Spared Nerve Injury Causes Sexually Dimorphic Mechanical Allodynia and Differential Gene Expression in Spinal Cords and Dorsal Root Ganglia in Rats

Neuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.Peer reviewe

Simulated sensitivity of African terrestrial ecosystem photosynthesis to rainfall frequency, intensity, and rainy season length

There is growing evidence of ongoing changes in the statistics of intra-seasonal rainfall variability over large parts of the world. Changes in annual total rainfall may arise from shifts, either singly or in a combination, of distinctive intra-seasonal characteristics –i.e. rainfall frequency, rainfall intensity, and rainfall seasonality. Understanding how various ecosystems respond to the changes in intra-seasonal rainfall characteristics is critical for predictions of future biome shifts and ecosystem services under climate change, especially for arid and semi-arid ecosystems. Here, we use an advanced dynamic vegetation model (SEIB-DGVM) coupled with a stochastic rainfall/weather simulator to answer the following question: how does the productivity of ecosystems respond to a given percentage change in the total seasonal rainfall that is realized by varying only one of the three rainfall characteristics (rainfall frequency, intensity, and rainy season length)? We conducted ensemble simulations for continental Africa for a realistic range of changes (−20% ~ +20%) in total rainfall amount. We find that the simulated ecosystem productivity (measured by gross primary production, GPP) shows distinctive responses to the intra-seasonal rainfall characteristics. Specifically, increase in rainfall frequency can lead to 28% more GPP increase than the same percentage increase in rainfall intensity; in tropical woodlands, GPP sensitivity to changes in rainy season length is ~4 times larger than to the same percentage changes in rainfall frequency or intensity. In contrast, shifts in the simulated biome distribution are much less sensitive to intra-seasonal rainfall characteristics than they are to total rainfall amount. Our results reveal three major distinctive productivity responses to seasonal rainfall variability—'chronic water stress', 'acute water stress' and 'minimum water stress' - which are respectively associated with three broad spatial patterns of African ecosystem physiognomy, i.e. savannas, woodlands, and tropical forests

Evaluation of land surface models in reproducing satellite-derived LAI over the high-latitude northern hemisphere. Part I: Uncoupled DGVMs

PublishedJournal ArticleLeaf Area Index (LAI) represents the total surface area of leaves above a unit area of ground and is a key variable in any vegetation model, as well as in climate models. New high resolution LAI satellite data is now available covering a period of several decades. This provides a unique opportunity to validate LAI estimates from multiple vegetation models. The objective of this paper is to compare new, satellite-derived LAI measurements with modeled output for the Northern Hemisphere. We compare monthly LAI output from eight land surface models from the TRENDY compendium with satellite data from an Artificial Neural Network (ANN) from the latest version (third generation) of GIMMS AVHRR NDVI data over the period 1986-2005. Our results show that all the models overestimate the mean LAI, particularly over the boreal forest. We also find that seven out of the eight models overestimate the length of the active vegetation-growing season, mostly due to a late dormancy as a result of a late summer phenology. Finally, we find that the models report a much larger positive trend in LAI over this period than the satellite observations suggest, which translates into a higher trend in the growing season length. These results highlight the need to incorporate a larger number of more accurate plant functional types in all models and, in particular, to improve the phenology of deciduous trees. © 2013 by the authors.The corresponding author also thanks the CONACYT-CECTI and the University of Exeter for their funding during the PhD studies. The National Center for Atmospheric Research is sponsored by the National Science Foundation

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial

Background: Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are part of the standard of care for patients with chronic kidney disease (CKD), both with and without type 2 diabetes. Endothelin A (ETA) receptor antagonists have also been shown to slow progression of CKD. Differing mechanisms of action of SGLT2 and ETA receptor antagonists may enhance efficacy. We outline a study to evaluate the effect of combination zibotentan/dapagliflozin versus dapagliflozin alone on albuminuria and estimated glomerular filtration rate (eGFR). // Methods: We are conducting a double-blind, active-controlled, Phase 2b study to evaluate the efficacy and safety of ETA receptor antagonist zibotentan and SGLT2i dapagliflozin in a planned 415 adults with CKD (Zibotentan and Dapagliflozin for the Treatment of CKD; ZENITH-CKD). Participants are being randomized (1:2:2) to zibotentan 0.25 mg/dapagliflozin 10 mg once daily (QD), zibotentan 1.5 mg/dapagliflozin 10 mg QD and dapagliflozin 10 mg QD alone, for 12 weeks followed by a 2-week off-treatment wash-out period. The primary endpoint is the change in log-transformed urinary albumin-to-creatinine ratio (UACR) from baseline to Week 12. Other outcomes include change in blood pressure from baseline to Week 12 and change in eGFR the study. The incidence of adverse events will be monitored. Study protocol–defined events of special interest include changes in fluid-related measures (weight gain or B-type natriuretic peptide). // Results: A total of 447 patients were randomized and received treatment in placebo/dapagliflozin (n = 177), zibotentan 0.25 mg/dapagliflozin (n = 91) and zibotentan 1.5 mg/dapagliflozin (n = 179). The mean age was 62.8 years, 30.9% were female and 68.2% were white. At baseline, the mean eGFR of the enrolled population was 46.7 mL/min/1.73 m2 and the geometric mean UACR was 538.3 mg/g. // Conclusion: This study evaluates the UACR-lowering efficacy and safety of zibotentan with dapagliflozin as a potential new treatment for CKD. The study will provide information about an effective and safe zibotentan dose to be further investigated in a Phase 3 clinical outcome trial. // Clinical Trial Registration Number: NCT0472483

Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.Peer reviewe

Multicriteria evaluation of discharge simulation in Dynamic Global Vegetation Models

PublishedJournal Article© 2015. American Geophysical Union. All Rights Reserved. In this study, we assessed the performance of discharge simulations by coupling the runoff from seven Dynamic Global Vegetation Models (DGVMs; LPJ, ORCHIDEE, Sheffield-DGVM, TRIFFID, LPJ-GUESS, CLM4CN, and OCN) to one river routing model for 16 large river basins. The results show that the seasonal cycle of river discharge is generally modeled well in the low and middle latitudes but not in the high latitudes, where the peak discharge (due to snow and ice melting) is underestimated. For the annual mean discharge, the DGVMs chained with the routing model show an underestimation. Furthermore, the 30 year trend of discharge is also underestimated. For the interannual variability of discharge, a skill score based on overlapping of probability density functions (PDFs) suggests that most models correctly reproduce the observed variability (correlation coefficient higher than 0.5; i.e., models account for 50% of observed interannual variability) except for the Lena, Yenisei, Yukon, and the Congo river basins. In addition, we compared the simulated runoff from different simulations where models were forced with either fixed or varying land use. This suggests that both seasonal and annual mean runoff has been little affected by land use change but that the trend itself of runoff is sensitive to land use change. None of the models when considered individually show significantly better performances than any other and in all basins. This suggests that based on current modeling capability, a regional-weighted average of multimodel ensemble projections might be appropriate to reduce the bias in future projection of global river discharge.National Natural Science Foundation of China. Grant Numbers: 41125004, 31321061, Chinese Ministry of Environmental Protection. Grant Number: 201209031, 111 Project. Grant Number: B14001, National Youth Top-notch Talent Support Program in China, Imbalance-P ERC-synergy, TRENDY, Global River Discharge Cente

Conformational and Structural Relaxations of Poly(ethylene oxide) and Poly(propylene oxide) Melts: Molecular Dynamics Study of Spatial Heterogeneity, Cooperativity, and Correlated Forward-Backward Motion

Performing molecular dynamics simulations for all-atom models, we characterize the conformational and structural relaxations of poly(ethylene oxide) and poly(propylene oxide) melts. The temperature dependence of these relaxation processes deviates from an Arrhenius law for both polymers. We demonstrate that mode-coupling theory captures some aspects of the glassy slowdown, but it does not enable a complete explanation of the dynamical behavior. When the temperature is decreased, spatially heterogeneous and cooperative translational dynamics are found to become more important for the structural relaxation. Moreover, the transitions between the conformational states cease to obey Poisson statistics. In particular, we show that, at sufficiently low temperatures, correlated forward-backward motion is an important aspect of the conformational relaxation, leading to strongly nonexponential distributions for the waiting times of the dihedrals in the various conformational statesComment: 13 pages, 13 figure

Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis

<p>Abstract</p> <p>Background</p> <p>The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.</p> <p>Objective</p> <p>To examine whether a dual CCR3 and H₁-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis.</p> <p>Methods</p> <p>Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and α₂-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation.</p> <p>Results</p> <p>Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine.</p> <p>Conclusions</p> <p>AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.</p> <p>Trial registration</p> <p>EudraCT No: 2005-002805-21.</p