Resistance training enhances the stability of sensorimotor coordination

Strategics for the control of human movement are constrained by the neuroanatomical characteristics of the motor system. In particular, there is evidence that the capacity of muscles for producing force has a strong influence on the stability of coordination in certain movement tasks. In the present experiment, our aim was to determine whether physiological adaptations that cause relatively long-lasting changes in the ability of muscles to produce force can influence the stability of coordination in a systematic manner. We assessed the effects of resistance training on the performance of a difficult coordination task that required participants to synchronize or syncopate movements of their index finger with an auditory metronome. Our results revealed that training that increased isometric finger strength also enhanced the stability of movement coordination. These changes were accompanied by alterations in muscle recruitment patterns. In Particular, the trained muscles were recruited in a more consistent fashion following the programme of resistance training. These results indicate that resistance training produces functional adaptations of the neuroanatomical constraints that underlie the control of voluntary movement.

Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

Constitutive activation of nuclear factor (NF)-kappa B is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-kappa B whose expression is elevated in AIPC. This study sought to determine the significance of CXCL8 signaling in regulating the response of AIPC cells to oxaliplatin, a drug whose activity is reportedly sensitive to NF-kappa B activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-kappa B activity, promoting antiapoptotic gene transcription. In addition, oxaliplatin increased the transcription and secretion of CXCL8 and the related CXC-chemokine CXCL1 and increased the transcription and expression of CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which transduces the biological effects of CXCL8 and CXCL1. Stimulation of AIPC cells with CXCL8 potentiated NF-kappa B activation in AIPC cells, increasing the transcription and expression of NF-kappa B-regulated antiapoptotic genes of the Bcl-2 and IAP families. Coadministration of a CXCR2-selective antagonist, AZ10397767 (Bioorg Med Chem Lett 18:798-803, 2008), attenuated oxaliplatin-induced NF-kappa B activation, increased oxaliplatin cytotoxicity, and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological inhibition of NF-kappa B or RNA interference-mediated suppression of Bcl-2 and survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results further support NF-kappa B activity as an important determinant of cancer cell sensitivity to oxaliplatin and identify the induction of autocrine CXCR2 signaling as a novel mode of resistance to this drug.

ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.

Resistance mechanisms to cancer chemotherapy

Resistance to chemotherapy ('drug resistance') is a fundamental problem that limits the effectiveness of many chemotherapies currently used to treat cancer. Drug resistance can occur due to a variety of mechanisms, such as increased drug inactivation, drug efflux from cancer cells, enhanced repair of chemotherapy-induced damage, activation of pro-survival pathways and inactivation of cell death pathways. In this article, we review some of the major mechanisms of drug resistance and discuss how new molecularly-targeted therapies are being increasingly used to overcome these resistance mechanisms.

Overexpression of the rhamnose catabolism regulatory protein, RhaR: a novel mechanism for metronidazole resistance in Bacteroides thetaiotaomicron

Objectives: The aim of the investigation was to use in vitro transposon mutagenesis to generate metronidazole resistance in the obligately anaerobic pathogenic bacterium Bacteroides thetaiotaomicron, and to identify the genes involved to enable investigation of potential mechanisms for the generation of metronidazole resistance.
Methods: The genes affected by the transposon insertion were identified by plasmid rescue and sequencing. Expression levels of the relevant genes were determined by semi-quantitative RNA hybridization and catabolic activity by lactate dehydrogenase/pyruvate oxidoreductase assays.
Results: A metronidazole-resistant mutant was isolated and the transposon insertion site was identified in an intergenic region between the rhaO and rhaR genes of the gene cluster involved in the uptake and catabolism of rhamnose. Metronidazole resistance was observed during growth in defined medium containing either rhamnose or glucose. The metronidazole-resistant mutant showed improved growth in the presence of rhamnose as compared with the wild-type parent. There was increased transcription of all genes of the rhamnose gene cluster in the presence of rhamnose and glucose, likely due to the transposon providing an additional promoter for the rhaR gene, encoding the positive transcriptional regulator of the rhamnose operon. The B. thetaiotaomicron metronidazole resistance phenotype was recreated by overexpressing the rhaR gene in the B. thetaiotaomicron wild-type parent. Both the metronidazole-resistant transposon mutant and RhaR overexpression strains displayed a phenotype of higher lactate dehydrogenase and lower pyruvate oxidoreductase activity in comparison with the parent strain during growth in rhamnose.
Conclusions: These data indicate that overexpression of the rhaR gene generates metronidazole resistance in B. thetaiotaomicron

Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects.

The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14+ monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14+ monocytes was significantly higher in ESN compared with SP (P=0.028) or USN (P=0.007), as well as in SP compared with USN subjects (P=0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8+ T cell counts in HAART-naïve SP subjects (r=0.7, P=0.015). Increased surface expression of CD91 on CD14+ monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.

Low-fat versus low-carbohydrate weight reduction diets:Effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial

OBJECTIVE Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.

RESEARCH DESIGN AND METHODS We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.

RESULTS Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.

CONCLUSIONS This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers

Background and aims

Public health campaigns recommend increased fruit and vegetable (FV) consumption as an effective means of cardiovascular risk reduction. During an 8 week randomised control trial among hypertensive volunteers, we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption. Circulating indices of inflammation, endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health. The responses of several such biomarkers to our previously described FV intervention are reported here.
Methods and results

Hypertensive volunteers were recruited from medical outpatient clinics. After a common 4 week run-in period during which FV consumption was limited to 1 portion per day, participants were randomised to 1, 3 or 6 portions daily for 8 weeks. Venous blood samples for biomarker analyses were collected during the pre and post-intervention vascular assessments. A total of 117 volunteers completed the 12 week study. Intervention-related changes in circulating levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) did not differ significantly between FV groups. Similarly, there were no significant between group differences of change in homeostasis model assessment (HOMA) scores.
Conclusions

Despite mediating a significant improvement in acetylcholine induced vasodilatation, increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study. Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials.

Chemotherapy-Induced Activation of ADAM-17: A Novel Mechanism of Drug Resistance in Colorectal Cancer

Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.

Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.

Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-a, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.

Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC.

mVps34 is activated following high-resistance contractions

Following resistance exercise in the fasted state, both protein synthesis and degradation in skeletal muscle are increased. The addition of essential amino acids potentiates the synthetic response suggesting that an amino acid sensor, which is involved in both synthesis and degradation, may be activated by resistance exercise. One such candidate protein is the class 3 phosphatidylinositol 3OH-kinase (PI3K) Vps34. To determine whether mammalian Vps34 (mVps34) is modulated by high-resistance contractions, mVps34 and S6K1 (an index of mTORC1) activity were measured in the distal hindlimb muscles of rats 0.5, 3, 6 and 18 h after acute unilateral high-resistance contractions with the contralateral muscles serving as a control. In the lengthening tibialis anterior (TA) muscle, S6K1 (0.5 h = 366.3 +/- 112.08%, 3 h = 124.7 +/- 15.96% and 6 h = 129.2 +/- 0%) and mVps34 (3 h = 68.8 +/- 15.1% and 6 h = 36.0 +/- 8.79%) activity both increased, whereas in the shortening soleus and plantaris (PLN) muscles the increase was significantly lower (PLN S6K1 0.5 h = 33.1 +/- 2.29% and 3 h = 47.0 +/- 6.65%; mVps34 3 h = 24.5 +/- 7.92%). HPLC analysis of the TA demonstrated a 25% increase in intramuscular leucine concentration in rats 1.5 h after exercise. A similar level of leucine added to C2C12 cells in vitro increased mVps34 activity 3.2-fold. These data suggest that, following high-resistance contractions, mVps34 activity is stimulated by an influx of essential amino acids such as leucine and this may prolong mTORC1 signalling and contribute to muscle hypertrophy.

Can the protein costs of bacterial resistance be offset by altered feeding behaviour?

1. Mounting an immune response is likely to be costly in terms of energy and nutrients, and so it is predicted that dietary intake should change in response to infection to offset these costs. The present study focuses on the interactions between a specialist grass-feeding caterpillar species, the African armyworm Spodoptera exempta, and an opportunist bacterium, Bacillus subtilis.
2. The main aims of the study were (i) to establish the macronutrient costs to the insect host of surviving a systemic bacterial infection, (ii) to determine the relative importance of dietary protein and carbohydrate to immune system functions, and (iii) to determine whether there is an adaptive change in the host's normal feeding behaviour in response to bacterial challenge, such that the nutritional costs of resisting infection are offset.
3. We show that the survival of bacterially infected larvae increased with increasing dietary protein-to-carbohydrate (P:C) ratio, suggesting a protein cost associated with bacterial resistance. As dietary protein levels increased, there was an increase in antibacterial activity, phenoloxidase (PO) activity and protein levels in the haemolymph, providing a potential source for this protein cost. However, there was also evidence for a physiological trade-off between antibacterial activity and phenoloxidase activity, as larvae whose antibacterial activity levels were elevated in response to immune activation had reduced PO activity.
4. When given a choice between two diets varying in their P:C ratios, larvae injected with a sub-lethal dose of bacteria increased their protein intake relative to control larvae whilst maintaining similar carbohydrate intake levels. These results are consistent with the notion that S. exempta larvae alter their feeding behaviour in response to bacterial infection in a manner that is likely to enhance the levels of protein available for producing the immune system components and other factors required to resist bacterial infections (‘self-medication’).

Contemporary Radio Art and Spatial Politics: The Critical Radio Utopias of Anna Friz

The article explores the work of the Canadian sound artist Anna Friz over the last decade. Her work deals explicitly with issues of technology and the relative absence of women's voices on radio. Exploring her work as a composer, installation artist, instrumentalist, performance artist and storyteller, and contextualising these practices within feminist critiques and radio conventions, the article explores Friz's ‘self-reflexive radio’. Ideas of ‘supermodernity’, ‘displacement’ and ‘critical utopia’ are deployed to discuss specific pieces of Friz's work in relation to identity and space. The article argues that Friz reconfigures the radio as a site of resistance to dominant constructions of contemporary globalised space and cultures, the politics of informational capitalism and the uneven flows that these cultures and politics engender.

Abrasive wear resistance of electroless Ni-P coated aluminium after post treatment

Electroless nickel (EN) coatings are recognised for their hardness and wear resistance in automotive and aerospace industries. In this work, electroless Ni–P coatings were deposited on aluminium alloy substrate LM24 (Al–9 wt.% Si alloy) and the effect of post treatment on the wear resistance was studied. The post treatments included heat treatment and lapping with two different surface textures. Scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), X-ray diffraction (XRD) and micro-abrasion tester were used to analyse morphology, structure and abrasive wear resistance of the coatings. Post heat treatment significantly improved the coating density and structure, giving rise to enhanced hardness and wear resistance. Microhardness of electroless Ni–P coatings with thickness of about 15 μm increased due to the formation of Ni3P after heat treatment.

Hopanoid Production Is Required for Low-pH Tolerance, Antimicrobial Resistance, and Motility in Burkholderia cenocepacia

Hopanoids are pentacyclic triterpenoids that are thought to be bacterial surrogates for eukaryotic sterols, such as cholesterol, acting to stabilize membranes and to regulate their fluidity and permeability. To date, very few studies have evaluated the role of hopanoids in bacterial physiology. The synthesis of hopanoids depends on the enzyme squalene-hopene cyclase (Shc), which converts the linear squalene into the basic hopene structure. Deletion of the 2 genes encoding Shc enzymes in Burkholderia cenocepacia K56-2, BCAM2831 and BCAS0167, resulted in a strain that was unable to produce hopanoids, as demonstrated by gas chromatography and mass spectrometry. Complementation of the Delta shc mutant with only BCAM2831 was sufficient to restore hopanoid production to wild-type levels, while introducing a copy of BCAS0167 alone into the Delta shc mutant produced only very small amounts of the hopanoid peak. The Delta shc mutant grew as well as the wild type in medium buffered to pH 7 and demonstrated no defect in its ability to survive and replicate within macrophages, despite transmission electron microscopy (TEM) revealing defects in the organization of the cell envelope. The Delta shc mutant displayed increased sensitivity to low pH, detergent, and various antibiotics, including polymyxin B and erythromycin. Loss of hopanoid production also resulted in severe defects in both swimming and swarming motility. This suggests that hopanoid production plays an important role in the physiology of B. cenocepacia.

Non-genetic mechanisms communicating antibiotic resistance:rethinking strategies for antimicrobial drug design

Introduction: Infections by multidrug-resistant bacteria are of great concern worldwide. In many cases, resistance is not due to the presence of specific antibiotic-modifying enzymes, but rather associated with a general impermeability of the bacterial cell envelope. The molecular bases of this intrinsic resistance are not completely understood. Moreover, horizontal gene transfers cannot solely explain the spread of intrinsic resistance among bacterial strains. Areas covered: This review focuses on the increased intrinsic antibiotic resistance mediated by small molecules. These small molecules can either be secreted from bacterial cells of the same or different species (e.g., indole, polyamines, ammonia, and the Pseudomonas quinolone signal) or be present in the bacterial cell milieu, whether in the environment, such as indole acetic acid and other plant hormones, or in human tissues and body fluids, such as polyamines. These molecules are metabolic byproducts that act as infochemicals and modulate bacterial responses toward antibiotics leading to increasing or decreasing resistance levels. Expert opinion: The non-genetic mechanisms of antibiotic response modulation and communication discussed in this review should reorient our thinking of the mechanisms of intrinsic resistance to antibiotics and its spread across bacterial cell populations. The identification of chemical signals mediating increased intrinsic antibiotic resistance will expose novel critical targets for the development of new antimicrobial strategies.