喉鳞状细胞癌中SIAH2表达的预后价值

目的:观察E3泛素连接酶SIAH2在喉鳞状细胞癌组织中的表达,探讨其在喉鳞状细胞癌中表达的预后价值。方法:应用免疫组织化学染色法检测119例喉组织标本SIAH2的定性表达,Western blot方法检测喉新鲜组织中SIAH2的定量表达,结合患者5年随访资料,利用Kaplan-Meier法绘制生存曲线,Log-rank法分析SIAH2的表达水平与喉鳞状细胞癌患者预后的关系,Cox比例风险回归模型分析喉鳞状细胞癌患者预后的独立预测因素。结果:SIAH2在喉鳞状细胞癌中阳性表达率为77.19%,显著高于不典型增生(53.13%)和癌旁正常喉组织(26.67%),差异具有统计学意义(χ~2=21.02,P<0.001)。SIAH2的表达与组织学分级、临床分期及淋巴结转移相关(均P<0.05);在正常喉组织(1.25±0.04)、不典型增生(1.38±0.05)及喉鳞状细胞癌组织(1.44±0.07)中SI-AH2的相对表达量逐渐升高(F=61.811,P<0.001);SIAH2阳性与阴性患者的5年生存率分别为18.18%和58.33%(χ~2=5.720,P=0.017),SIAH2阳性与阴性患者的中位生存时间分别为25个月和60个月(P<0.05);多因素回归分析表明高表达SIAH2是喉鳞状细胞癌患者总生存期的独立预测因子。结论:SIAH2可能作为一个癌基因参与喉鳞状细胞癌的发生发展,过表达SIAH2与喉鳞状细胞癌患者的不良预后有关,提示SIAH2作为一个潜在的靶基因可能对喉鳞状细胞癌的治疗有帮助。

SlMYB75,an MYB-type transcription factor,promotes anthocyanin accumulation and enhances volatile aroma production in tomato fruits

Genetic manipulation of genes to upregulate specific branches of metabolic pathways is a method that is commonly used to improve fruit quality.However,the use of a single gene to impact several metabolic pathways is difficult.Here,we show that overexpression of the single gene SlMYB75(SlMYB75-OE)is effective at improving multiple fruit quality traits.In these engineered fruits,the anthocyanin content reached 1.86mg g−1 fresh weight at the red-ripe stage,and these SlMYB75-OE tomatoes displayed a series of physiological changes,including delayed ripening and increased ethylene production.In addition to anthocyanin,the total contents of phenolics,flavonoids and soluble solids in SlMYB75-OE fruits were enhanced by 2.6,4,and 1.2 times,respectively,compared to those of wild-type(WT)fruits.Interestingly,a number of aroma volatiles,such as aldehyde,phenylpropanoid-derived and terpene volatiles,were significantly increased in SlMYB75-OE fruits,with some terpene volatiles showing more than 10 times higher levels than those in WT fruits.Consistent with the metabolic assessment,transcriptomic profiling indicated that the genes involved in the ethylene signaling,phenylpropanoid and isoprenoid pathways were greatly upregulated in SlMYB75-OE fruits.Yeast one-hybrid and transactivation assays revealed that SlMYB75 is able to directly bind to the MYBPLANT and MYBPZM cis-regulatory elements and to activate the promoters of the LOXC,AADC2 and TPS genes.The identification of SlMYB75 as a key regulator of fruit quality attributes through the transcriptional regulation of downstream genes involved in several metabolic pathways opens new avenues towards engineering fruits with a higher sensory and nutritional quality.

Investigation and optimization of sampling characteristics of light field camera for flame temperature measurement

It is essential to investigate the light field camera parameters for the accurate flame temperature measurement because the sampling characteristics of the flame radiation can be varied with them. In this study, novel indices of the light field camera were proposed to investigate the directional and spatial sampling characteristics of the flame radiation. Effects of light field camera parameters such as focal length and magnification of the main lens, focal length and magnification of the microlens were investigated. It was observed that the sampling characteristics of the flame are varied with the different parameters of the light field camera. The optimized parameters of the light field camera were then proposed for the flame radiation sampling. The larger sampling angle(23 times larger) is achieved by the optimized parameters compared to the commercial light field camera parameters. A non-negative least square(NNLS) algorithm was used to reconstruct the flame temperature. The reconstruction accuracy was also evaluated by the optimized parameters. The results suggested that the optimized parameters can provide higher reconstruction accuracy for axisymmetric and non-symmetric flame conditions in comparison to the commercial light field camera.

Molecular regulatory events of flower and fruit abscission in horticultural plants

Flower and fruit abscission is a highly programmed physiological process,which is closely related to the yield of horticultural plants.The coordination of many regulatory factors associated with metabolic and signaling pathways plays a key role in the flower and fruit shedding.Hormones,peptides,carbohydrates,polyamines or cell wall modifying proteins regulate flower and fruit shedding.This article reviewed the recent studies of flower and fruit abscission,including the molecular regulation mechanism of abscission zone formation,typical structure and location of abscission zones,and other factors affecting flower and fruit abscission,such as stresses,hormones,peptides,carbohydrates,polyamines and cell wall modifying proteins.Overall,the review summarizes the developmental mechanism and the diversity of abscission zones,and the key factors affecting flower and fruit abscission of horticultural plants,aiming to provide guidance for studying the molecular regulatory mechanism of flower and fruit abscission.

SlGRAS4 accelerates fruit ripening by regulating ethylene biosynthesis genes and SlMADS1 in tomato

GRAS proteins are plant-specific transcription factors that play crucial roles in plant development and stress responses.However,their involvement in the ripening of economically important fruits and their transcriptional regulatory mechanisms remain largely unclear.Here,we demonstrated that SlGRAS4,encoding a transcription factor of the GRAS family,was induced by the tomato ripening process and regulated by ethylene.Overexpression of SlGRAS4 accelerated fruit ripening,increased the total carotenoid content and increased PSY1 expression in SlGRAS4-OE fruit compared to wild-type fruit.The expression levels of key ethylene biosynthesis genes(SlACS2,SlACS4,SlACO1,and SlACO3)and crucial ripening regulators(RIN and NOR)were increased in SlGRAS4-OE fruit.The negative regulator of tomato fruit ripening,SlMADS1,was repressed in OE fruit.Exogenous ethylene and 1-MCP treatment revealed that more endogenous ethylene was derived in SlGRAS4-OE fruit.More obvious phenotypes were observed in OE seedlings after ACC treatment.Yeast one-hybrid and dual-luciferase assays confirmed that SlGRAS4 can directly bind SlACO1 and SlACO3 promoters to activate their transcription,and SlGRAS4 can also directly repress SlMADS1 expression.Our study identified that SlGRAS4 acts as a new regulator of fruit ripening by regulating ethylene biosynthesis genes in a direct manner.This provides new knowledge of GRAS transcription factors involved in regulating fruit ripening.

SIZHD17 is involved in the control of chlorophyll and carotenoid metabolism in tomato fruit

Chlorophylls and carotenoids are essential and bene fi cial substances for both plant and human health.Identifying the regulatory network of these pigments is necessary for improving fruit quality.In a previous study,we identi fi ed an R2R3-MYB transcription factor,SlMYB72,that plays an important role in chlorophyll and carotenoid metabolism in tomato fruit.Here,we demonstrated that the SlMYB72-interacting protein SlZHD17,which belongs to the zinc-fi nger homeodomain transcription factor family,also functions in chlorophyll and carotenoid metabolism.Silencing SIZHD 17 in tomato improved multiple bene fi cial agronomic traits,including dwar fi sm,accelerated fl owering,and earlier fruit harvest.More importantly,downregulating SIZHD17 in fruits resulted in larger chloroplasts and a higher chlorophyll content.Dual-luciferase,yeast one-hybrid and electrophoretic mobility shift assays clari fi ed that SlZHD17 regulates the chlorophyll biosynthesis gene SIPOR-B and chloroplast developmental regulator SITKN2 in a direct manner.Chlorophyll degradation and plastid transformation were also retarded after suppression of SIZHD17 in fruits,which was caused by the inhibition of SISGR1,a crucial factor in chlorophyll degradation.On the other hand,the expression of the carotenoid biosynthesis genes SIPSY1 and SIZISO was also suppressed and directly regulated by SlZHD17,which induced uneven pigmentation and decreased the lycopene content in fruits with SIZHD17 suppression at the ripe stage.Furthermore,the protein-protein interactions between SlZHD17 and other pigment regulators,including SlARF4,SlBEL11,and SlTAGL1,were also presented.This study provides new insight into the complex pigment regulatory network and provides new options for breeding strategies aiming to improve fruit quality.

Experimental Study on Enhancement of Bubble Absorption of Gaseous CO2 with Nanofluids in Ammonia

In order to study the effects of nanoparticles on the CO_2 absorption in ammonia,nanofluids with different ammonia concentration and different nanoparticle solid loading were prepared by a two-step method.The nanofluids-enhanced gas absorption test devices were also established. The CO_2 absorption in TiO_2,CuO,SiO_2 nanofluids,which nanoparticles solid loading were 1. 0-8. 0 g/L,was tested respectively. In comparison with the blank absorption experiment,the effects of nanoparticle solid loading,nanoparticle types,ammonia concentration on the removal efficiency and removal rate were obtained. Experimental results show that adding nanoparticles can enhance the removal efficiency and removal rate,which increase first and then decrease with the increase of nanoparticle solid loading,and there exists an optimum solid loading of TiO_2 nanoparticles. The effect of SiO_2 nanofluid is inhibitory on the reaction. The enhancement factor of CuO nanofluid is always hovering around 1,which does not show the obvious enhancement or inhibition on the reaction. The optimum solid loading decreases gradually with the increase of ammonia concentration. In addition,according to the experimental results,the mechanism of enhanced absorption was analyzed theoretically.

Rapid and user-friendly open-source CRISPR/Cas9 system for single-or multi-site editing of tomato genome

CRISPR/Cas9-induced genome editing is a powerful tool for studying gene function in a variety of organisms,including plants.Using multi-sgRNAs to target one or more genes is helpful to improve the efficacy of gene editing and facilitate multi-gene editing.Here,we describe a CRISPR/Cas9 system which can be conveniently developed as a CRISPR kit.SgRNA expression cassettes can be rapidly generated by one-step PCR using our CRISPR kit.In our kit,there are two binary vectors pHNCas9 and pHNCas9HT.The binary vector pHNCas9 was constructed to allow to assemble up to eight sgRNA expression cassettes by one-step Golden Gate cloning.Another binary vector pHNCas9HT can be used to generate a large number of single target constructs by directly transforming ligation reactions products into A.tumefaciens without several procedures,such as PCR and plasmid extraction.The two binary vectors are designed according to the principles of standard BioBrick assembly to be used as an open-source tool.For example,we used BioBrick as a visual T-DNA tag.We also developed a primer design aid to complement the system.With this primer design aid,researchers can rapidly obtain primers and GC content,and sgRNA sequence of target site.Our CRISPR/Cas9 system can perform single-and multi-site editing and multiple gene editing to produce various types of mutations in tomato.This rapid and user-friendly CRISPR/Cas9 system for tomato can be potentially used for mutagenesis of important crop species for genetic improvement and is suitable for research into the function of genes.

Mossbauer Spectra for Ultrafine Particles Fe_(3)O_(4)

The procedure of preparing specimens of ultrafine particles (UFP) Fe_3O_4 was studied and the measurement and analysis of the Mssbauer spectra at room temperature was made.After the hyperfine field due to iron was analyzed carefully,it is shown that the interaction of the interfaces be- tween grains of UFP Fe_3O_4 has stronger effects (enlarging the quadrupole splitting in Mssbauer spectrum) and it is found that superparamagnetic effects appear,which means that the magnetic property of UFP Fe_3O_4 is different from that of bulk Fe_3O_4.

CEPC Technical Design Report

The Circular Electron Positron Collider(CEPC)is a large scientific project initiated and hosted by China,fostered through extensive collaboration with international partners.The complex comprises four accelerators:a 30 GeV Linac,a 1.1 GeV Damping Ring,a Booster capable of achieving energies up to 180 GeV,and a Collider operating at varying energy modes(Z,W,H,and tt).The Linac and Damping Ring are situated on the surface,while the subterranean Booster and Collider are housed in a 100 km circumference underground tunnel,strategically accommodating future expansion with provisions for a potential Super Proton Proton Collider(SPPC).The CEPC primarily serves as a Higgs factory.In its baseline design with synchrotron radiation(SR)power of 30 MW per beam,it can achieve a luminosity of 5×10^(34)cm^(-2)s^(-1)per interaction point(IP),resulting in an integrated luminosity of 13 ab^(-1)for two IPs over a decade,producing 2.6 million Higgs bosons.Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons,facilitating precise measurements of Higgs coupling at sub-percent levels,exceeding the precision expected from the HL-LHC by an order of magnitude.This Technical Design Report(TDR)follows the Preliminary Conceptual Design Report(Pre-CDR,2015)and the Conceptual Design Report(CDR,2018),comprehensively detailing the machine's layout,performance metrics,physical design and analysis,technical systems design,R&D and prototyping efforts,and associated civil engineering aspects.Additionally,it includes a cost estimate and a preliminary construction timeline,establishing a framework for forthcoming engineering design phase and site selection procedures.Construction is anticipated to begin around 2027-2028,pending government approval,with an estimated duration of 8 years.The commencement of experiments and data collection could potentially be initiated in the mid-2030s.

A versatile volume-based modeling technique of distributed local quadratic convergence for aeroengines

For advanced aero-engine design and research,modeling and simulation in a digital environment is indispensable,especially for engines of complicated configurations,such as var-iable cycle engines(VCE)and adaptive cycle engines(ACE).Also,in the research of future smart engines,reliable real-time digital twins are paramount.However,the 2 dominant methods that used in solving the simulation models,Newton-Raphson(N-R)method and volume-based method,are not fully qualified for the study requirements,because neither of them reaches the satisfactory balance of convergence rate and calculating efficiency.In this study,by deeply analyzing the mathematical principle of these 2 methods,a novel modeling and solving method for aero-engine simulation,which integrates the advantages of both N-R and volume-based methods,is established.It has distributed architecture and local quadratic convergence rate.And a novel modeling method for variable area bypass injectors(VABI)is put forward.These facilitate simulation of various configurations of aero-engines.The modeling cases,including a high bypass-ratio(BPR)turbofan and an ACE,illustrate that the novel technique decreases the iterations by about two-thirds comparing with volume-based method,while the success rate of convergence remains over 99%.This proves its superiority in both convergence and calculating efficiency over the conventional ones.This technique can be used in advanced gas turbine en-gine design and control strategy optimization,and study of digital twins.

A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis

Both preclinical and established rheumatoid arthritis(RA)patients display alterations in the gut microbiome.Prevotella spp.are preferentially enriched in a subset of RA patients.Here,we isolated a Prevotella strain,P.copri RA,from the feces of RA patients and showed that colonization of P.copri RA exacerbated arthritis in a collagen-induced arthritis(CIA)model.With the presence of P.copri RA colonization,a high-fiber diet exacerbated arthritis via microbial alterations and intestinal inflammation.Colonization of P.copri together with a high-fiber diet enabled the digestion of complex fiber,which led to the overproduction of organic acids,including fumarate,succinate and short-chain fatty acids.Succinate promoted proinflammatory responses in macrophages,and supplementation with succinate exacerbated arthritis in the CIA model.Our findings highlight the importance of dysbiosis when evaluating the effects of dietary interventions on RA pathogenesis and provide new insight into dietary interventions or microbiome modifications to improve RA management.

Design and test of 4ZZ-4A2 full-hydraulic self-propelled jujube harvester

The cultivated area of jujube in Xinjiang has increased rapidly in recent years.While the jujube harvest by hand has the shortage of high labor intensity,low efficiency and high labor cost,in addition,the harvesting machinery applying to dwarf and dense planting mode of jujubes is unavailable in Xinjiang.The 4ZZ-4A2 based on the full-hydraulic self-propelled jujube harvester was designed to solve the above problems.The harvester was mainly composed of a frame,a vibrating device,a jujube collecting and conveying device,an air separation device,a steering system,a hydraulic system and a jujube suction device and was capable of completing vibration,collection,conveying,cleaning and sundries removal work of jujubes through one step.The jujubes dropped on the ground were picked up at the same time.The AMESim simulation software was adopted to perform simulation analysis on the overall hydraulic system.The results showed that the speed of the vibrating motor was stable at about 650 r/min(the corresponding vibration frequency is 10.83 Hz)with the torque of 80 N·m,the speed of the conveyor motor was stable at 77 r/min with the torque of 77 N·m;the speed of the fan motor was stable at 54 r/min with the torque of 53.6 N·m;the speed of the walking motor fluctuated around 100 r/min with the torque of about 1000 N·m;the hydraulic steering system responded rapidly and could satisfy the actual working requirements of the jujube harvester.The jujube garden test results showed that the harvester could reach to the optimum harvesting effect when running at the speed of 0.5 m/s.Under such speed,the ground jujube picking rate was 45.1%,the tree jujube harvesting rate was 93.2%,the loss rate was 2.9%,and the damage rate was 0.9%.This study can provide theoretical basis and technical support for the jujube harvester.

Optimizing mechanical and magnetic properties of AlCoCrFeNi high-entropy alloy via FCC to BCC phase transformation

FCC,BCC and B2 phases,the most common phases in high-entropy alloys(HEAs),are widely investigated to tailor their mechanical and magnetic performances.The detailed investigation of FCC to BCC/B2 phase transformation of Al Co Cr Fe Ni HEA in this paper reveals its evolution and structure-properties relations in terms of both temperature and holding duration.With increasing heat treatment temperature and duration,such transition will progress simultaneously at both the dendric core(DC)region and interdendric(ID)region and the volume of phase transformation from FCC to BCC phases is greater than FCC to B2 phases,resulting in increased yield strength and saturation magnetization.The obvious phase transition of the Al Co Cr Fe Ni HEA at 1200℃can enhance its yield strength and saturation magnetization as a sacrifice of its fracture strain.However,an excellent combination of mechanical-magnetic properties was achieved when heat-treated at 1100℃for 50 h by optimizing both the transformation and the size of B2 phases.Our present study could pave ways to design the HEAs or other alloys with an optimum combination of mechanical and magnetic properties for application-oriented viewpoints.

Modulating gut microbiota in autoimmune diseases:a cutting-edge strategy from prophylaxis to therapeutics

The gut microbiome is emerging as a pivotal player in the pathogenesis and development of autoimmune diseases(ADs)[1].A comprehensive understanding of the interaction among gut microbiota,drug metabolism,and host immune reaction will shed light on the development of precision medicine for ADs.Microbiota-based interventions,such as specific diet,probiotics/prebiotics,or restricted consortium transplantation,have shown promising preventive and therapeutic potentials in pre-clinical and clinical trials[2].

Tailoring mechanical and magnetic properties of AlCoCrFeNi high-entropy alloy via phase transformation

Phase constitutions,either changed by alloying or by phase transformation,are the key factors to determine the magnetic and mechanical performances of high-entropy alloys(HEAs).Using the AlCoCrFeNi HEA as a candidate alloy,this paper demonstrates the effect of phase transformation on both the mechanical and magnetic properties in the multi-phase system.With increasing heat treatment temperature,the sigma(σ)and face-centered-cubic(FCC)phases disappeared at 1000℃and 1200℃,respectively.Such volume fraction changes ofσ,FCC and body-centered-cubic(BCC)phases have divergent effects on mechanical and magnetic properties.The excellent strength-ductility combination will be achieved as the disappearance ofσphase and formation of FCC phase.As for the magnetic properties,the volume fraction of BCC phase plays a major role in determining its saturation magnetization.When the volume fraction change of BCC phase is not evident,the higher volume fraction of FCC phase will influence its magnetization at 2 T.Our present work might provide insights into analyzing the evolution of both mechanical and magnetic properties of HEAs caused by complex phase transformation.

Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils

Inhibitory immune receptors set thresholds for immune cell activation,and their deficiency predisposes a person to autoimmune responses.However,the agonists of inhibitory immune receptors remain largely unknown,representing untapped sources of treatments for autoimmune diseases.Here,we show that V-set and transmembrane domain-containing 1(VSTM1)is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1(Gal1)is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production.However,in patients with systemic lupus erythematosus(SLE),circulating Gal1 is oxidized and cannot be recognized by VSTM1,leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability.Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes.Interestingly,serum levels of glutathione,an antioxidant able to convert oxidized Gal1 to its reduced form,were negatively correlated with SLE disease activity.Taken together,our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

Disturbed gut virome with potent interferonogenic property in systemic lupus erythematosus

Accumulating evidence suggests an essential role of disturbed gut microbiota in the etiopathogenesis of systemic lupus erythematosus(SLE),but it remains unclear as to gut virome.In this study,fecal virus-like particles(VLPs)isolated from 76 non-treated SLE patients and 75 healthy controls were subjected to gut virome profiling.The proportion of bacteriophages was significantly elevated in the SLE gut,and the altered viral taxa were correlated with clinical parameters.Gut virome and bacteriome were closely associated with each other in SLE patients.The combination of gut viral and bacterial markers displayed better performance in distinguishing SLE patients from healthy controls.Further,VLPs from non-treated SLE patients promoted interferon-a production in an epithelial cell line and human immune cells.Intriguingly,the interferon-stimulatory capacity diminished in VLPs from post-treated SLE patients.Our findings may shed novel insights into SLE pathogenesis.Further in-depth understanding of gut virome might help develop future biomarkers and therapeutics for SLE patients.

East Asian monsoon intensification promoted weathering of the magnesium-rich southern China upper crust and its global significance

The Oligocene-Miocene boundary Asian climatic reorganization linked to the northward migration of the East Asian monsoon into subtropical China is a potentially important but poorly constrained atmospheric CO_(2) consumption process.Here,we performed a first-order estimate of the CO_(2) consumption induced by silicate chemical weathering and organic carbon burial in subtropical China related to this climatic reorganization.Our results show that an increase in long-term CO_(2 )consumption by silicate weathering varies from 0.06×10^(12)to 0.87×10^(12)mol yr^(-1)depending on erosion flux reconstructions,with an~50%contribution of Mg-silicate weathering since the late Oligocene.The organic carbon burial flux is approximately 25%of the contemporary CO_(2) consumption by silicate weathering.The results highlight the significant role of weathering of the Mg-rich upper continental crust in East China,which would contribute to the rapid decline in atmospheric CO_(2) during the late Oligocene and the Neogene rise in the seawater Mg content.If this climatic reorganization was mainly induced by the Tibetan Plateau uplift,our study suggests that the growth of the Himalayan-Tibetan Plateau can lead to indirect modification of the global carbon and magnesium cycles by changing the regional hydrological cycle in areas of East Asia that are tectonically less active.

Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine(FSY)into IL-2 for proximity-enabled covalent binding to IL-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia sulfur-fluoride exchange when in proximity,resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells.Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation,as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3(LAG-3)and enhanced expression of programmed cell death protein-1(PD-1).Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease(GvHD)resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment.The efficacy of L72-FSY was further improved by N-terminal PEGylation,which increased its circulatory retention for preferential and sustained effects.This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.