Direct enhancement of nuclear singlet order by dynamic nuclear polarization

Hyperpolarized singlet order is available immediately after dissolution DNP, avoiding need for additional preparation steps. We demonstrate this procedure on a sample of [1,2–13C2]pyruvic aci

Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder.

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS.MethodsMedications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks.ResultsUse of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02).ConclusionsConcomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome

Acute and Chronic Effects of 12 Weeks of Combined Exercise Training on Plasma IL-6 in Post-Menopausal Women

Post-menopausal women exhibit higher levels of IL-6, a pro-inflammatory cytokine and anti-inflammatory myokine, and up-regulation of cellular receptors and cofactors for IL-6. Exercise is associated with an acute elevation of IL-6, but consistent exercise training diminishes this response. PURPOSE: to analyze the acute and chronic effects of 12 weeks of combined resistance and aerobic exercise training on plasma IL-6 in overweight or obese, post-menopausal women (55-75 years). METHODS: Forty-three women were randomly assigned to an exercise (EX, n=22) or an education (ED, n=21) group. EX completed resistance training (2 sets of 8 resistance exercises at 80% of 1RM) followed by aerobic training (25-minute treadmill walk at 70-80% of HRR) three times per week for 12 weeks. ED attended classes and activities two times per week for 12 weeks to control for seasonal variation and social interaction. Blood samples were collected a total of 8 times: 4 times before training (BT) (before the acute exercise bout (PRE), immediately after exercise (PO), 1 hour after exercise (1HR), and 2 hours after exercise (2HR)) and 4 times after training (AT). Lean, post-menopausal, and age-matched women were recruited for collection of one resting blood sample to serve as healthy controls (LN, n=11). Plasma IL-6 was determined using an ELISA kit according to manufacturer instructions. RESULTS: Baseline IL-6 concentration was significantly lower in the LN group compared to the EX (LN BT PRE: 1.0 ± 0.5; EX BT PRE: 2.8 ± 1.3 pg/mL; p\u3c0.001) and ED (LN BT PRE: 1.0 ± 0.5; ED BT PRE: 3.8 ± 1.7 pg/mL; p\u3c0.001) groups. No statistically significant BT/AT x group interaction was observed (p\u3e0.05) when the BT and AT PRE time points of the EX and ED groups were compared. In the EX group, PO was significantly higher than PRE (PRE 2.6 ± 1.2; PO 4.3 ± 1.8 pg/mL; p\u3c0.001), and PO was significantly higher than 1 HR (PO 4.3 ± 1.8; 1HR 3.4 ± 1.2 pg/mL; p=0.038) and 2HR (PO 4.3 ± 1.8; 2 HR 3.9 ± 1.6 pg/mL; p=0.005). No statistically significant differences were observed when corresponding time points before and after the intervention within a group were compared (i.e., EX BT PRE to EX AT PRE) (p\u3e0.05). CONCLUSION:The training intervention may not have been long enough and/or intense enough to observe a chronic effect of combined exercise training on plasma IL-6. Significant elevation of IL-6 immediately post-exercise was observed in the EX group, but this response was not blunted by consistent exercise training

The Influence of Physical Activity on Monocyte Phenotype on Circulating Platelet-Monocyte Complexes in Overweight/Obese Persons

Elevated platelet-monocyte complexes (PMC) promote atherosclerosis and are associated with cardiovascular disease. It is unknown whether consistent physical activity (PA) decreases circulating PMCs. Additionally, no one has determined the monocyte phenotype most associated with PMCs. Purposes: 1) to examine the influence of PA on PMCs and their association with inflammatory /prothrombotic markers such as C-reactive protein (CRP), L-selectin (LS), platelet factor 4 (PF4), von Willebrand Factor (vWF), and hemoglobin A1C (HbA1c) and 2) to determine the monocyte phenotype most likely to form PMCs. Methods: Thirty-one overweight/obese subjects (44±5yr, BMI 34.2±5 kg×m2) were divided into two groups: sedentary (SED, n=17) and physically active (PA, n=14) based on physical activity logs. SED participated in \u3c 1 h of formal exercise while PA participated in moderate-high intensity exercise at least 3 h per week. Flow cytometry was used to identify PMCs on the monocyte phenotypes: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14+CD16++). Platelets were identified using the marker CD42a. Results: Percentage of circulating PMCs and median fluorescence intensity of CD42a (MedFI; marker of platelet density per monocyte) were not different between groups; however, monocyte phenotype significantly impacted PMC percentage and MedFI where the lower the CD16 expression, the greater the adhesion of platelets. Classical monocytes (CD16-) had the highest % of PMC, etc. (Fig 1). HbA1c was greater (p=0.031) and LS (p=0.019) was lower in SED compared to PA (Fig. 2). There were no significant associations between any blood marker and PMC percentage, but PF4 was correlated with percent of CD16 -(r= -0.482, p=0.031) and CD16+(r= 0.473, p=0.035) monocytes. Conclusions: The absence of a separation between groups in VO2max may partially explain the lack of a difference in PMCs between groups. Regarding our second aim, classical monocytes appear to be more involved in PMC formation than do CD16+ monocytes with CD16++ having the lowest percentage of cells with platelets adhered (PMC). This observation may be due to the shedding of adhesion molecules from platelets and monocytes during activation from classical (CD16-) to a more inflammatory state (ie. CD16+)

Using error correction to determine the noise model

Quantum error correcting codes have been shown to have the ability of making quantum information resilient against noise. Here we show that we can use quantum error correcting codes as diagnostics to characterise noise. The experiment is based on a three-bit quantum error correcting code carried out on a three-qubit nuclear magnetic resonance (NMR) quantum information processor. Utilizing both engineered and natural noise, the degree of correlations present in the noise affecting a two-qubit subsystem was determined. We measured a correlation factor of c=0.5+/-0.2 using the error correction protocol, and c=0.3+/-0.2 using a standard NMR technique based on coherence pathway selection. Although the error correction method demands precise control, the results demonstrate that the required precision is achievable in the liquid-state NMR setting.Comment: 10 pages, 3 figures. Added discussion section, improved figure

Coarse-Graining and Self-Dissimilarity of Complex Networks

Can complex engineered and biological networks be coarse-grained into smaller and more understandable versions in which each node represents an entire pattern in the original network? To address this, we define coarse-graining units (CGU) as connectivity patterns which can serve as the nodes of a coarse-grained network, and present algorithms to detect them. We use this approach to systematically reverse-engineer electronic circuits, forming understandable high-level maps from incomprehensible transistor wiring: first, a coarse-grained version in which each node is a gate made of several transistors is established. Then, the coarse-grained network is itself coarse-grained, resulting in a high-level blueprint in which each node is a circuit-module made of multiple gates. We apply our approach also to a mammalian protein-signaling network, to find a simplified coarse-grained network with three main signaling channels that correspond to cross-interacting MAP-kinase cascades. We find that both biological and electronic networks are 'self-dissimilar', with different network motifs found at each level. The present approach can be used to simplify a wide variety of directed and nondirected, natural and designed networks.Comment: 11 pages, 11 figure

Application of DEN refinement and automated model building to a difficult case of molecular-replacement phasing: the structure of a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum.

Phasing by molecular replacement remains difficult for targets that are far from the search model or in situations where the crystal diffracts only weakly or to low resolution. Here, the process of determining and refining the structure of Cgl1109, a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum, at ∼3 Å resolution is described using a combination of homology modeling with MODELLER, molecular-replacement phasing with Phaser, deformable elastic network (DEN) refinement and automated model building using AutoBuild in a semi-automated fashion, followed by final refinement cycles with phenix.refine and Coot. This difficult molecular-replacement case illustrates the power of including DEN restraints derived from a starting model to guide the movements of the model during refinement. The resulting improved model phases provide better starting points for automated model building and produce more significant difference peaks in anomalous difference Fourier maps to locate anomalous scatterers than does standard refinement. This example also illustrates a current limitation of automated procedures that require manual adjustment of local sequence misalignments between the homology model and the target sequence

Exercise-Induced Th17 Lymphocyte Response and Their Relationship to Cardiovascular Disease Risk Factors in Obese, Post-Menopausal Women

Obesity-induced inflammation promotes type 2 diabetes and cardiovascular disease (CVD). A causative link between adaptive immunity and pathogenesis of obesity-associated diseases has been established. PURPOSE: To examine the effects of exercise on circulating T-helper (Th) 17 lymphocytes in overweight/obese post-menopausal women. METHODS: Twenty-seven overweight/obese women (BMI 32.7 ± 5.1 kg×m-2, 55-75 yr) were randomly assigned to the exercise (EX, n=14) or education (ED, n=13) groups. EX performed a 25-min walk (75-80% HRR) and 2 sets of 8 resistance exercises (70-80% 1RM) with blood samples obtained at: pre-exercise, post-exercise, one-hour and two-hour post-exercise. Blood samples were obtained at the same time points in resting ED. Whole blood was stained using the extracellular markers CD4, CD196, CD194, CD26, and CD161 to identify Th17 lymphocytes via flow cytometry. RESULTS: Acute exercise increased lymphocyte number (p = 0.0001), but decreased percent of CD4+ cells (p = 0.019) at PO. We observed a diurnal response (main effect) where CD26 expression was significantly lower by 2H compared to PRE (PR: 10631 ± 208; 2H: 9961 ± 271 MFI). There was a main effect (p=0.024) of group for CD26 expression (EX: 10745 ± 251; ED 9880 ± 260 MFI). The difference may have been driven by the apparent exercise-induced plateau of CD26 expression at 2H, which minimized the diurnal reduction observed in ED (p \u3e 0.05). There was a tendency (p = 0.09) for a group x time interaction in Th17 cell number at 1HR (EX = 25.3 ± 4.8; ED =37.2 ± 5.2 x 103 cells×ml-1). BMI was significantly correlated with Th17% (r = 0.5, p = 0.008). HbA1c was positively correlated with Th17 number and percentage (r = 0.598, p = 0.003; r = 0.614, p = 0.001, respectively), as well as CCR4+ Th17 cells (r = 0.421, p = 0.036). Multiple regression analysis revealed that BMI, fat percentage, and HbA1c were significant predictors (69%, r2 = 0.685) of Th17 cell %. CONCLUSION: Exercise reduced CD26 expression, the receptor responsible for Th17 cell migration, but did not significantly alter Th17 concentration (p = 0.09). CD26 upregulation may indicate that Th17 cells, via chemokine release, promote the stress-dependent migratory response of T-helper cells (CD4+). Obese individuals may experience a preferential differentiation of Th17 cells, based on their association with adiposity (BMI and %fat) and HbA1c

Spatial Regulation and the Rate of Signal Transduction Activation

Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement

Acute Exercise-Induced Response of Platelet-Monocyte Complexes in Obese, Postmenopausal Women

Inactivity-related diseases such as cardiovascular disease (CVD) are linked to chronic low-grade, systemic inflammation. Platelet-monocyte complexes (PMCs) are markers of in vivo platelet activation and atherosclerosis, and may be early indicators of subclinical inflammation. PURPOSE: To examine the effects of an exercise bout on PMCs in those at risk for CVD. METHODS: Twenty-five overweight-obese (BMI 32.7 ± 5.2 kg×m-2, 55-75 yr) women were randomly assigned to either the exercise (EX, n=13) or non-exercise control (CON, n=12) group. EX performed 2 sets of 8 resistance exercises and a 25-min treadmill walk at 70-80% HRR. Blood was obtained pre-exercise (PR), post- (PO), 1-hour and 2 hours post-exercise (1HR and 2HR). Blood was obtained at the same time points in CON. PMCs were identified via flow cytometry and analyzed in each monocyte phenotype. Monocyte phenotypes were defined as: Mon1 (CD14+CD16−CCR2+), Mon2 (CD14+CD16+CCR2+), and Mon3 (CD14+CD16+CCR2−). All events positive for both CD14 and CD42a (marker for platelets) were considered PMCs. RESULTS: A main effect for time revealed an increase in PMC number at PO (p=0.036) which appears to have been driven by EX (EX = 61.5%; CON = 33.8% increase). PMCs formed with Mon1 and Mon2 followed a similar response. A significant group x time interaction for Mon3 PMC number (p=0.002) indicated an increase from PR to PO (PR = 5218±1170, PO = 8195±1152 cells·ml-1), and a decrease from PO to 1HR and 2HR (1HR = 3767±820 cells·ml-1 2HR = 3818±814 cells·ml-1) in EX. PMC number remained constant for CON at all timepoints. Estimated VO2max was negatively correlated with CD42a MFI (a marker of platelet density per monocyte) (r = -0.583, p = 0.003). Systolic blood pressure (SBP) positively correlated with percent PMC (% CD42a positive monocytes; r = 0.458, p = 0.042). CONCLUSION: Aerobic fitness appears to reduce platelet activation indicated by the negative relationship between VO2max and CD42a MFI. Chronic elevations in resting SBP are linked to PMC percentage, possibly due to sheer stress-induced platelet activation. It is possible that PMC elevation at PO is at least partially driven by exercise-induced increases in BP. These results support previous literature, indicating that PMCs are a CVD risk marker and may elucidate one mechanism by which physical fitness reduces risk for CVD