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Abstract: A number of hydroxamic acid derivatives which inhibit human histone deacetylases were investigated for efficacy against cultured bloodstream form Trypanosoma brucei. Three out of the four classes tested displayed significant activity. The majority of compounds blocked parasite growth in the submicromolar range. The most potent was a member of the sulphonepiperazine series with an IC50 of 34nM. These results identify lead compounds with potential for the development of a novel class of trypanocidal agent. [Copyright &y& Elsevier]

The transient species formed following excitation of fac-[Re(CO)3(F2dppz)(py)]+(F2dppz = 11,12-difluorodipyrido[3,2-a:2′,3′-c]phenazine) bound to double-stranded polynucleotides [poly(dA-dT)]2or [poly(dG-dC)]2have been studied by transient visible and infra-red spectroscopy in both the picosecond and nanosecond time domains. The latter technique has been used to monitor both the metal complex and the DNA by monitoring the regions 1900–2100 and 1500–1750 cm−1respectively. These data provide direct evidence for electron transfer from guanine to the excited state of the metal complex, which proceeds both on a sub-picosecond time scale and with a lifetime of 35 ps, possibly due to the involvement of two excited states. No electron transfer is found for the [poly(dA-dT)]2complex, although characteristic changes are seen in the DNA-region TRIR consistent with changes in the binding of the bases in the intercalation site upon excitation of the dppz-complex. [ABSTRACT FROM AUTHOR]

The trypanocidal activity of the ODC (ornithine decarboxylase) inhibitor DFMO (difluoromethylornithine) has validated polyamine biosynthesis as a target for chemotherapy. As DFMO is one of only two drugs used to treat patients with late-stage African trypanosomiasis, the requirement for additional drug targets is paramount. Here, we report the biochemical properties of TbSpSyn (Trypanosoma brucei spermidine synthase), the enzyme immediately downstream of ODC in this pathway. Recombinant TbSpSyn was purified and shown to catalyse the formation of spermidine from putrescine and dcSAM (decarboxylated S-adenosylmethionine). To determine the functional importance of TbSpSyn in BSF (bloodstream form) parasites, we used a tetracycline-inducible RNAi (RNA interference) system. Down-regulation of the corresponding mRNA correlated with a decrease in intracellular spermidine and cessation of growth. This phenotype could be complemented by expressing the SpSyn (spermidine synthase) gene from Leishmania major in cells undergoing RNAi, but could not be rescued by addition of spermidine to the medium due to the lack of a spermidine uptake capacity. These results therefore genetically validate TbSpSyn as a target for drug development and indicate that in the absence of a functional biosynthetic pathway, BSF T. brucei cannot scavenge sufficient spermidine from their environment to meet growth requirements. [ABSTRACT FROM AUTHOR]

The synthesis of 3-phenylindenone (1a), 6-methoxy-3- phenylindenone (1b), 2-bromo-6-methoxy-3-phenylindenone (1c) and 2-ethoxycarbonyl-6-methoxy-3-phenylindenone (1d) is described using two methods - synthesis via indanone precursors and synthesis via propanedione precursors. Crystal structures of 2-bromo- 6-methoxy-3-phenylindanone, the synthetic precursor to 1b and 2-bromo-6-methoxy-3-phenylindenone were obtained. Preliminary photochemical studies showed that 1b dimerizes readily, but no transient species were detectable using ns-flash photolysis. [ABSTRACT FROM AUTHOR]

The synthesis of two new ‘first generation’ azobenzene based thymidine phosphoramidites 1 and 2 having the chromophore (DABCYL) covalently incorporated as an ester in the 3′-O- and 5′-O-positions of the deoxyribose, and the incorporation of these molecules into 16-mer Chronic Myeloid Leukaemia (CML) antisense oligonucleotides, giving 7 and 8, respectively, is described. These compounds were designed as highly coloured probes, and to participate in a Fluorescence Resonance Energy Transfer (FRET) mechanism in the design of novel molecular beacons. [Copyright &y& Elsevier]

Presents information on ultra-high molecular weight polyethylene (UHMWPE). Information on polymer synthesis; Viscometric measure of molecular weight; Details of UHMWPE powder processing.

Background: Depression is a leading cause of disability worldwide, and treatments could be more effective. Identifying methods to improve treatment success has the potential to reduce disease burden dramatically. Preparing or "priming" someone to respond more effectively to psychotherapy (e.g., cognitive behavioral therapy [CBT]) by preceding sessions with aerobic exercise, a powerful neurobiological activator, could enhance the success of the subsequently performed therapy. However, the success of this priming approach for increasing engagement of working mechanisms of psychotherapy (e.g., increased working alliance and behavioral activation) has yet to be formally tested. Methods: The CBT + trial will be a parallel-arm randomized controlled trial that will recruit 40 adult participants with DSM-5 diagnosed depression (verified with clinical interview) via referrals, mass emails, local flyers, and social media posts. Participants will be randomized to an ActiveCBT or CalmCBT condition. The ActiveCBT group will receive an 8-week CBT intervention primed with 30 min of moderate-intensity aerobic exercise (cycling on a stationary bike at a 13 rating of perceived exertion). The CalmCBT group will receive the same 8-week CBT intervention while resting for 30 min before CBT (i.e., cycling vs no cycling is the only difference). The primary outcome measures will be mean working alliance (assessed with the client version of the Working Alliance Inventory—Short Revised) and mean behavioral activation (self-reported Behavioral Activation for Depression Scale) recorded at each of the 8 therapy sessions. Secondary outcomes include evaluation of state anhedonia and serum brain-derived neurotrophic factor before the active/calm conditions, between the condition and therapy, and after the therapy. Additional exploratory analyses will evaluate group differences in algorithm-generated ratings of therapist-participant interactions via the Lyssn platform. Discussion: The novel approach of priming CBT with moderate-intensity aerobic exercise evaluated in a randomized controlled trial (CBT + trial) has the potential to demonstrate the usefulness of exercise as an augmentation strategy that improves working mechanisms of therapy and overall treatment outcomes for adults with depression. Trial registration: ClinicalTrials.gov NCT06001346. Registered on August 21, 2023. [ABSTRACT FROM AUTHOR]

Surf tourism authenticity has received limited theoretical attention. This study analyzed the surf tourism authenticity and its development by investigating Chinese tourists' online content using grounded theory modified by Corbin and Strauss. The findings concluded that surf tourism authenticity consists of objective and existential authenticity perceived by surf tourists. Objective authenticity is necessary for realizing existential authenticity, but passing the rite of struggle is a sufficient condition. Tourists' physical and mental competence are decisive factors that interactively determine whether or not they are able to pass the rite of struggle. This study contributes to the literature by (1) introducing authenticity to depict the surf tourism experience; (2) highlighting the importance of objective authenticity alongside existential authenticity for understanding surf tourism authenticity and discussing these two elements from a holistic perspective; and (3) proposing the rite of struggle to promote a better understanding of the relationship between two authenticities. [ABSTRACT FROM AUTHOR]

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents. [ABSTRACT FROM AUTHOR]

Trypanothione reductase is thought to be important in maintaining an intracellular reducing environment in trypanosomatids. To investigate the role of trypanotione reductase we transfected Leishmania donovani and Trypanosoma cruzi with an expression vector containing the L. donovani trypanothione reductase gene and achieved over-expression of enzyme activity (10–14-fold) in transformed cells. Following treatment of L. donovani cells with the thiol-oxidizing agent diamide, the ability to regenerate dihydrotrypanothione from trypanothione disulphide was considerably enhanced in cells which over-expressed trypanothione reductase. However, the growth of transformed and control cells was equally sensitive to inhibition by nifurtimox, nitrofurazone and gentian violet, drugs that are thought to act by inducing oxidative damage. Likewise, growth of transformed and control cells were equally susceptible to inhibition by hydrogen peroxide, and control and transformed L. donovani promastigotes metabolized hydrogen peroxide at comparable rates. Thus, these experiments suggest that the ability to regenerate dihydrotrypanothione from trypanothione disulphide is not a rate-limiting step in the metabolism of hydrogen peroxide. [ABSTRACT FROM AUTHOR]

The extent and kinetics of induction have been determined for eight mRNAs induced by α- and γ-interferons in HeLa cells. The mRNAs which code for a 2-5A synthetase, metallothionien II, HLA class I antigen and five unknown proteins were induced 2 - > 100-fold by α-interferons. In the continued presence of α-interferon some mRNAs were maintained at the induced levels until at least 40 h, whereas others were induced only transiently. When the effects of α- and γ-interferons were compared, the induced levels and kinetics were very similar for one mRNA (1-8) but were significantly different for the others. One mRNA (6-16) was induced more than 100-fold by α-interferon but not significantly by γ-interferon. Parallel analysis of the level of c-myc mRNA showed it to decrease twofold in response to α-interferon, but to increase more than threefold in response to γ-interferon, despite a more profound inhibition of cell growth by the latter. There must, therefore, be differences in how the levels of different mRNAs are sustained by α-interferons and how α- and γ-interferons regulate the levels of the same mRNAs. [ABSTRACT FROM AUTHOR]

Cruzipain, the major cysteine proteinase of Trypanasoma cruzi has been proposed as a target for chemotherapy against Chagas' disease. To investigate the role of cruzipain we transfected T. cruzi epimastigotes with a recombinant cosmid containing approximately 20 tandemly repeated cruzipain genes. Transformed cells had multiple episomal copies of the vector and exhibited considerable overexpression of cruzipain activity. The upregulation was maintained throughout the parasite life-cycle, and electrophoretic detection techniques indicated that overexpression was correlated with correctly processed enzyme. Immunoelectron microscopy demonstrated that cruzipain had the same developmentally regulated subcellular localisation in transformed and non-transformed cells, in the insect epmastigote form, the enzyme was restricted to vesicles of the endosomal/Iysosomal system, whereas in the intracellular forms it was also readily detectable on the cell surface. Phenotypic analysis of the transformed parasites showed that they had an enhanced ability to undergo metacyclogenesis and suggested an association between overexpression of cruzipain and increased resistance to the cysteine proteinase inhibitor Cbz-Phe-Phe-CHN2 (where Cbz is benzoyloxycarbonyl). The increased resistance, however, was less than might be expected if cruzipain was the primary target of the inhibitor. Transgenic parasites did not exhibit increased infectivity. [ABSTRACT FROM AUTHOR]

A Leishmania donovani promastigote cDNA library was screened with serum obtained from a patient infected with visceral leishmaniasis. Sequence analysis of a clone obtained from this library revealed that the 600-bp insert corresponded to the carboxy-terminal region of an antigen related to the 70-kDa heat-shock protein family. The full-length sequence of the corresponding gene (1959 nucleotides) was determined after isolation of genomic clones. Genes encoding the antigen are present on a single chromosome as a series of approximately twelve 3.7- kb direct tandem repeats. The antigen can be identified as a 70-kDa heat-shock cognate protein by virtue of its molecular mass, sequence and constitutive expression during heat shock. It is expressed at all stages of the parasite life-cycle. Antibodies against the Agt11 fusion protein were detected in more than 50% of serum samples obtained from patients with visceral leishmaniasis, but were not detected in sera from patients with cutaneous leishmaniasis or Chagas' disease. [ABSTRACT FROM AUTHOR]

The EXCEL™ VR, an accelerometer-based pacemaker (AC), and the Leg-end™, a pacemaker utilizing a piezoelectric crystal (PZ), were compared under ergometric conditions and during stair climbing to assess the appropriateness of their rate responses. The pacemakers, programmed to the manufacturers' nominal settings in order to compare different technologically based sensors under identical conditions, were strapped over subjects' left mid-pectoral region. Placement of the devices was randomized to control for positional effects. Ten healthy subjects (55–72 years) completed a graded exercise treadmill test to 80% of maximum predicted heart rate (HR). An additional group of ten subjects (50–66 years) completed exercise protocols involving bicycle ergometry and stair climbing. Throughout all tests, pacemaker pulse rates and subjects' intrinsic HR were monitored continuously. For the treadmill exercise, the average correlations between the AC and PZ pacemakers' pulse rate and HR for the group as a whole were r = 0.92 and r = 0.82, respectively. Individual subject comparisons were also made between each pacemaker rate and intrinsic HR. The mean difference from intrinsic rate was 11 ppm for the AC pacemaker and 24 ppm for the PZ pacemaker. In addition, the PZ pacemaker's maximal pulse rate was significantly lower (105 ± 9.6 ppm) than the other two rates (AC 137 ± 6 ppm; intrinsic HR 129 ± 2 beats/min). Throughout the bicycle ergometry testing, the intrinsic HR was higher than the AC and PZ pacing rates. However, the AC's rate was significantly higher than the PZ's rate. When subjects ascended stairs, the intrinsic HR and AC rote were closely correlated, but the PZ rate was significantly lower. When subjects descended stairs, neither pacemaker's rate matched intrinsic HR. These results indicate that the AC pacemaker more closely matches intrinsic HR in healthy subjects during ergometric activity and stair climbing than does the PZ pacemaker. Although the three activities evaluated in this study may be lacking representation of other common daily tasks, these results do lend support for considering the use of an AC pacemaker. These data also suggest the need for further research using activity-based rate-responsive pacemakers after parameter optimization for each subject to address issues of sensitivity to and specificity of human movement. [ABSTRACT FROM AUTHOR]