Ammonia is believed to eventually play an important role in substituting conventional fossil fuels for future energy systems. In this study, to gain a deep insight into the combustion properties of ...co-firing ammonia/methane fuel blends for the power and steel industry, a detailed chemical-kinetics mechanism model was developed for comprehensively modelling ammonia/methane fuels combustion. Characteristics of ignition delay time, unstretched laminar flame speed and NO, CO2 and CO emissions in the exhaust gas were obtained over a wide range of equivalence ratios and ammonia fractions. High NO emissions will be a main problem as CO and CO2 emissions tend to drop when adding ammonia into methane. To gain a further understanding of the effect of ammonia substituting methane for combustion use, analyses of laminar premixed flame structures were performed. The impact of ammonia substitution was illustrated by analysing relevant specific radicals. Furthermore, to study the combustion characteristics of ammonia/methane under more practical conditions, effects of engine relevant conditions (elevated pressure and initial temperature) were also studied. Results indicate that pressure has a more prominent effect than initial temperature and there is a good potential that unwanted emissions can be reduced significantly under industrial conditions.
•Co-firing NH3/CH4 is a possible choice to reduce carbon emissions.•A comprehensive study on combustion characteristics of NH3/CH4.•A detailed chemical mechanism is proposed for ammonia-based fuel.•Different properties such as flame speed, emission level, etc. are studied.•Engine relevant conditions are studied for practical application of NH3/CH4.
Background
We describe a multidisciplinary approach for comprehensive care of amputees with concurrent targeted muscle reinnervation (TMR) at the time of amputation.
Methods
Our TMR cohort was ...compared to a cross‐sectional sample of unselected oncologic amputees not treated at our institution (N = 58). Patient‐Reported Outcomes Measurement Information System (NRS, PROMIS) were used to assess postamputation pain.
Results
Thirty‐one patients underwent amputation with concurrent TMR during the study; 27 patients completed pain surveys; 15 had greater than 1 year follow‐up (mean follow‐up 14.7 months). Neuroma symptoms occurred significantly less frequently and with less intensity among the TMR cohort. Mean differences for PROMIS pain intensity, behavior, and interference for phantom limb pain (PLP) were 5.855 (95%CI 1.159‐10.55; P = .015), 5.896 (95%CI 0.492‐11.30; P = .033), and 7.435 (95%CI 1.797‐13.07; P = .011) respectively, with lower scores for TMR cohort. For residual limb pain, PROMIS pain intensity, behavior, and interference mean differences were 5.477 (95%CI 0.528‐10.42; P = .031), 6.195 (95%CI 0.705‐11.69; P = .028), and 6.816 (95%CI 1.438‐12.2; P = .014), respectively. Fifty‐six percent took opioids before amputation compared to 22% at 1 year postoperatively.
Conclusions
Multidisciplinary care of amputees including concurrent amputation and TMR, multimodal postoperative pain management, amputee‐centered rehabilitation, and peer support demonstrates reduced incidence and severity of neuroma and PLP.
Breeding apples is a long-term endeavour and it is imperative that new cultivars are selected to have outstanding consumer appeal. This study has taken the approach of merging sensory science with ...genome wide association analyses in order to map the human perception of apple flavour and texture onto the apple genome. The goal was to identify genomic associations that could be used in breeding apples for improved fruit quality. A collection of 85 apple cultivars was examined over two years through descriptive sensory evaluation by a trained sensory panel. The trained sensory panel scored randomized sliced samples of each apple cultivar for seventeen taste, flavour and texture attributes using controlled sensory evaluation practices. In addition, the apple collection was subjected to genotyping by sequencing for marker discovery. A genome wide association analysis suggested significant genomic associations for several sensory traits including juiciness, crispness, mealiness and fresh green apple flavour. The findings include previously unreported genomic regions that could be used in apple breeding and suggest that similar sensory association mapping methods could be applied in other plants.
A majority of the nearly 2 million Americans living with limb loss suffer from chronic pain in the form of neuroma-related residual limb and phantom limb pain (PLP). Targeted muscle reinnervation ...(TMR) surgically transfers amputated nerves to nearby motor nerves for prevention of neuroma. The objective of this study was to determine whether TMR at the time of major limb amputation decreases the incidence and severity of PLP and residual limb pain.
A multi-institutional cohort study was conducted between 2012 and 2018. Fifty-one patients undergoing major limb amputation with immediate TMR were compared with 438 unselected major limb amputees. Primary outcomes included an 11-point Numerical Rating Scale (NRS) and Patient-Reported Outcomes Measurement Information System (PROMIS) pain intensity, behavior, and interference.
Patients who underwent TMR had less PLP and residual limb pain compared with untreated amputee controls, across all subgroups and by all measures. Median “worst pain in the past 24 hours” for the TMR cohort was 1 out of 10 compared to 5 (PLP) and 4 (residual) out of 10 in the control population (p = 0.003 and p < 0.001, respectively). Median PROMIS t-scores were lower in TMR patients for both PLP (pain intensity 36.3 vs 48.3, pain behavior 50.1 vs 56.6, and pain interference 40.7 vs 55.8) and residual limb pain (pain intensity 30.7 vs 46.8, pain behavior 36.7 vs 57.3, and pain interference 40.7 vs 57.3). Targeted muscle reinnervation was associated with 3.03 (PLP) and 3.92 (residual) times higher odds of decreasing pain severity compared with general amputee participants.
Preemptive surgical intervention of amputated nerves with TMR at the time of limb loss should be strongly considered to reduce pathologic phantom limb pain and symptomatic neuroma-related residual limb pain.
Akt Pathway Inhibitors Uko, Nne E; Güner, Osman F; Matesic, Diane F ...
Current topics in medicinal chemistry,
01/2020, Volume:
20, Issue:
10
Journal Article
Peer reviewed
Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the ...war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.
To identify by systematic review published prevalence estimates of radiographic ankle osteoarthritis (OA) and to subsequently estimate the prevalence of ankle pain and symptomatic, radiographic ankle ...OA within community-dwelling older adults from North Staffordshire, UK.
Electronic databases were searched using terms for ankle, osteoarthritis and radiography. Data regarding population, radiographic methods, definitions and prevalence estimates of ankle OA were extracted from papers meeting predetermined selection criteria. Adults aged ≥50 years and registered with four general practices in North Staffordshire were mailed a health questionnaire. Ankle pain in the previous month was determined using a foot and ankle pain manikin. Respondents reporting pain in or around the foot in the last 12 months were invited to attend a research clinic where weight-bearing, antero-posterior and lateral ankle radiographs were obtained and scored for OA using a standardised atlas. Prevalence estimates for ankle pain and symptomatic, radiographic ankle OA were calculated using multiple imputation and weighted logistic regression, and stratified by age, gender and socioeconomic status.
Eighteen studies were included in the systematic review. The methods of radiographic classification of ankle OA were poorly reported and showed heterogeneity. No true general population prevalence estimates of radiographic ankle OA were found, estimates in select sporting and medical community-dwelling populations ranged from 0.0-97.1%. 5109 participants responded to the health survey questionnaire (adjusted response 56%). Radiographs were obtained in 557 participants. The prevalence of ankle pain was 11.7% (10.8,12.6) and symptomatic, radiographic ankle OA grade≥2 was 3.4% (2.3, 4.5) (grade≥1: 8.8% (7.9,9.8); grade = 3: 1.9% (1.0,2.7). Prevalence was higher in females, younger adults (50-64 years) and those with routine/manual occupations.
No general population prevalence estimates of radiographic ankle OA were identified in the published literature. Our prevalence study found that ankle pain was common in community-dwelling older adults, whereas moderate to severe symptomatic, radiographic ankle OA occurred less frequently. Further investigations of the prevalence of ankle OA using more sensitive imaging modalities are warranted.
An accurate representation of the spatial distribution of stable hydrogen and oxygen isotopes in modern precipitation is required for many hydrological, paleoclimate, and ecological applications. No ...standardized method for achieving such a representation exists, and potential errors associated with previously employed methods are not understood. Using resampling, we test the accuracy of interpolated δD and δ18O estimates made using four methods. Prediction error for all methods is strongly related to number of data and will likely decline with the addition of new data. The best method lowers estimation error by 10–15% relative to others tested and gives an average error, using all available data, ≈2.5% of the global range. We present and interpret global maps of interpolated δD, δ18O, and deuterium excess in precipitation and the 95% confidence intervals for these values created using the optimal method. These depict global and regional patterns, make evident the robustness of interpolated isotopic patterns, and highlight target areas for future precipitation sampling.
Intra‐annual variation in the stable isotope ratios of precipitation imparts a time‐dependent isotopic signal to continental hydrological and ecological systems. This variation is forced by seasonal ...climate cycles, with temperature and precipitation intensity each driving isotopic seasonality in different parts of the globe. In order to better characterize and understand the isotopic seasonality of precipitation and to advance applications such as the inversion of isotope/climate relationships for paleoclimate seasonality reconstruction, these relationships are analyzed using a database of precipitation isotope ratio observations and gridded maps. The results confirm the overwhelming dominance of temperature‐ and precipitation amount–related isotopic seasonality within specific, well‐defined geographic zones and indicate that these zones encompass most of Earth's continental land surface. Analysis of global maps of precipitation isotopic seasonality, however, indicates spatially patterned variation in isotope/climate relationships, including patterns related to continentality in temperature‐dominated regions and meridional trends in amount‐dominated areas. These features reflect more complex climatological controls on isotope seasonality and suggest limitations and opportunities for paleoclimate reconstruction using isotopic archives.
The lateral parabrachial nucleus is a conduit for visceral signals that cause anorexia. We previously identified a subset of neurons located in the external lateral parabrachial nucleus (PBel) that ...express calcitonin gene-related peptide (CGRP) and inhibit feeding when activated by illness mimetics. We report here that in otherwise normal mice, functional inactivation of CGRP neurons markedly increases meal size, with meal frequency being reduced in a compensatory manner, and renders mice insensitive to the anorexic effects of meal-related satiety peptides. Furthermore, CGRP neurons are directly innervated by orexigenic hypothalamic AgRP neurons, and photostimulation of AgRP fibers supplying the PBel delays satiation by inhibiting CGRP neurons, thereby contributing to AgRP-driven hyperphagia. By establishing a role for CGRP neurons in the control of meal termination and as a downstream mediator of feeding elicited by AgRP neurons, these findings identify a node in which hunger and satiety circuits interact to control feeding behavior.
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•Parabrachial CGRP neurons contribute to physiological control of appetite•Inactivation of CGRP neurons decreases perception of meal-induced satiety signals•Hunger-activated AgRP neurons are connected to and inhibit CGRP neurons•CGRP neurons constrict feeding elicited by AgRP neuron activation
Campos et al. show that parabrachial CGRP neurons transduce meal-related satiety signals and inactivation of these neurons impairs the ability of mice to terminate meals. CGRP neurons are also inhibited by orexigenic AgRP neurons, and concurrent activation of AgRP neurons and silencing of CGRP neurons leads to uncontrolled feeding.
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•The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in microglia-mediated inflammation.•Activation of microglia is ...involved in pathogenesis of neurodegenerative and neuroinflammatory diseases.•AMS-17 inhibits microglia activation in vitro and in vivo by inhibiting expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1β and inducible nitric oxide synthase (iNOS).•The present results provide promising evidences for the inhibitory effects of AMS-17 in inflammation which can be further developed for the treatment of inflammation-associated neurological disorders.
The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays an important role in microglia-mediated inflammation. Dysregulation of NLRP3 signaling results in microglial activation and triggers inflammatory responses contributing to the development of neurological disorders including ischemic stroke, schizophrenia, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Inhibition of the NLRP3-linked inflammatory pathways reduces microglia-induced inflammation and is considered as a promising therapeutic approach for neuro-inflammatory diseases. In the present study, we report the development of AMS-17, a rationally-designed tertiary sulfonylurea compound for inhibition of inflammation in microglia. AMS-17 inhibited expression of the NLRP3, and its downstream components and cytokines such as caspase-1, tumor necrosis factor-α (TNF-α), IL-1β and inducible nitric oxide synthase (iNOS). It also suppressed lipopolysaccharide (LPS)-induced N9 microglial cell phagocytosis in vitro and activation of the microglia in mouse brain in vivo. Together, these results provide promising evidences for the inhibitory effects of AMS-17 in inflammation. This proof-of-concept study provides a new chemical scaffold, designed with the aid of pharmacophore modeling, with NLRP3 inhibitory activity which can be further developed for the treatment of inflammation-associated neurological disorders.
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