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Molecular targets in the treatment of alcoholic hepatitis

World Journal of Gastroenterology 2012年第39期18卷 5504-5513页

作者： Ashwin D Dhanda Richard Wl lee peter l collins C Anne McCune Department of liver Medicine University Hospitals Bristol NHS Foundation TrustBS2 8HW BristolUnited Kingdom Department of Cellular and Molecular Medicine School of Clinical SciencesUniversity of BristolBS9 1TD BristolUnited Kingdom

Alcohol related costs to health and society are high. One of the most serious complications of alcohol misuse to the individual is the development of alcoholic hepatitis (AH), a clinical syndrome of jaundice and progressive inflammatory liver injury in patients with a history of recent heavy alcohol use. It has a poor outcome and few existing successful therapies. The use of glucocorticoids in patients with severe AH is still controversial and there remains a group of patients with glucocorticoid-resistant disease. However, as our understanding of the pathogenesis of the condition improves there are opportunities to develop new targeted therapies with specific actions to control liver inflammation without having a detrimental effect on the immune system as a whole. In this article we review the molecular mechanisms of AH concentrating on the activation of the innate and adaptive immune response. We consider existing treatments including glucocorticoids, anti-tumor necrosis factor therapy and pentoxifylline and their limitations. Using our knowledge of the disease pathogenesis we discuss possible novel therapeutic approaches. New targets include pro-inflammatory cytokines such as interleukin (Il)-17, chemokines and their receptors (for example Il-8, CXCl9 and CXCR3) and augmentation of anti-inflam- matory molecules such as Il-10 and Il-22. And there is also future potential to consider combination therapy to selectively modulate the immune response and gain control of disease.

关键词： Alcoholic hepatitis Tumour necrosis factor-m Pentoxifylline Interleukins Chemokine receptors

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Infection does not increase long-term mortality in patients with acute severe alcoholic hepatitis treated with corticosteroids

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World Journal of Gastroenterology 2017年第11期23卷 2052-2059页

作者： Ashwin D Dhanda Ashish Sinha Vicky Hunt Sarah Saleem Matthew E Cramp peter l collins Institute of Translational and Stratified Medicine Plymouth University Peninsula Schools of Medicine and Dentistry South West liver Unit Plymouth Hospitals NHS Trust Department of liver Medicine University Hospitals Bristol NHS Foundation Trust

AIM To determine whether infection in patients with acute severe alcoholic hepatitis(AAH) treated with corticosteroids is associated with increased *** Consecutive patients with AAH were treated with steroids and recruited to the study. Clinically relevant infections(body temperature > 38 ℃ or l count > 0.25 ×109/l, consolidation on chest radiograph or clinically relevant positive microbiological culture of bodily fluid) were recorded prospectively. Clinical and laboratory parameters were recorded and survival at 90 d and 6 mo was determined. Univariate analysis of factors associated with 90-d mortality was performed and significant variables included in a multivariate *** Seventy-two patients were included in the final analysis(mean age 47.9 years, 26% female, mean discriminant function 53.0). Overall mortality in the group occurred in 15(21%), 23(32%) and 31(43%) at day 28, day 90 and 1 year respectively. 36(50%) had a clinically relevant infection during their hospitalisation(23 after initiation of steroids). The median time to development of incident infection after commencement of steroids was 10 d. The commonest site of infection was ascites(31%) and bacteraemia(31%) followed by urinary tract(19%) and respiratory tract(8%). Forty-one separate organisms were isolated in 33 patients; the most frequent genus was Escherichia(22%) and Enterococcus(20%). Infection was not associated with 90-d or 1 year mortality but was associated with higher creatinine, model for end-stage liver disease and lille score. Baseline urea was the only independent predictor of 90-d *** Clinically relevant infections are common in patients with AAH but are not associated with increased 90-d or 1 year mortality.

关键词： Alcoholic hepatitis Escherichia Infection lille score Corticosteroids

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Immune dysfunction in acute alcoholic hepatitis

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World Journal of Gastroenterology 2015年第42期21卷 11904-11913页

作者： Ashwin D Dhanda peter l collins School of Clinical Sciences University of Bristol NIHR Academic Clinical lecturer in Hepatology Institute of Translational and Stratified Medicine Plymouth University Peninsula Schools of Medicine and Dentistry South West liver Unit Plymouth Hospitals NHS Trust Department of liver Medicine University Hospitals Bristol NHS Foundation Trust

Acute alcoholic hepatitis(AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogenassociated molecular particles(PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors(mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this.

关键词： Alcoholic hepatitis Alcoholic liver disease Toll-l

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Is liver biopsy necessary in the management of alcoholic hepatitis?

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World Journal of Gastroenterology 2013年第44期19卷 7825-7829页

作者： Ashwin D Dhanda peter l collins C Anne McCune Department of liver Medicine University Hospitals Bristol NHS Foundation Trust Bristol BS2 8HW United Kingdom School of Clinical Sciences University of Bristol Bristol BS2 8HW United Kingdom

Acute alcoholic hepatitis(AAH)is characterised by deep jaundice in patients with a history of heavy alcohol use,which can progress to liver failure.A clinical diagnosis of AAH can be challenging to make in patients without a clear alcohol history or in the presence of risk factors for other causes of acute liver *** causes of acute on chronic liver failure such as sepsis or variceal haemorrhage should be *** biopsy remains the only reliable method to make an accurate ***,there is controversy surrounding the use of liver biopsy in patients with AAH because of the risks of performing a percutaneous biopsy and limitations in access to transjugular *** review the existing literature and find there are few studies directly comparing clinical and histological diagnosis of *** the small number of studies that have been conducted the correlation between a clinical and histological diagnosis of AAH is *** to this lack of agreement together with difficulties in accessing transjugular liver biopsy outside tertiary referral centres and research institutions,we cannot advocate universal biopsy for AAH but there remains a definite role for liver biopsy where there is clinical diagnostic doubt or dual *** adds value in a clinical trial context to ensure a homogeneous trial population and to further our understanding of the disease *** prospective studies are required to determine whether non-invasive markers can be used to accurately diagnose AAH.

关键词： Alcoholic hepatitis liver biopsy Diagnosis Prognosis Transjugular liver biopsy

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Dual Additives for Stabilizing li Deposition and SEI Formation in Anode-Free li-Metal Batteries

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Energy & Environmental Materials 2024年第3期7卷 84-92页

作者： Baolin Wu Chunguang Chen Dmitri l.Danilov Zhiqiang Chen Ming Jiang Rüdiger-A.Eichel peter H.l.Notten Forschungszentrum Jülich(IEK-9) D-52425Jülich Germany RWTH Aachen University D-52074Aachen Germany lNM Institute of MechanicsChinese Academy of SciencesBeijing 100190China School of Engineering Sciences University of Chinese Academy of SciencesBeijing 100049China Eindhoven University of Technology P.O.Box 5135600 MBEindhoven The Netherlands School of Electronics and Information Institute of Carbon Neutrality and New EnergyHangzhou Dianzi UniversityHangzhou 310018China University of Technology Sydney BroadwaySydney NSW 2007Australia

Anode-free li-metal batteries are of significant interest to energy storage industries due to their intrinsically high ***,the accumulative li dendrites and dead li continuously consume active li during *** results in a short lifetime and low Coulombic efficiency of anode-free li-metal *** effective electrolyte additives can improve the li deposition homogeneity and solid electrolyte interphase(SEI)stability for anode-free li-metal ***,we reveal that introducing dual additives,composed of liAsF6 and fluoroethylene carbonate,into a low-cost commercial carbonate electrolyte will boost the cycle life and average Coulombic efficiency of NMC‖Cu anode-free li-metal *** NMC‖Cu anode-free li-metal batteries with the dual additives exhibit a capacity retention of about 75%after 50 cycles,much higher than those with bare electrolytes(35%).The average Coulombic efficiency of the NMC‖Cu anode-free li-metal batteries with additives can maintain 98.3%over 100 *** contrast,the average Coulombic efficiency without additives rapidly decline to 97%after only 50 *** situ Raman measurements reveal that the prepared dual additives facilitate denser and smoother li morphology during li *** dual additives significantly suppress the li dendrite growth,enabling stable SEI formation on anode and cathode *** results provide a broad view of developing low-cost and high-effective functional electrolytes for high-energy and long-life anode-free li-metal batteries.

关键词： anode-free lithium metal battery dual additives in situ Raman li growth SEI formation

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地球演化历史中氧逸度变化对壳幔循环启动、风化和超大陆循环的指示

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Science Bulletin 2024年第1期69卷 97-102页

作者：王瑞邬绍宸 Roberto F.Weinberg William J.collins peter A.Cawood State Key laboratory of Geological Processes and Mineral Resources Institute of Earth SciencesChina University of GeosciencesBeijing 100083China Frontiers Science Center for Deep-time Digital Earth China University of Geosciences(Beijing)Beijing 100083China School of Earth Atmosphere and EnvironmentMonash UniversityClayton VIC 3800Australia The Institute for Geoscience Research Curtin UniversityPerth WA 6102Australia

We apply a zircon redox index to a global compilation of detrital zircons to track the variation of oxidation state,expressed asΔFMQ,through Earth's *** from I-type rocks,which comprise mantle and crustal igneous protoliths,including tonalite–trondhjemite–granodiorites(TTGs),generally have a high oxidation state(ΔFMQ>0).In contrast,zircons from igneous rocks derived from supracrustal source rocks(S-type)are commonly reduced(ΔFMQlity density function derived from the Gaussian-Kernel-Density-Estimation,we use the maximum likelihood estimation(MlE)to distinguish Stype from I-type zircons through Earth's history using zircon *** S-type magma production shows a ca.600 Ma cyclicity that is closely related to the supercontinent *** link a cyclic drop in redox values after 2.6 Ga to periodic S-type magma generation associated with burial and melting of metasedimentary rocks during supercontinent assembly and ***ΔFMQ of the detrital zircons rise at~3.5 Ga followed by a consistent averageΔFMQ>0 over the last 3 *** that the redox state of magmas is independent of crustal thickness and silica variation,and elevated values are likely more closely related to tectonic setting,we suggest that the consistent averageΔFMQ>0 from ca.3.5 Ga onwards relates to recycling of oceanic lithosphere back into the mantle in what eventually became established as subduction *** more reduced magmas associated with sedimentary sources,became established at 2.6 Ga,presumably in response to continental rocks rising above sealevel,and follow peaks of productivity associated with the supercontinent cycle.

关键词： Oxidation state Supercontinent Weathering Subduction Zircon Granite

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A flexible,thin-film microchannel electrode array device for selective subdiaphragmatic vagus nerve recording

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Microsystems & Nanoengineering 2024年第1期10卷 115-128页

作者： Jongcheon lim peter A.Zoss Terry l.Powley Hyowon lee Matthew P.Ward Weldon School of Biomedical Engineering Purdue UniversityWest LafayetteINUSA Birck Nanotechnology Center Purdue UniversityWest LafayetteINUSA Center for Implantable Devices Purdue UniversityWest LafayetteINUSA Department of Psychological Sciences Purdue UniversityWest LafayetteINUSA Purdue Institute of Integrative Neuroscience Purdue UniversityWest LafayetteINUSA Indiana University School of Medicine IndianapolisINUSA

The vagus nerve(VN)plays an important role in regulating physiological conditions in the gastrointestinal(GI)tract by communicating via the parasympathetic pathway to the enteric nervous system(ENS).However,the lack of knowledge in the neurophysiology of the VN and GI tract limits the development of advanced treatments for autonomic dysfunctions related to the *** better understand the complicated underlying mechanisms of the VN-GI tract neurophysiology,it is necessary to use an advanced device enabled by microfabrication *** several candidates including intraneural probe array and extraneural cuff electrodes,microchannel electrode array devices can be used to interface with smaller numbers of nerve fibers by securing them in the separate channel *** microchannel electrode array devices to interface teased nerve structures are relatively bulky with thickness around 200µ*** thick design can potentially harm the delicate tissue structures,including the nerve *** this paper,we present a flexible thin film based microchannel electrode array device(thickness:11.5µm)that can interface with one of the subdiaphragmatic nerve branches of the VN in a *** demonstrated recording evoked compound action potentials(ECAP)from a transected nerve ending that has multiple nerve ***,our analysis confirmed that the signals are from C-fibers that are critical in regulating autonomic neurophysiology in the GI tract.

关键词： electrode recording film

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Unifying concepts in methanogenic,aerobic,and anammox sludge granulation

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Environmental Science and Ecotechnology 2024年第1期17卷 17-30页

作者： Simon Mills Anna Christine Trego Marco Prevedello Jo De Vrieze Vincent O’Flaherty Piet N.l.lens Gavin collins Microbial Communities laboratory School of Biological and Chemical SciencesNational University of Ireland GalwayUniversity RoadGalwayH91 TK33Ireland Microbial Ecology laboratory School of Biological and Chemical Sciences University of GalwayUniversity RoadGalwayH91 TK33Ireland Center for Microbial Ecology and Technology(CMET) Ghent UniversityCoupure Links 653B-9000GentBelgium University of Galway University RoadGalwayH91 TK33Ireland

The retention of dense and well-functioning microbial biomass is crucial for effective pollutant removal in several biological wastewater treatment *** solids retention is often achieved through aggregation of microbial communities into dense,spherical aggregates known as granules,which were initially discovered in the *** granules have since been widely applied in upflow anaerobic digesters for waste-to-energy ***,granular biomass has been applied in aerobic wastewater treatment and anaerobic ammonium oxidation(anammox)*** mechanisms underpinning the formation of methanogenic,aerobic,and anammox granules are the subject of ongoing *** each granule type has been extensively studied in isolation,there has been a lack of comparative studies among these granulation *** is likely that there are some unifying concepts that are shared by all three sludge *** these unifying concepts could allow a unified theory of granulation to be ***,we review the granulation mechanisms of methanogenic,aerobic,and anammox granular sludge,highlighting several common concepts,such as the role of extracellular polymeric substances,cations,and operational parameters like upflow velocity and shear *** have then identified some unique features of each granule type,such as different internal structures,microbial compositions,and quorum sensing ***,we propose that future research should prioritize aspects of microbial ecology,such as community assembly or interspecies interactions in individual granules during their formation and growth.

关键词： Granule Granulation Anaerobic digestion Anammox Aerobic granule

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Quantifying source-sink relationships in leaf-color modified rice genotypes during grain filling

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Journal of Integrative Agriculture 2024年第9期23卷 2923-2940页

作者： Zhenxiang Zhou Paul CStruik Junfei Gu peter E.l.van der Putten Zhiqin Wang Jianchang Yang Xinyou Yin Centre for Crop Systems Analysis Department of Plant SciencesWageningen University&ResearchWageningen 6700 AKThe Netherlands College of Agriculture Yangzhou UniversityYangzhou 225009China

leaf-color modification can affect canopy photosynthesis,with potential effects on rice yield and yield *** source-sink relationships through crop management is often used to improve crop *** study investigated whether and how modifying leaf color alters source-sink relationships and whether current crop cultivation practices remain applicable for leaf-color modified *** collected data of total biomass and nitrogen(N)accumulation in rice genotypes of four genetic backgrounds and their leaf-color modified variants(greener or yellower)were analyzed,using a recently established modelling method to quantify the source-sink(im)balance during grain *** all leaf-color variants,only one yellower-leaf variant showed a higher source capacity than its normal *** was associated with greater post-flowering N-uptake that prolonged the functional leaf-N duration,and this greater post-flowering N-uptake was possible because of reduced pre-flowering N-uptake.A density experiment showed that current management practices(insufficient planting density accompanied by abundant N application)are unsuitable for the yellower-leaf genotype,ultimately limiting its yield ***-color modification affects source-sink relationships by regulating the N trade-off between pre-and post-flowering uptake,as well as N translocation between source and sink *** best exploit leaf-color modification for improving crop productivity,adjustments of crop management practices are required.

关键词： source-sink relationship biomass nitrogen Oryza sativa leaf-color modification

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Towards implementation of alloy-specific thermo-fluid modelling for laser powder-bed fusion of Mg alloys

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Journal of Magnesium and Alloys 2024年第6期12卷 2327-2344页

作者： Mohammad Hoseini-Athar Mikael Ersson peter Hedström Department of Material Science and Engineering KTH Royal Institute of TechnologyStockholmSE-10044 Sweden

Multi-physics thermo-fluid modeling has been extensively used as an approach to understand melt pool dynamics and defect formation as well as optimizing the process-related parameters of laser powder-bed fusion(l-PBF).However,its capabilities for being implemented as a reliable tool for material design,where minor changes in material-related parameters must be accurately captured,is still in *** the present research,first,a thermo-fluid computational fluid dynamics(CFD)model is developed and validated against experimental *** the predicted material properties of the pure Mg and commercial ZK60 and WE43 Mg alloys,parametric studies are done attempting to elucidate how the difference in some of the material properties,i.e.,saturated vapor pressure,viscosity,and solidification range,can influence the melt pool *** is found that a higher saturated vapor pressure,associated with the ZK60 alloy,leads to a deeper unstable keyhole,increasing the keyhole-induced porosity and evaporation mass *** viscosity and wider solidification range can increase the non-uniformity of temperature and velocity distribution on the keyhole walls,resulting in increased keyhole instability and formation of ***,the WE43 alloy showed the best behavior in terms of defect formation and evaporation mass loss,providing theoretical support to the extensive use of this alloy in *** summary,this study suggests an approach to investigate the effect of materials-related parameters on l-PBF melting and solidification,which can be extremely helpful for future design of new alloys suitable for l-PBF.

关键词： Mg alloys laser powder-bed fusion(l-PBF) Melt pool dynamics Computational fluid dynamics Fluid flow

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