Lack of effects of statins on high-density lipoprotein subfractions in HIV-1-infected patients receiving protease inhibitors

Background

We evaluated the effect of 45 days of rosuvastatin or pravastatin treatment on the distribution of HDL subfractions in HIV-1-infected individuals receiving boosted protease inhibitors (PIs) with cardiovascular risk.

Effects of human land use on the terrestrial and aquatic sources of fluvial organic matter in a temperate river basin (The Meuse River,Belgium)

The impact of human activities on the concentrations and composition of dissolved organic matter (DOM) and particulate organic matter (POM) was investigated in the Walloon Region of the Meuse River basin (Belgium). Water samples were collected at different hydrological periods along a gradient of human disturbance (50 sampling sites ranging from 8.0 to 20,407 km²) and during a 1.5 year monitoring of the Meuse River at the city of Liège. This dataset was completed by the characterization of the DOM pool in groundwaters. The composition of DOM and POM was investigated through elemental (C:N ratios), isotopic (δ¹³C) and optical measurements including excitation emission matrix fluorescence with parallel factor analysis (EEM–PARAFAC). Land use was a major driver on fluvial OM composition at the regional scale of the Meuse Basin, the composition of both fluvial DOM and POM pools showing a shift toward a more microbial/algal and less plant/soil-derived character as human disturbance increased. The comparison of DOM composition between surface and groundwaters demonstrated that this pattern can be attributed in part to the transformation of terrestrial sources by agricultural practices that promote the decomposition of soil organic matter in agricultural lands and subsequent microbial inputs in terrestrial sources. In parallel, human land had contrasting effects on the autochthonous production of DOM and POM. While the in-stream generation of fresh DOM through biological activity was promoted in urban areas, summer autochthonous POM production was not influenced by land use. Finally, soil erosion by agricultural management practices favored the transfer of terrestrial organic matter via the particulate phase. Stable isotope data suggest that the hydrological transfer of terrestrial DOM and POM in human-impacted catchment are not subject to the same controls, and that physical exchange between these two pools of organic matter is limited.     

Fine-tuning of actin dynamics by the HSPB8-BAG3 chaperone complex facilitates cytokinesis and contributes to its impact on cell division

The small heat shock protein HSPB8 and its co-chaperone BAG3 are proposed to regulate cytoskeletal proteostasis in response to mechanical signaling in muscle cells. Here, we show that in dividing cells, the HSPB8-BAG3 complex is instrumental to the accurate disassembly of the actin-based contractile ring during cytokinesis, a process required to allow abscission of daughter cells. Silencing of HSPB8 markedly decreased the mitotic levels of BAG3 in HeLa cells, supporting its crucial role in BAG3 mitotic functions. Cells depleted of HSPB8 were delayed in cytokinesis, remained connected via a disorganized intercellular bridge, and exhibited increased incidence of nuclear abnormalities that result from failed cytokinesis (i.e., bi- and multi-nucleation). Such phenotypes were associated with abnormal accumulation of F-actin at the intercellular bridge of daughter cells at telophase. Remarkably, the actin sequestering drug latrunculin A, like the inhibitor of branched actin polymerization CK666, normalized F-actin during cytokinesis and restored proper cell division in HSPB8-depleted cells, implicating deregulated actin dynamics as a cause of abscission failure. Moreover, this HSPB8-dependent phenotype could be corrected by rapamycin, an autophagy-promoting drug, whereas it was mimicked by drugs impairing lysosomal function. Together, the results further support a role for the HSPB8-BAG3 chaperone complex in quality control of actin-based structure dynamics that are put under high tension, notably during cell cytokinesis. They expand a so-far under-appreciated connection between selective autophagy and cellular morphodynamics that guide cell division.     

Computational model of airway narrowing: mature vs. immature rabbit.

Immature rabbits have greater maximal airway narrowing and greater maximal fold increases in airway resistance during bronchoconstriction than mature animals. We have previously demonstrated that excised immature rabbit lungs have more distensible airways, a lower shear modulus, and structural differences in the relative composition and thickness of anatomically similar airways. In the present study, we incorporated anatomic and physiological data for mature and immature rabbits into a computational model of airway narrowing. We then investigated the relative importance of maturational differences in these factors as determinants of the greater airway narrowing that occurs in the immature animal. The immature model demonstrated greater sensitivity to agonist, as well as a greater maximal fold increase in airway resistance. Exchanging values for airway compliance between the mature and immature models resulted in the mature model exhibiting a greater maximal airway response than the immature model. In contrast, exchanging the shear moduli or the composition of the airway wall relative to the airway size produced relatively small changes in airway reactivity. Our results strongly suggest that the mechanical properties of the airway, i.e., greater compliance of the immature airway, can be an important factor contributing to the greater airway narrowing of the immature animal.     

Effect of NHS walk-in centre on local primary healthcare services: before and after observational study

ObjectiveTo assess the effect of an NHS walk-in centre on local primary and emergency healthcare services.DesignBefore and after observational study.SettingLoughborough, which had an NHS walk-in centre, and Market Harborough, the control town.Participants12 general practices.ResultsThe change between the before and after study periods was not significantly different in the two towns for daily rate of emergency general practice consultations (mean difference −0.02/1000 population, 95% confidence interval −0.75 to 0.71), the time to the sixth bookable routine appointment (−0.24 half-days, −1.85 to 1.37), and daily rate of attendances at out of hours services (0.07/1000 population, −0.06 to 0.19). However, attendance at the local minor injuries unit was significantly higher in Loughborough than Market Harborough (rate ratio 1.22, 1.12 to 1.33). Non-ambulance attendances at accident and emergency departments fell less in Loughborough than Market Harborough (rate ratio 1.17, 1.03 to 1.33).ConclusionsThe NHS walk-in centre did not greatly affect the workload of local general practitioners. However, the workload of the local minor injuries unit increased significantly, probably because it was in the same building as the walk-in centre.

What is already known on this topic

Walk-in centres are well established in North America but differ from NHS centres as they are run by doctors not nurses

What this study adds

Introduction of an NHS walk-in centre did not affect the workload of local general practitionersAttendance increased at the minor injuries unit, which was in the same buildingNon-ambulance attendances at accident and emergency departments decreased but not by as much as in the control area     

Cellular determinants of the mutational specificity of 1-nitroso-6-nitropyrene and 1-nitroso-8-nitropyrene in the lacI gene of Escherichia coli.

We have characterized 202 lacI⁻ mutations, and 158 dominant lacI^−d mutations following treatment of Escherichia coli strains NR6112 and EE125 with 1-nitroso-6-nitropyrene (1,6-NONP), an activated metabolite of the carcinogen 1,6-dinitropyrene. In all, 91% of the induced point mutations occurred at G:C residues. The −(G:C) frameshifts were the dominant mutational class in the lacI⁻ collections of both NR6112 and EE125, and in the lacI^−d collection of NR6112. Frameshift mutations occurred preferentially in runs of guanine residues, and their frequency increased with the length of the reiterated sequence. In strain EE125, which contained the plasmid pKM101, there was a marked stimulation in the frequency of base substitution mutations that was particularly apparent in the lacI^−d collection. This study completes a comprehensive analysis of 1194 lacI⁻ and 348 lacI^−d mutations induced by either 1,6-NONP or its positional isomer 1-nitroso-8-nitropyrene (1,8-NONP) in strains of E. coli that differ with regard to their ability to carry out nucleotide excision repair and/or their ability to express the translesion synthesis DNA polymerase RI (MucAB) encoded by plasmid pKM101. Among the mutations are 763 frameshift mutations, 367 base substitutions and 47 deletions; these mutations have been characterized at more than 300 distinct sites in the lacI gene. Our studies provide detailed insight into the DNA sequence alterations and mutational mechanisms associated with dinitropyrene mutagenesis. We review the mutational spectra, and discuss cellular lesion repair or tolerance mechanisms that modulate the observed mutational specificity.     

DNA alkylation and formation of DNA interstrand cross-links by potential antitumour 2,5-bis(1-aziridinyl)-1,4-benzoquinones

A series of 3,6-substituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone derivatives was shown to alkylate calf thymus DNA and to form DNA interstrand cross-links. Alkylation and cross-link formation were enhanced after electrochemical reduction of the compounds and increased with lower pH in the pH range from 4.5 to 8.0. Reduction especially shifts the pH at which cross-linking and alkylation occurs to higher values, which are more physiologically relevant. This shift is probably caused by the increase in pK_a value of the aziridine ring after reduction of the quinone moiety. The inactivation of single-stranded bacteriophage M13mp19 DNA to form phages in an E. coli host, by the 3,6-unsubstituted parent compound 2,5-bis(1-aziridinyl)-1,4-benzoquinone (TW13) was dependent upon reduction and pH in a similar way as was alkylation. The compound in our series with the least bulky, 3,6-substitutents, TW13, caused a high amount of cross-link formation. Compounds with methyl-substituted aziridine rings showed low cross-linking ability. Our results support the concept that the protonated reduced compound is the reactive species that alkylates DNA, and that steric factors play an important role in the reactivity towards DNA. A correlation is observed between the ability to induce DNA interstrand cross-links and inactivation of M13mp19 bacteriophage DNA. Cross-link formation was also demonstrated in E. coli K12 cells, where the compounds are reduced endogenously by bacterial reductases.