by reduction of complexed iron was low. The existence of charged ferri-hydroxide complexes at pH 2.5 was verified by voltammetry. Results suggest that initiation of bacterial iron reduction may result in neutralization of acid mine drainage. However, this effect is extremely sensitive to iron speciation within a relatively small and critical pH range.

Twelve 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives were synthesized and their biological interactions with human plasma and erythrocyte acetylcholinesterase (AChE) and butrylcholinesterase (BuChE) enzymes were assessed. Compounds 3i-3l of newly synthesized N-substituted pyrazolines, which were presented as selective and irreversible MAO-B inhibitors in our previous report, were found to inhibit human erythrocyte and plasma AChE activities selectively and non-competitively suggesting that these compounds may interact with a region close to the peripheral site of the enzyme molecule which could shift the proper positioning of the catalytic center. Compounds 3e-3h inhibited both AChE and BuChE activities of human erythrocytes, but the inhibitory potencies of these compounds towards BuChE were found to be higher than that of towards AChE. Inhibition was found to be non-competitive and reversible. These data suggested that newly synthesized N-substituted pyrazoline derivatives can be evaluated as both MAO-B and cholinesterase inhibitors which may have promising features in the treatment of Alzheimer's and Parkinson's diseases.

Eighteen 1-phenyl-, 1-thiocarbamoyl- and 1-N-substitutedthiocarbamoyl-3-phenyl-5-heteroaryl-2-pyrazoline derivatives were synthesized and tested for their antidepressant and anticonvulsant activities. Their chemical structures were proved by spectral and microanalysis. The antidepressant activities of the compounds were investigated by the "forced swimming test". Results showed that compounds II-a, b, c, III-1b, 1c, 4a showed activities equivalent to or higher than pargyline hydrochloride (CAS 306-07-0) and tranylcypromine sulfate (CAS 13492-01-8) that were used as reference antidepressant drugs. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES), subcutaneous metrazol (ScMet.) and rotarod toxicity tests in mice according to the phase I tests of the Antiepileptic Drug Development programme. Compounds I-a, II-a, b, c, III-1b, 2a, 2c were found protective against MES and III-1b, 1c, 2a, 2c were found protective against ScMet.

The growth of acidophilic iron respiring bacteria at pH > 4.5 may be a key to the transition from acidic to circumneutral conditions that would occur during restoration of acid mine drainage sites. Flasks containing Acidiphilium cryptum ATCC 33463 were incubated initially under aerobic conditions in liquid medium containing Fe(2)(SO(4))(3) and glucose at an initial pH of 5. Significant iron respiration was observed after flasks were sealed to prevent oxygenation; at the same time, medium pH increased from 4.5 to 6. No soluble Fe(III) was detected throughout the experiments, consistent with pH conditions, indicating that bacteria were able to respire using precipitated ferric iron species. In addition, the concentration of soluble Fe(2+) reached a plateau, even though iron respiration appeared to continue, possibly due to precipitation of mixed Fe (II)/Fe(III)-oxide as magnetite. Results suggest that A. cryptum has a wide range of pH tolerance, which may enable it to play a role in controlling acid generation by means of establishing growth conditions favorable to neutrophilic bacteria such as sulfate reduction.

Twelve new 1-N-substituted thiocarbomoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives were synthesized and evaluated their for antidepressant, anxiogenic and mammalian monoamine oxidase (MAO)-A and Binhibitory activities by in vivo and in vitro tests. MAO was isolated and purified from the mitochondrial pellet of bovine liver homogenates and human platelets. All of the new compounds inhibited the total MAO activity of liver homogenates and the inhibition was found to be time-dependent. Four compounds (3 i-3 l) inhibited MAO-B selectively and irreversibly in a classical non-competitive manner with IC(50) values in the range of 22.00-91.50 microM. The rest of the compounds appeared to be non-selective reversible inhibitors. It was suggested that the p-methoxy group on the phenyl ring in the compounds increased the inhibitory effect and selectivity toward MAO-B. The reversible and unselective inhibition of MAO by the remaining compounds was suggested to be related to their properties of acting ability to act as both as substrate and inhibitor at the same time. However, none of the novel compounds showed antidepressant activity as expected suggesting formation of inactive metabolites. We conclude that the compounds appeared as which functioned as selective MAO-B inhibitors might have promising features as therapeutic properties in the treatment of Parkinson disease. In vivo studies are needed to verify this hypothesis.

Several 1-thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives have been synthesized by reacting 1,3-diphenyl-2-propen-1-one (chalcones) with thiosemicarbazide, or hydrazine hydrate and then with various isothiocyanates. Their chemical structures have been proven by UV, IR, 1H-NMR and elemental analysis. Antidepressant activities were investigated by "Porsolt's Behavioural Despair Test". 1-Thiocarbamoyl-3-(phenyl and 4-chlorophenyl-5-(4-methyl and 4-methoxyphenyl-2-pyrazoline (compounds III, IV, VII, VIII) and 3-(4-methylphenyl)-5-(4-methoxyphenyl)-2-pyrazoline (compound XII) showed equivalent or higher activity than pargyline hydrochloride and tranylcypromine sulfate.

Several 8-thiocarbamoyl-7,8-diazabicyclo[4.3.0]non-6-enes were prepared by condensing two alpha,beta-unsaturated ketones (2-benzylidene and 2,6-dibenzylidene cyclohexanones) with hydrazine hydrate and reacting the resulting compounds with various isothiocyanates. The structures of the synthesized compounds were confirmed by spectra (IR, 1H-NMR) and microanalysis; they were tested for antidepressant activity using Porsolt's behavioural despair test.

Ten new 3-(2-phenethyl)-5-substituted-tetrahydro-2H-1,3,5-thiadiazine-2- thiones were synthesized by the reaction of phenylethylamine with carbon disulfide and potassium hydroxide, followed by formaldehyde and appropriate amino acids. The structures of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. The antifungal activities of the compounds were tested by tube dilution method against yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) and minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values were determined. All compounds proved to be highly effective against yeast-like fungi (MFC range: 1.56-12.5 micrograms/ml).