Development of vacuum ultraviolet spectroscopy for measuring edge impurity emission in the EAST tokamak

The dominant wavelength range of edge impurity emissions moves from the visible range to the vacuum ultraviolet(VUV)range,as heating power increasing in the Experimental Advanced Superconducting Tokamak(EAST).The measurement provided by the existing visible spectroscopies in EAST is not sufficient for impurity transport studies for high-parameters plasmas.Therefore,in this study,a VUV spectroscopy is newly developed to measure edge impurity emissions in EAST.One Seya-Namioka VUV spectrometer(McPherson 234/302)is used in the system,equipped with a concave-corrected holographic grating with groove density of 600 grooves mm-1.Impurity line emissions can be observed in the wavelength range ofλ=50-700 nm,covering VUV,near ultraviolet and visible ranges.The observed vertical range is Z=-350-350 mm.The minimum sampling time can be set to 5 ms under full vertical binning(FVB)mode.VUV spectroscopy has been used to measure the edge impurity emission for the 2019 EAST experimental campaign.Impurity spectra are identified for several impurity species,i.e.,lithium(Li),carbon(C),oxygen(O),and iron(Fe).Several candidates for tungsten(W)lines are also measured but their clear identification is very difficult due to a strong overlap with Fe lines.Time evolutions of impurity carbon emissions of CⅡat 134.5 nm and CⅢat 97.7 nm are analyzed to prove the system capability of time-resolved measurement.The measurements of the VUV spectroscopy are very helpful for edge impurity transport study in the high-parameters plasma in EAST.

Fighting age-related orthopedic diseases: focusing on ferroptosis

Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It is closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid metabolism, and the biosynthesis of compounds with antioxidant activities, including glutathione. In the past 10 years, increasing evidence has indicated a potentially strong relationship between ferroptosis and the onset and progression of age-related orthopedic diseases, such as osteoporosis and osteoarthritis. Therefore, in-depth knowledge of the regulatory mechanisms of ferroptosis in age-related orthopedic diseases may help improve disease treatment and prevention. This review provides an overview of recent research on ferroptosis and its influences on bone and cartilage homeostasis. It begins with a brief overview of systemic iron metabolism and ferroptosis,particularly the potential mechanisms of ferroptosis. It presents a discussion on the role of ferroptosis in age-related orthopedic diseases, including promotion of bone loss and cartilage degradation and the inhibition of osteogenesis. Finally, it focuses on the future of targeting ferroptosis to treat age-related orthopedic diseases with the intention of inspiring further clinical research and the development of therapeutic strategies.

Measurement of molybdenum ion density for L-mode and H-mode plasma discharges in the EAST tokamak

We report the measurement of total molybdenum ion density for L-mode and H-mode plasmas on EAST using spectral lines observation and calculation based on an impurity transport code.A flat-filed extreme ultraviolet spectrometer with some spatial resolution is used to obtain the radial profiles of molybdenum spectral line emissions.The absolute calibration for the extreme ultraviolet spectrometer is finished by comparing the calculated bremsstrahlung intensity with the readings of CCD detector.Molybdenum ion transport study is performed using the radial ion density profiles and one-dimensional impurity transport code STRAHL.The total molybdenum density profiles are determined from the transport analysis.The molybdenum density during L-mode and H-mode phases are obtained,which are about 3 and 4 orders of magnitude smaller than the electron density,respectively.An inward pinch is found during the H-mode phase that leads to the peaked profile of molybdenum density.

Space-resolved vacuum-ultraviolet spectroscopy for measuring impurity emission from divertor region of EAST tokamak

The measurement of impurity distribution in the divertor region of tokamaks is key to studying edge impurity transport.Therefore,a space-resolved vacuum-ultraviolet(VUV)spectrometer is designed to measure impurity emission in the divertor region on EAST.For good spectral resolution,an eagle-type VUV spectrometer with 1 m long focal length with spherical holograph grating is used in the system.For light collection,a collimating mirror is installed between the EAST plasma and the VUV spectrometer to extend the observing range to cover the upper divertor region.Two types of detectors,i.e.a back-illuminated charge-coupled device detector and a photomultiplier-tube detector,are adopted for the spectral measurement and high-frequency intensity measurement for feedback control,respectively.The angle between the entrance and exit optical axis is fixed at 15°.The detector can be moved along the exit axis to maintain a good focusing position when the wavelength is scanned by rotating the grating.The profile of impurity emissions is projected through the space-resolved slit,which is set horizontally.The spectrometer is equipped with two gratings with 2400 grooves/mm and2160 grooves/mm,respectively.The overall aberration of the system is reduced by accurate detector positioning.As a result,the total spectral broadening can be reduced to about 0.013 nm.The simulated performance of the system is found to satisfy the requirement of measurement of impurity emissions from the divertor area of the EAST tokamak.

Observation and characterization of the effect of electron cyclotron waves on toroidal rotation in EAST L-mode discharges

The change in the toroidal rotation of plasma caused by electron cyclotron wave（ECW） injection has been observed in EAST. It is found that the response of the rotation is similar for all possible ECW toroidal injection angles. The core toroidal rotation velocity increases in the co-current direction along with a rise in the plasma temperature and stored energy. The profile of the electron temperature, ion temperature and toroidal rotation velocity gradually become peaked.The change in toroidal rotation in the core increases with the ECW injection power. Different behavior is observed when the ECWs are injected into low hybrid current drive（LHCD） target plasmas, where the electron temperature and rotation profile become peaked, while the ion temperature profile flattens after ECW injection, suggesting different transport characteristics in energy and momentum.

Measurement of tungsten impurity spectra with a two-crystal X-ray crystal spectrometer on EAST

Spectral measurement of tungsten(W)impurity is essential to study impurity transport.Therefore,an X-ray crystal spectrometer(XCS)on EAST was used to measure the line spectra from highly ionized W ions.On EAST,both poloidal XCS and tangential XCS have been developed to measure the plasma temperature as well as the rotation velocity.Recently,He-like and H-like argon spectra have also been obtained using a two-crystal setup.W lines are identified in this study.Through a careful analysis,the W lines of 3.9336,3.9321,and 3.664(A)are found to be diffracted by He-like or H-like crystals.The lines are confirmed with the NIST database.We also calculated the ion temperature with Doppler broadening of these lines.The ion temperature from the W lines is entirely consistent with that from Ar line spectra.The measurement of these W line spectra could be used to study W impurity transport in future work.

Inversion techniques to obtain local rotation velocity and ion temperature profiles for the x-ray crystal spectrometer on EAST

Inversion techniques are conducted based on the tangential x-ray crystal spectroscopy(TXCS)geometry on EAST to obtain the local profiles of ion temperature(Ti)and toroidal rotation velocity(vt).Firstly,local emissivity profiles of the impurity argon are obtained using the asymmetrical Abel inversion.Then,the local vt and Ti profiles are calculated by considering the local emissivity profiles and the TXCS detailed geometry.In addition,how the changes in the vt profiles affect the accuracy in the Ti profiles is discussed in detail.It is also found that the lineintegrated Ti profiles are becoming less accurate with the increase in the radial gradient in the local vt profiles.Nonetheless,accurate Ti radial profiles are reconstructed after considering the effects of the emissivity and velocity,which are verified by comparing the inverted vt and Ti profiles with those local profile measurements from the Charge eXchange Recombination Spectroscopy(CXRS)on EAST.

Measurement of impurity lines with two-crystal x-ray spectrometers on EAST

To simultaneously measure the He-like and H-like argon spectra, a two-crystal assembly has been deployed to replace the previous single crystal on the tangential x-ray crystal spectrometer.By selecting appropriate crystals with similar Bragg angles, plasma temperature in the range of 0.5 keV≤Te≤10 keV and rotation can be diagnosed based on the He-like and H-like argon spectra. However, due to the added complexity in the two-crystal assembly in which the spectra might be diffracted by two crystals, some additional impurity lines were identified. For example,tungsten（W） lines in different ionization states were diffracted by the He-like and H-like crystal.Additional molybdenum（Mo） lines in the wavelength range of He-like and H-like argon spectra lines were also summarized. The existence of these additional lines caused the fitted temperature to be different from the true values. This paper presents the identified lines through a comparison with available database, which should be included in the fitting procedure.

First experimental results of intrinsic torque on EAST

Direct measurements of the intrinsic torque profile in L-mode plasmas on the EAST tokamak have been performed using the balanced neutral beam injection.Co-and counter-current neutral beams are modulated to balance the intrinsic and externally injected torques, which result in the rotation profile close to zero and flat.The experimental results show that the intrinsic torque derived from momentum balance equations is found to be in the co-current direction, peaked in the plasma edge and negligibly small in the core.

Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

With the escalating prevalence of global heat waves,heat stroke has become a prominent health concern,leading to substantial liver damage.Unlike other forms of liver injury,heat strokeinduced damage is characterized by heat cytotoxicity and heightened inflammation,directly contributing to elevated mortality rates.While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction,their specific correlation with heat stroke liver injury remains unclear.Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke,initiating IL-1bmediated inflammation.Using single-cell RNA sequencing of murine macrophages,a distinct and highly susceptible Kupffer cell subtype,Clec4Ft/CD206t,emerged,with heme oxygenase 1(HMOX-1)playing a pivotal role.Mechanistically,heat-induced HMOX-1,regulated by early growth response factor 1,mediated ferroptosis in Kupffer cells,specifically in the Clec4F t/CD206 t subtype(KC2),activating phosphatidylinositol 4-kinase beta and promoting PI4P production.This cascade triggered NLRP3 inflammasome activation and maturation of IL-1b.These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells,particularly in Clec4F t/CD206 t KCs.Such an approach has the potential to mitigate inflammation and alleviate acute liver injury in the context of heat stroke,offering a promising avenue for future therapeutic interventions.

Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

Pressure overload–induced cardiac hypertrophy is a common cause of heart failure(HF),and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes.However,the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown.Here,we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines(PEs)and Acsl4 expression are significantly increased in mice with transverse aortic constriction(TAC)–induced HF compared to sham-operated mice.In addition,we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis.Notably,both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF.Moreover,silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth.Mechanistically,we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway,which leads to increased production of the proinflammatory cytokine IL-1β,and neutralizing IL-1βimproved cardiac function in Acsl4 transgenic mice following TAC.These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling.Together,these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway

Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis.However,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain unclear.Here,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.Mice lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron homeostasis.Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3.Moreover,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA levels.Using a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter region.We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of Yap.Notably,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO mice.Mechanistically,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver injury.These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

Copper homeostasis and cuproptosis in health and disease

all cell types.Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function,copper homeostasis is tightly regulated.Recent studies identified a novel copper-dependent form of cell death called cuproptosis,which is distinct from all other known pathways underlying cell death.Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid(TCA)cycle,which leads to subsequent protein aggregation,proteotoxic stress,and ultimately cell death.Here,we summarize our current knowledge regarding copper metabolism,copper-related disease,the characteristics of cuproptosis,and the mechanisms that regulate cuproptosis.In addition,we discuss the implications of cuproptosis in the pathogenesis of various disease conditions,including Wilson’s disease,neurodegenerative diseases,and cancer,and we discuss the therapeutic potential of targeting cuproptosis.

The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

The essential trace element iron regulates a wide range of biological processes in virtually all living organisms.Because both iron deficiency and iron overload can lead to various pathological conditions,iron homeostasis is tightly regulated,and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease.In recent years,significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system.Here,we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease,processes in which both the host and the pathogen compete for iron.We also discuss the evidence and implications that immune cells such as macrophages,T cells,and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions,in which iron serves as a co-factor in toll-like receptor 4(TLR4)signaling,mitochondrial respiration,posttranslational regulation,and epigenetic modification.In addition,we discuss the therapeutic implications of targeting ferroptosis,iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection,controlling inflammation,and improving the efficacy of immunotherapy.

The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms

Iron homeostasis is essential for health;moreover,hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia.Here,we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells.We validated the results in C57BL/6J mice and a mouse model of hemochromatosis(Hfe^(−/−)mice).Our screen revealed that the anti-rheumatoid arthritis drug auranofin(AUR)potently upregulates hepcidin expression.Interestingly,we found that canonical signaling pathways that regulate iron,including the Bmp/Smad and IL-6/Jak2/Stat3 pathways,play indispensable roles in mediating AUR’s effects.In addition,AUR induces IL-6 via the NF-κB pathway.In C57BL/6J mice,acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation.Whereas chronically treating male Hfe^(−/−)mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling,decreasing systemic iron overload,but less effective in females.Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells,providing a mechanistic explanation for ineffectiveness of AUR in female Hfe^(−/−)mice.Notably,high-dose AUR(25 mg/kg)induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase(TXNRD)activity.We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by highdose AUR without comprising its beneficial effect on iron metabolism.In conclusion,our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis,and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms,suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.

Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis

The recent outbreak of COVID-19 has been rapidly spreading on a global scale.To date,there is no specific vaccine against the causative virus,SARS-CoV-2,nor is there an effective medicine for treating COVID-19,thus raising concerns with respect to the effect of risk factors such as clinical course and pathophysiological parameters on disease severity and outcome in patients with COVID-19.By extracting and analyzing all available published clinical data,we identified several major clinical characteristics associated with increased disease severity and mortality among patients with COVID-19.Specifically,preexisting chronic conditions such as hypertension,cardiovascular disease,chronic kidney disease,and diabetes are strongly associated with an increased risk of developing severe COVID-19;surprisingly,however,we found no correlation between chronic liver disease and increased disease severity.In addition,we found that both acute cardiac injury and acute kidney injury are highly correlated with an increased risk of COVID-19-related mortality.Given the high risk of comorbidity and the high mortality rate associated with tissue damage,organ function should be monitored closely in patients diagnosed with COVID-19,and this approach should be included when establishing new guidelines for managing these high-risk patients.Moreover,additional clinical data are needed in order to determine whether a supportive therapy can help mitigate the development of severe,potentially fatal complications,and further studies are needed to identify the pathophysiology and the mechanism underlying this novel coronavirus-associated infectious disease.Taken together,these findings provide new insights regarding clinical strategies for improving the management and outcome of patients with COVID-19.

Zooming in and out of ferroptosis in human disease

Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation.In the past decade,it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body,including various cancers,neurodegenerative diseases,cardiovascular diseases,lung diseases,liver diseases,kidney diseases,endocrine metabolic diseases,iron-overload-related diseases,orthopedic diseases and autoimmune diseases.Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions.Indeed,there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models.In this review,we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease,while providing evidence in support of ferroptosis as a target for the treatment of these diseases.We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.

Targeting ferroptosis opens new avenues for the development of novel therapeutics

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics,including altered iron homeostasis,reduced defense against oxidative stress,and abnormal lipid peroxidation.Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types,neurodegenerative disease,diseases involving tissue and/or organ injury,and inflammatory and infectious diseases.

Ferroptosis:an emerging player in immune cells

Ferroptosis is an iron-dependent form of cell death characterized by an accumulation of lipid peroxides.A growing body of recent evidence supports the notion that ferroptosis plays an important role in mediating a wide variety of cellular processes in diseases.Notably,ferroptosis can play a significant role in mediating various functions in immune cells and immunotherapies.Here,we discuss our current understanding regarding the regulatory role of ferroptosis in immune cells,including T cells,B cells,granulocytes,monocytes,and macrophages.In addition,we discuss the general effect of immune cell ferroptosis on human pathophysiology and immunotherapies,thereby suggesting new strategies for targeting ferroptosis in order to modulate the immune system and unravel the mechanisms that underlie ferroptosis in the immune response。