A new electrochemical method for the determination of chondroitin sulfate based on its supramolecular interaction with cupferron-lead(II) complex

In this paper, the interaction of cupferron (Cup) and lead (II) complex [Cup-Pb (II)] with chondroitin sulfate (CS) was investigated by linear sweep voltammetric method. In the selected medium of pH 5.5 (acetic acid-hexamine buffer solution), Cup can interact with Pb (II) to form a stable complex of [Cup-Pb(II)], which has a sensitive second order derivative polarographic reductive peak at -0.64V (vs.SCE). After the addition of CS into Cup-Pb (II) complex solution, the reductive peak current decreased without any shift of the peak potential and no new peak appeared, which indicated that an unelectroactive supramolecular complex of CS with [Cup-Pb(II)] was formed. The binding reaction conditions were carefully investigated. Under the optimal conditions, the interaction mechanism was discussed. The decrease of reductive peak current was directly proportional to the CS concentration, thus a new quantitative determination method for CS was established with the linear regression equation as ΔIp″(nA)=36.97 C/mg L-1+12.45 (n=10, γ=0.995). The effects of other substances on the determination were carefully investigated and three synthetic samples were determined with satisfactory results. The binding constant (βs) and the binding number (m) of CS with [Cup-Pb(II)] complex were calculated from the voltammetric data with the results as βs=1.89×1010 and m≈2.5

Identification of novel <i>Pf</i>DHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and <i>in vivo</i> antimalarial activity

<p><i>Plasmodium falciparum</i> dihydroorotate dehydrogenase (<i>Pf</i>DHODH) catalyses the fourth reaction of <i>de novo</i> pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known <i>Pf</i>DHODH inhibitors using the GALAHAD module with IC₅₀ values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere–Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a Q_FIT value of more than 81 were docked in the <i>Pf</i>DHODH enzyme to further explore the binding modes of these compounds. <i>In silico</i> pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated <i>in vivo</i> for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.</p

Phenotypically adapted Mycobacterium tuberculosis populations from sputum are tolerant to first line drugs

Tuberculous sputum contains multiple Mycobacterium tuberculosis (Mtb) populations with different requirements for isolation in vitro. These include cells forming colonies on solid media (platable Mtb), cells requiring standard liquid medium for growth (non-platable Mtb), and cells requiring supplementation of liquid medium with culture supernatant for growth (SN-dependent Mtb). Here we describe protocols for the cryopreservation and direct assessment of antimicrobial tolerance of these Mtb populations within sputum. Our results show that first line drugs achieved only modest cidal effects on all three populations over 7 days (1-2.5xlog10 reductions) and SN-dependent Mtb were more tolerant to streptomycin and isoniazid compared to platable and non-platable Mtb. Susceptibility of platable Mtb to bactericidal drugs was significantly increased after passage in vitro, thus tolerance observed in the sputum populations was likely associated with mycobacterial adaptation to the host environment at some time prior to expectoration. Our findings support the use of a simple ex vivo system for testing drug efficacies against mycobacteria phenotypically adapted during tuberculosis infection

Systemic and pulmonary inflammation is independent of skeletal muscle changes in patients with chronic obstructive pulmonary disease

BACKGROUND: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. OBJECTIVES: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. METHODS: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m(2) and/or fat-free mass index (FFMI) less than 15 or 17 kg/m(2) in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. RESULTS: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics. CONCLUSION: Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD

The level of BCR-ABL1 kinase activity before treatment does not identify CML patients who fail to achieve a complete cytogenetic response on Imatinib

Imatinib is currently the first line therapy for newly diagnosed patients with chronic myeloid leukemia. However, 20–25% of patients do not achieve durable complete cytogenetic responses. The mechanism underlying this primary resistance is unknown, but variations in BCR-ABL1 kinase activity may play a role and can be investigated by measuring the autophosphorylation levels of BCR-ABL1 or of a surrogate target such as Crkl. In this study we used flow cytometry to investigate the in vitro inhibition of Crkl phosphorylation by imatinib in CD34+ cells in diagnostic samples from two groups of patients distinguished by their cytogenetic response. No difference in inhibition of Crkl phosphorylation was observed in the two groups. The observation that increasing the dose of imatinib in vivo did not increase the level of cytogenetic response in some non-responders suggests that in at least a proportion of patients imatinib resistance may be due to activation of BCR-ABL1-independent pathway

Cold dust and young starbursts: spectral energy distributions of Herschel SPIRE sources from the HerMES survey

We present spectral energy distributions (SEDs) for 68 Herschel sources detected at 5σ at 250, 350 and 500 μm in the HerMES SWIRE-Lockman field. We explore whether existing models for starbursts, quiescent star-forming galaxies and active galactic nucleus dust tori are able to model the full range of SEDs measured with Herschel. We find that while many galaxies (∼56 per cent) are well fitted with the templates used to fit IRAS, Infrared Space Observatory (ISO) and Spitzer sources, for about half the galaxies two new templates are required: quiescent (‘cirrus’) models with colder (10–20 K) dust and a young starburst model with higher optical depth than Arp 220. Predictions of submillimetre fluxes based on model fits to 4.5–24 μm data agree rather poorly with the observed fluxes, but the agreement is better for fits to 4.5–70 μm data. Herschel galaxies detected at 500 μm tend to be those with the highest dust masses

The Herschel Multi-Tiered Extragalactic Survey: source extraction and cross-identifications in confusion-dominated SPIRE images

We present the cross-identification and source photometry techniques used to process Herschel SPIRE imaging taken as part of the Herschel Multi-Tiered Extragalactic Survey (HerMES). Cross-identifications are performed in map-space so as to minimize source-blending effects. We make use of a combination of linear inversion and model selection techniques to produce reliable cross-identification catalogues based on Spitzer MIPS 24-μm source positions. Testing on simulations and real Herschel observations shows that this approach gives robust results for even the faintest sources (S250∼ 10 mJy). We apply our new technique to HerMES SPIRE observations taken as part of the science demonstration phase of Herschel. For our real SPIRE observations, we show that, for bright unconfused sources, our flux density estimates are in good agreement with those produced via more traditional point source detection methods (SUSSEXtractor) by Smith et al. When compared to the measured number density of sources in the SPIRE bands, we show that our method allows the recovery of a larger fraction of faint sources than these traditional methods. However, this completeness is heavily dependent on the relative depth of the existing 24-μm catalogues and SPIRE imaging. Using our deepest multiwavelength data set in the GOODS-N, we estimate that the use of shallow 24-μm catalogues in our other fields introduces an incompleteness at faint levels of between 20–40 per cent at 250 μm