Proactive modulation of long-interval intracortical inhibition during response inhibition

Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABA(B) receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied

Response inhibition activates distinct motor cortical inhibitory processes

We routinely cancel preplanned movements that are no longer required. If stopping is forewarned, proactive processes are engaged to selectively decrease motor cortex excitability. However, without advance information there is a nonselective reduction in motor cortical excitability. In this study we examined modulation of human primary motor cortex inhibitory networks during response inhibition tasks with informative and uninformative cues using paired-pulse transcranial magnetic stimulation. Long- (LICI) and short-interval intracortical inhibition (SICI), indicative of GABAB- and GABAA-receptor mediated inhibition, respectively, were examined from motor evoked potentials obtained in task-relevant and task-irrelevant hand muscles when response inhibition was preceded by informative and uninformative cues. When the participants (10 men and 8 women) were cued to stop only a subcomponent of the bimanual response, the remaining response was delayed, and the extent of delay was greatest in the more reactive context, when cues were uninformative. For LICI, inhibition was reduced in both muscles during all types of response inhibition trials compared with the pre-task resting baseline. When cues were uninformative and left-hand responses were suddenly canceled, task-relevant LICI positively correlated with response times of the responding right hand. In trials where left-hand responding was highly probable or known (informative cues), task-relevant SICI was reduced compared with that when cued to rest, revealing a motor set indicative of responding. These novel findings indicate that the GABAB-receptor-mediated pathway may set a default inhibitory tone according to task context, whereas the GABAA-receptor-mediated pathways are recruited proactively with response certainty. NEW &amp; NOTEWORTHY We examined how informative and uninformative cues that trigger both proactive and reactive processes modulate GABAergic inhibitory networks within human primary motor cortex. We show that GABAB inhibition was released during the task regardless of cue type, whereas GABAA inhibition was reduced when responding was highly probable or known compared with rest. GABAB-receptor-mediated inhibition may set a default inhibitory tone, whereas GABAA circuits may be modulated proactively according to response certainty. </jats:p

Persistence and Quiescence of Seismicity on Fault Systems

We study the statistics of simulated earthquakes in a quasistatic model of two parallel heterogeneous faults within a slowly driven elastic tectonic plate. The probability that one fault remains dormant while the other is active for a time Dt following the previous activity shift is proportional to the inverse of Dt to the power 1+x, a result that is robust in the presence of annealed noise and strength weakening. A mean field theory accounts for the observed dependence of the persistence exponent x as a function of heterogeneity and distance between faults. These results continue to hold if the number of competing faults is increased. This is related to the persistence phenomenon discovered in a large variety of systems, which specifies how long a relaxing dynamical system remains in a neighborhood of its initial configuration. Our persistence exponent is found to vary as a function of heterogeneity and distance between faults, thus defining a novel universality class.Comment: 4 pages, 3 figures, Revte

Implications of Gauge Unification for Time Variation of the Fine Structure Constant

Unification of the gauge couplings would imply that time variations of the fine structure constant are accompanied by calculable and very significant time variations in the QCD scale parameter $\Lambda_{QCD}$. Since $\Lambda_{QCD}$ is the dominant factor in setting the hadron masses, estimates made by simple variations of the fine structure constant may not provide meaningful limits. There may also be related variations in Yukawa couplings and the electroweak scale. Implications for the 21 cm hyperfine transition, big bang nucleosynthesis, and the triple alpha process are discussed. We find that the first of these already provides strong constraints on the underlying theory. It is emphasized more generally that time (and space) variations of fundamental couplings and their correlations may be a significant probe of ultra-high-energy physics.Comment: 13 pages, uses JHEP.cl

Effect of implementing a heart failure admission care bundle on hospital readmission and mortality rates: interrupted time series study

This study aimed to evaluate the impact of developing and implementing a care bundle intervention to improve care for patients with acute heart failure admitted to a large London hospital. The intervention comprised three elements, targeted within 24 hours of admission: N-terminal pro-B-type natriuretic peptide (NT-proBNP) test, transthoracic Doppler two-dimensional echocardiography and specialist review by cardiology team. The SHIFT-Evidence approach to quality improvement was used. During implementation, July 2015–July 2017, 1169 patients received the intervention. An interrupted time series design was used to evaluate impact on patient outcomes, including 15 618 admissions for 8951 patients. Mixed-effects multiple Poisson and log-linear regression models were fitted for count and continuous outcomes, respectively. Effect sizes are slope change ratios pre-intervention and post-intervention. The intervention was associated with reductions in emergency readmissions between 7 and 90 days (0.98, 95% CI 0.97 to 1.00), although not readmissions between 0 and 7 days post-discharge. Improvements were seen in in-hospital mortality (0.96, 95% CI 0.95 to 0.98), and there was no change in trend for hospital length of stay. Care process changes were also evaluated. Compliance with NT-proBNP testing was already high in 2014/2015 (162 of 163, 99.4%) and decreased slightly, with increased numbers audited, to 2016/2017 (1082 of 1101, 98.2%). Over this period, rates of echocardiography (84.7–98.9%) and specialist input (51.6–90.4%) improved. Care quality and outcomes can be improved for patients with acute heart failure using a care bundle approach. A systematic approach to quality improvement, and robust evaluation design, can be beneficial in supporting successful improvement and learning

On the redshift-evolution of the Lyman-alpha escape fraction and the dust content of galaxies

The Ly-alpha emission line has been proven a powerful tool by which to study evolving galaxies at the highest redshifts. However, in order to use Lya as a physical probe of galaxies, it becomes vital to know the Lya escape fraction (fescLya). Unfortunately, due to the resonant nature of Lya, fescLya may vary unpredictably and requires empirical measurement. Here we compile Lya luminosity functions between redshift z=0 and 8 and, combined with H-alpha and ultraviolet data, assess how fescLya evolves with redshift. We find a strong upwards evolution in fescLya over the range z=0.3-6, which is well-fit by the power-law fescLya \propto (1+z)^\xi, with \xi =(2.57_-0.12^+0.19). This predicts that fescLya should reach unity at z=11.1. By comparing fescLya and E(B-V) in individual galaxies we derive an empirical relationship between fescLya and E(B-V), which includes resonance scattering and can explain the redshift evolution of fescLya between z=0 and 6 purely as a function of the evolution in the dust content of galaxies. Beyond z~6.5, fescLya drops more substantially; an effect attributed to either ionizing photon leakage, or an increase in the neutral gas fraction of the intergalactic medium. While distinguishing between those two scenarios may be extremely challenging, by framing the problem this way we remove the uncertainty of the halo mass from Lya-based tests of reionization. We finally derive a new method by which to estimate the dust content of galaxies based purely upon the observed Lya and UV LFs. These data are characterized by an exponential with an e-folding redshift of ~3.5.Comment: Accepted by the Astrophysical Journal. 14 pages in emulateapj template with 4 figure

Mid-IR Luminosities and UV/Optical Star Formation Rates at z<1.4

UV continuum and mid-IR emission constitute two widely used star formation indicators at intermediate and high redshifts. We study 2430 galaxies with z<1.4 in the Extended Groth Strip with MIPS 24 mic observations from FIDEL, spectroscopy from DEEP2, and UV, optical, and near-IR photometry from AEGIS. The data are coupled with stellar population models and Bayesian SED fitting to estimate dust-corrected SFRs. In order to probe the dust heating from stellar populations of various ages, the derived SFRs were averaged over various timescales--from 100 Myr for "current" SFR to 1--3 Gyr for long-timescale SFRs. These SED-based UV/optical SFRs are compared to total infrared luminosities extrapolated from 24 mic observations. We find that for the blue, actively star forming galaxies the correlation between the IR luminosity and the UV/optical SFR shows a decrease in scatter when going from shorter to longer SFR-averaging timescales. We interpret this as the greater role of intermediate age stellar populations in heating the dust than what is typically assumed. This holds over the entire redshift range. Many so-called green valley galaxies are simply dust-obscured actively star-forming galaxies. However, there exist 24 mic-detected galaxies, some with L>10^11 L_sun, yet with little current star formation. For them a reasonable amount of dust absorption of stellar light is sufficient to produce the observed levels of IR. In our sample optical and X-ray AGNs do not contribute on average more than ~50% to the mid-IR luminosity, and we see no evidence for a large population of "IR excess" galaxies (Abridged).Comment: Accepted for publication in ApJ. Content identical to arXiv version 1. No color figure

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems

The WiggleZ Dark Energy Survey: the transition to large-scale cosmic homogeneity

We have made the largest-volume measurement to date of the transition to large-scale homogeneity in the distribution of galaxies. We use the WiggleZ survey, a spectroscopic survey of over 200,000 blue galaxies in a cosmic volume of ~1 (Gpc/h)^3. A new method of defining the 'homogeneity scale' is presented, which is more robust than methods previously used in the literature, and which can be easily compared between different surveys. Due to the large cosmic depth of WiggleZ (up to z=1) we are able to make the first measurement of the transition to homogeneity over a range of cosmic epochs. The mean number of galaxies N(<r) in spheres of comoving radius r is proportional to r^3 within 1%, or equivalently the fractal dimension of the sample is within 1% of D_2=3, at radii larger than 71 \pm 8 Mpc/h at z~0.2, 70 \pm 5 Mpc/h at z~0.4, 81 \pm 5 Mpc/h at z~0.6, and 75 \pm 4 Mpc/h at z~0.8. We demonstrate the robustness of our results against selection function effects, using a LCDM N-body simulation and a suite of inhomogeneous fractal distributions. The results are in excellent agreement with both the LCDM N-body simulation and an analytical LCDM prediction. We can exclude a fractal distribution with fractal dimension below D_2=2.97 on scales from ~80 Mpc/h up to the largest scales probed by our measurement, ~300 Mpc/h, at 99.99% confidence.Comment: 21 pages, 16 figures, accepted for publication in MNRA

Isotopic and molecular distributions of biochemicals from fresh and buried Rhizophora mangle leaves†

Rhizophora mangle L. (red mangrove) is the dominant species of mangrove in the Americas. At Twin Cays, Belize (BZ) red mangroves are present in a variety of stand structures (tall >5 m in height, transition ~2–4 m and dwarf ~1–1.5 m). These height differences are coupled with very different stable carbon and nitrogen isotopic values[1] (mean tall δ(13)C = -28.3‰, δ(15)N = 0‰; mean tall δ(13)C = -25.3‰, δ(15)N = -10‰). To determine the utility of using these distinct isotopic compositions as 'biomarkers' for paleoenvironmental reconstruction of mangrove ecosystems and nutrient availability, we investigated the distribution and isotopic (δ(13)C and δ(15)N) composition of different biochemical fractions (water soluble compounds, free lipids, acid hydrolysable compounds, individual amino acids, and the residual un-extractable compounds) in fresh and preserved red mangrove leaves from dwarf and tall trees. The distribution of biochemicals are similar in dwarf and tall red mangrove leaves, suggesting that, regardless of stand structure, red mangroves use nutrients for biosynthesis and metabolism in a similar manner. However, the δ(13)C and δ(15)N of the bulk leaf, the biochemical fractions, and seven amino acids can be used to distinguish dwarf and tall trees at Twin Cays, BZ. The data support the theory that the fractionation of carbon and nitrogen occurs prior to or during uptake in dwarf and tall red mangrove trees. Stable carbon and nitrogen isotopes could, therefore, be powerful tools for predicting levels of nutrient limitation at Twin Cays. The δ(13)C and δ(15)N of biochemical fractions within preserved leaves, reflect sedimentary cycling and nitrogen immobilization. The δ(15)N of the immobilized fraction reveals the overlying stand structure at the time of leaf deposition. The isotopic composition of preserved mangrove leaves could yield significant information about changes in ecosystem dynamics, nutrient limitation and past stand structure in mangrove paleoecosystems