Effects of relative submergence on flow and sediment patterns around clasts

River morphodynamics and sediment transportMechanics of sediment transpor

A Role for cAMP in Long-Term Depression at Hippocampal Mossy Fiber Synapses

AbstractMossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor–independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor–mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons

Coexpression analysis of large cancer datasets provides insight into the cellular phenotypes of the tumour microenvironment

Background: Biopsies taken from individual tumours exhibit extensive differences in their cellular composition due to the inherent heterogeneity of cancers and vagaries of sample collection. As a result genes expressed in specific cell types, or associated with certain biological processes are detected at widely variable levels across samples in transcriptomic analyses. This heterogeneity also means that the level of expression of genes expressed specifically in a given cell type or process, will vary in line with the number of those cells within samples or activity of the pathway, and will therefore be correlated in their expression.Results: Using a novel 3D network-based approach we have analysed six large human cancer microarray datasets derived from more than 1,000 individuals. Based upon this analysis, and without needing to isolate the individual cells, we have defined a broad spectrum of cell-type and pathway-specific gene signatures present in cancer expression data which were also found to be largely conserved in a number of independent datasets.Conclusions: The conserved signature of the tumour-associated macrophage is shown to be largely-independent of tumour cell type. All stromal cell signatures have some degree of correlation with each other, since they must all be inversely correlated with the tumour component. However, viewed in the context of established tumours, the interactions between stromal components appear to be multifactorial given the level of one component e.g. vasculature, does not correlate tightly with another, such as the macrophage

Converging rapid deployment prostheses with minimal access surgery: analysis of early outcomes

Background: Sutureless prostheses may have added benefit when combined with minimal access surgery, although this has not been fully assessed in the literature. This study aims to provide a comparative analysis of the Perceval valve comparing median sternotomy (MS) with mini-sternotomy (MIS). Methods: A retrospective analysis of prospectively collected data was conducted for all isolated aortic valve replacement (AVR), using the Perceval valve, for severe aortic stenosis cases in the period 2014 to 2019. Patients undergoing concomitant valve or revascularisation surgery were excluded. Results: A total of 78 patients were included: MS group 41; MIS group 37. Operatively, bypass times were comparable between MS and MIS groups (mean 89.3 vs 83.4, p = 0.307), as were aortic cross clamp times (58.4 vs 55.9, p = 0.434). There were no operative deaths or new onset post-operative neurology. MIS was a predictor of reduced stay in the intensive care unit (coef − 3.25, 95% CI [− 4.93, − 0.59], p = 0.036) and hospital stay overall (p = 0.004). Blood transfusion units were comparable as were the incidence of heart block (n = 5 vs n = 3, p = 0.429) and new onset atrial fibrillation (n = 15 vs n = 9, p = 0.250). Follow-up echocardiography found a significant improvement in effective orifice area, left ventricular dimension and volume indices, and LVEF (p > 0.05) for all patients. Multivariate analysis found mini-sternotomy to be a predictor for reduced LV diastolic volume (coef − 0.35, 95% CI [− 1.02, − 0.05], p = 0.05). Conclusions: The combination of minimal access surgery and sutureless AVR may enhance patient recovery and provide early LV remodelling

Understanding saturated hydraulic conductivity under seasonal changes in climate and land use

The goal of this study was to understand better the co-play of intrinsic soil properties and extrinsic factors of climate and management in the estimation of saturated hydraulic conductivity (Ksat) in intensively managed landscapes. For this purpose, a physically-based, modeling framework was developed using hydro-pedotransfer functions (PTFs) and watershed models integrated with Geographic Information System (GIS) modules. The integrated models were then used to develop Ksat maps for the Clear Creek, Iowa watershed and the state of Iowa. Four types of saturated hydraulic conductivity were considered, namely the baseline (Kb), the bare (Kbr), the effective with no-rain (Ke-nr) and the effective (Ke) in order to evaluate how management and seasonality affect Ksat spatiotemporal variability. Kb is dictated by soil texture and bulk density, whereas Kbr, Ke-nr, and Ke are driven by extrinsic factors, which vary on an event to seasonal time scale, such as vegetation cover, land use, management practices, and precipitation. Two seasons were selected to demonstrate Ksat dynamics in the Clear Creek watershed, IA and the state of Iowa; specifically, the months of October and April that corresponded to the before harvesting and before planting conditions, respectively. Statistical analysis of the Clear Creek data showed that intrinsic soil properties incorporated in Kb do not reflect the degree of soil surface disturbance due to tillage and raindrop impact. Additionally, vegetation cover affected the infiltration rate. It was found that the use of Kbinstead of Ke in water balance studies can lead to an overestimation of the amount of water infiltrated in agricultural watersheds by a factor of two. Therefore, we suggest herein that Keis both the most dynamic and representative saturated hydraulic conductivity for intensively managed landscapes because it accounts for the contributions of land cover and management, local hydropedology and climate condition, which all affect the soil porosity and structure and hence, Ksat

The dual role of LSD1 and HDAC3 in STAT5-dependent transcription is determined by protein interactions, binding affinities, motifs and genomic positions

STAT5 interacts with other factors to control transcription, and the mechanism of regulation is of interest as constitutive active STAT5 has been reported in malignancies. Here, LSD1 and HDAC3 were identified as novel STAT5a interacting partners in pro-B cells. Characterization of STAT5a, LSD1 and HDAC3 target genes by ChIP-seq and RNA-seq revealed gene subsets regulated by independent or combined action of the factors and LSD1/HDAC3 to play dual role in their activation or repression. Genes bound by STAT5a alone or in combination with weakly associated LSD1 or HDAC3 were enriched for the canonical STAT5a GAS motif, and such binding induced activation or repression. Strong STAT5 binding was see

Chronic methamphetamine effects on brain structure and function in rats

Methamphetamine (MA) addiction is a growing epidemic worldwide. Chronic MA use has been shown to lead to neurotoxicity in rodents and humans. Magnetic resonance imaging (MRI) studies in MA users have shown enlarged striatal volumes and positron emission tomography (PET) studies have shown decreased brain glucose metabolism (BGluM) in the striatum of detoxified MA users. The present study examines structural changes of the brain, observes microglial activation, and assesses changes in brain function, in response to chronic MA treatment. Rats were randomly split into three distinct treatment groups and treated daily for four months, via i.p. injection, with saline (controls), or low dose (LD) MA (4 mg/kg), or high dose (HD) MA (8 mg/kg). Sixteen weeks into the treatment period, rats were injected with a glucose analog, [18F] fluorodeoxyglucose (FDG), and their brains were scanned with micro-PET to assess regional BGluM. At the end of MA treatment, magnetic resonance imaging at 21T was performed on perfused rats to determine regional brain volume and in vitro [3H]PK 11195 autoradiography was performed on fresh-frozen brain tissue to measure microglia activation. When compared with controls, chronic HD MA-treated rats had enlarged striatal volumes and increases in [3H]PK 11195 binding in striatum, the nucleus accumbens, frontal cortical areas, the rhinal cortices, and the cerebellar nuclei. FDG microPET imaging showed that LD MA-treated rats had higher BGluM in insular and somatosensory cortices, face sensory nucleus of the thalamus, and brainstem reticular formation, while HD MA-treated rats had higher BGluM in primary and higher order somatosensory and the retrosplenial cortices, compared with controls. HD and LD MA-treated rats had lower BGluM in the tail of the striatum, rhinal cortex, and subiculum and HD MA also had lower BGluM in hippocampus than controls. These results corroborate clinical findings and help further examine the mechanisms behind MA-induced neurotoxicity

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer

PURPOSE: Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. PATIENTS AND METHODS: Men with chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. RESULTS: In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status ≥ 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade ≥ 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. CONCLUSION: In chemotherapy-naïve men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays