The role of proton dynamics in the development and maintenance of multidrug resistance in cancer

With a projected 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm in 2015, improving treatment is an essential focus of cancer research today. Multi-drug resistance (MDR) is the leading cause of chemotherapeutic failure in the treatment of cancer, the term denoting a characteristic of the disease-causing agent to avoid damage by drugs designed to bring about their destruction. MDR is also characterised by a reversal of the pH gradient across cell membranes leading to an acidification of the outer milieu and an alkalinisation of the cytosol that is maintained by the proton pump vacuolar-type ATPase (V-ATPase) and the proton transporters: Na+/H+ exchanger (NHE1), Monocarboxylate Transporters (MCTs), Carbonic anhydrases (CAs) (mainly CA-IX), adenosinetriphosphate synthase, Na+/HCO3− co-transporter and the Cl−/HCO3−exchanger. This review aims to give an introduction to MDR. It will begin with an explanation for what MDR actually is and go on to look at the proposed mechanisms by which a state of drug resistance is achieved. The role of proton-pumps in creating an acidic extracellular pH and alkaline cytosol, as well as key biomechanical processes within the cell membrane itself, will be used to explain how drug resistance can be sustained

Amygdala and fusiform gyrus temporal dynamics: Responses to negative facial expressions

<p>Abstract</p> <p>Background</p> <p>The amygdala habituates in response to repeated human facial expressions; however, it is unclear whether this brain region habituates to schematic faces (i.e., simple line drawings or caricatures of faces). Using an fMRI block design, 16 healthy participants passively viewed repeated presentations of schematic and human neutral and negative facial expressions. Percent signal changes within anatomic regions-of-interest (amygdala and fusiform gyrus) were calculated to examine the temporal dynamics of neural response and any response differences based on face type.</p> <p>Results</p> <p>The amygdala and fusiform gyrus had a within-run "U" response pattern of activity to facial expression blocks. The initial block within each run elicited the greatest activation (relative to baseline) and the final block elicited greater activation than the preceding block. No significant differences between schematic and human faces were detected in the amygdala or fusiform gyrus.</p> <p>Conclusion</p> <p>The "U" pattern of response in the amygdala and fusiform gyrus to facial expressions suggests an initial orienting, habituation, and activation recovery in these regions. Furthermore, this study is the first to directly compare brain responses to schematic and human facial expressions, and the similarity in brain responses suggest that schematic faces may be useful in studying amygdala activation.</p

The effects of varying glenohumeral joint angle on acute volume load, muscle activation, swelling, and echo-Intensity on the biceps brachii in resistance-trained individuals

There is a paucity of data on how manipulating joint angles during isolation exercises may impact overall session muscle activation and volume load in resistance-trained individuals. We investigated the acute effects of varying glenohumeral joint angle on the biceps brachii with a crossover repeated measure design with three different biceps curls. One session served as the positive control (CON), which subjects performed 9 sets of bicep curls with their shoulder in a neutral position. The experimental condition (VAR), varied the glenohumeral joint angle by performing 3 sets in shoulder extension (30 degrees), 3 sets neutral (0 degrees), and 3 sets in flexion (90 degrees). Volume load and muscle activation (EMG) were recorded during the training sessions. Muscle swelling and strain were assessed via muscle thickness and echo-intensity responses at pre, post, 24 h, 48 h, and 72 h. There were no significant differences between conditions for most dependent variables. However, the overall session EMG amplitude was significantly higher (p = 0.0001) in VAR compared to CON condition (95%-CI: 8.4% to 23.3%). Our findings suggest that varying joint angles during resistance training (RT) may enhance total muscle activation without negatively affecting volume load within a training session in resistance-trained individuals7

Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene

Importance of the difference in surface pressures of the cell membrane in doxorubicin resistant cells that do not express Pgp and ABCG2

P-glycoprotein (Pgp) represents the archetypal mechanism of drug resistance. But Pgp alone cannot expel drugs. A small but growing body of works has demonstrated that the membrane biophysical properties are central to Pgp-mediated drug resistance. For example, a change in the membrane surface pressure is expected to support drug–Pgp interaction. An interesting aspect from these models is that under specific conditions, the membrane is predicted to take over Pgp concerning the mechanism of drug resistance especially when the surface pressure is high enough, at which point drugs remain physically blocked at the membrane level. However it remains to be determined experimentally whether the membrane itself could, on its own, affect drug entry into cells that have been selected by a low concentration of drug and that do not express transporters. We demonstrate here that in the case of the drug doxorubicin, alteration of the surface pressure of membrane leaflets drive drug resistance

The Last Eight-Billion Years of Intergalactic CIV Evolution

We surveyed the HST UV spectra of 49 low-redshift quasars for z < 1 CIV candidates, relying solely on the characteristic wavelength separation of the doublet. After consideration of the defining traits of CIV doublets (e.g., consistent line profiles, other associated transitions, etc.), we defined a sample of 38 definite (group G = 1) and five likely (G = 2) doublets with rest equivalent widths W_r for both lines detected at >= 3 sigma. We conducted Monte-Carlo completeness tests to measure the unblocked redshift (dz) and co-moving pathlength (dX) over which we were sensitive to CIV doublets of a range of equivalent widths and column densities. The absorber line density of (G = 1+2) doublets is dN/dX = 4.1+0.7/-0.6 for log N(C^+3) >= 13.2, and dN/dX has not evolved significantly since z = 5. The best-fit power-law to the G = 1 frequency distribution of column densities f(N(C^+3)) = k(N(C^+3)/N_0)^alpha_N has coefficient k = (0.67+0.18/-0.16) x 10^-14 cm^2 and exponent alpha_N = -1.50+0.17/-0.19, where N_0 = 10^14 cm^-2. Using the power-law model of f(N(C^+3)), we measured the C^+3 mass density relative to the critical density: Omega(C^+3) = (6.20+1.82/-1.52) x 10^-8 for 13 <= log N(C^+3) <= 15. This value is a 2.8+/-0.7 increase in Omega(C^+3) compared to the error-weighted mean from several 1 < z < 5 surveys for CIV absorbers. A simple linear regression to Omega(C^+3) over the age of the Universe indicates that Omega(C^+3) has slowly but steadily increased from z = 5 --> 0, with dOmega(C^+3)/dt_age = (0.42+/-0.2) x 10^-8 Gyr^-1.Comment: 61 pages; accepted by ApJ; includes changes based on referee repor

Visual Mental Imagery Activates Topographically Organized Visual Cortex: PET Investigations

Cerebral blood flow was measured using positron emission tomography (PET) in three experiments while subjects performed mental imagery or analogous perceptual tasks. In Experiment 1, the subjects either visualized letters in grids and decided whether an X mark would have fallen on each letter if it were actually in the grid, or they saw letters in grids and decided whether an X mark fell on each letter. A region identified as part of area 17 by the Talairach and Tournoux (1988) atlas, in addition to other areas involved in vision, was activated more in the mental imagery task than in the perception task. In Experiment 2, the identical stimuli were presented in imagery and baseline conditions, but subjects were asked to form images only in the imagery condition; the portion of area 17 that was more active in the imagery condition of Experiment 1 was also more activated in imagery than in the baseline condition, as was part of area 18. Subjects also were tested with degraded perceptual stimuli, which caused visual cortex to be activated to the same degree in imagery and perception. In both Experiments 1 and 2, however, imagery selectively activated the extreme anterior part of what was identified as area 17, which is inconsistent with the relatively small size of the imaged stimuli. These results, then, suggest that imagery may have activated another region just anterior to area 17. In Experiment 3, subjects were instructed to close their eyes and evaluate visual mental images of upper case letters that were formed at a small size or large size. The small mental images engendered more activation in the posterior portion of visual cortex, and the large mental images engendered more activation in anterior portions of visual cortex. This finding is strong evidence that imagery activates topographically mapped cortex. The activated regions were also consistent with their being localized in area 17. Finally, additional results were consistent with the existence of two types of imagery, one that rests on allocating attention to form a pattern and one that rests on activating stored visual memories.Psycholog