Heterogeneous population distribution enhances resistance to wheat lodging by optimizing the light environment

Lodging is still the key factor that limits continuous increases in wheat yields today,because the mechanical strength of culms is reduced due to low-light stress in populations under high-yield cultivation.The mechanical properties of the culm are mainly determined by lignin,which is affected by the light environment.However,little is known about whether the light environment can be sufficiently improved by changing the population distribution to inhibit culm lodging.Therefore,in this study,we used the wheat cultivar“Xinong 979”to establish a low-density homogeneous distribution treatment(LD),high-density homogeneous distribution treatment(HD),and high-density heterogeneous distribution treatment(HD-h)to study the regulatory effects and mechanism responsible for differences in the lodging resistance of wheat culms under different population distributions.Compared with LD,HD significantly reduced the light transmittance in the middle and basal layers of the canopy,the net photosynthetic rate in the middle and lower leaves of plants,the accumulation of lignin in the culm,and the breaking resistance of the culm,and thus the lodging index values increased significantly,with lodging rates of 67.5%in 2020–2021 and 59.3%in 2021–2022.Under HD-h,the light transmittance and other indicators in the middle and basal canopy layers were significantly higher than those under HD,and the lodging index decreased to the point that no lodging occurred.Compared with LD,the activities of phenylalanine ammonia-Lyase(PAL),4-coumarate:coenzyme A ligase(4CL),catechol-O-methyltransferase(COMT),and cinnamyl-alcohol dehydrogenase(CAD)in the lignin synthesis pathway were significantly reduced in the culms under HD during the critical period for culm formation,and the relative expression levels of TaPAL,Ta4CL,TaCOMT,and TaCAD were significantly downregulated.However,the activities of lignin synthesis-related enzymes and their gene expression levels were significantly increased under HD-h compared with HD.A partial least squares path modeling analysis found significant positive effects between the canopy light environment,the photosynthetic capacity of the middle and lower leaves of plants,lignin synthesis and accumulation,and lodging resistance in the culms.Thus,under conventional high-density planting,the risk of wheat lodging was significantly higher.Accordingly,the canopy light environment can be optimized by changing the heterogeneity of the population distribution to improve the photosynthetic capacity of the middle and lower leaves of plants,promote lignin accumulation in the culm,and enhance lodging resistance in wheat.These findings provide a basis for understanding the mechanism responsible for the lower mechanical strength of the culm under high-yield wheat cultivation,and a theoretical basis and for developing technical measures to enhance lodging resistance.

Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently lacking.Herein,we report an ICGN model to address this gap.ICGN was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered orally.Two and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were conducted.Fecal microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal function.Approximately 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both stages.Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was reduced.Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces.FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal function.These findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its pro-gression.MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

The special issue:“Financial innovation for Emission Trading Scheme”

Against the existential and ubiquitous threat of climate changes to the environment,human health,and economic well-being,the proliferation of carbon neutrality from both government and private sector recently prevails in order to strengthen preparedness for the future global crisis.More than 70 countries and regions have pledged to achieve the goal of carbon neutrality by 2050(ICAP,2020).While the momentum toward adopting carbon neutrality targets continue to build,a growing body of countries and subnational governments move toward carbon pricing through rolling out,speeding-up,or strengthening the construct of emission trading scheme(ETS)and carbon financial market.Notwithstanding the laudable objectives of ETS to enable emission reduction,the potential of ETS is still largely untapped,largely stemming from poor financial innovation.This special issue is,therefore,aimed at promoting research on the carbon financial innovations,financial derivatives services,the use of Fintech and the optimization on architectures of the ETS such that ETSs could drive the transformation toward low-carbon development path and the achievement of Carbon Neutrality targets.

Identification ACTA2 and KDR as key proteins for prognosis of PD-1/PD-L1 blockade therapy in melanoma

Programmed cell death protein 1(PD-1)/programmed cell death ligand 1(PD-L1)blockade is an important therapeutic strategy for melanoma,despite its low clinical response.It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients.We analyzed clinical dataset GSE96619,which contains clinical information from five melanoma patients before and after anti-PD-1 therapy(five pairs of data).We identified 704 DEGs using these five pairs of data,and then the number of DEGs was narrowed down to 286 in patients who responded to treatment.Next,we performed KEGG pathway enrichment and constructed a DEG-associated protein-protein interaction network.Smooth muscle actin 2(ACTA2)and tyrosine kinase growth factor receptor(KDR)were identified as the hub genes,which were significantly downregulated in the tumor tissue of the two patients who re-sponded to treatment.To confirm our analysis,we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xeno-graft model.This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD-1/PD-L1 blockade therapy.

Analysis on the clinical and endoscopic parameters in 1247 patients with reflux esophagitis

Aim: To summarize and analyze the clinical and endoscopic parameters in patients with reflux esophagitis(RE). Methods:1247 patients with RE were diagnosed in our hospital endoscopy center from September 2010 to August 2012. The general information of the patients and the relationship between endoscopic classification and concomitant diseases were analyzed. Results: According to the endoscopic findings, 1247 subjects (4.70%) were found to have RE:932 (74.74%) males and 315 (25.26%) females, and the male to female ratio was 2.96:1. The peak age of prevalence was 50 to 59 (27.35%) which is followed by 40 to 49 (23.10%). In this study, most of the patients had a mild degree of esophagitis representing LA-A in 60.63% and LA-B in 34.24%. The antrum hyperemia was found in 291 patients with esophagitis (23.34%), followed by antrum erosion (20.13%) and hatal hernia (15.88%). There is no statistically significant relevance between Helicobacter pylori infection and RE (P > 0.05), but Barrett’s esophagus, duodenal ulcer, gastroesophageal tumors, a history of gastroesophageal surgery and antrum hyperemia were found to be associated with RE (P . Conclusion: The prevalence rate of endoscopic RE in our study was 4.70%, and most patients had a mild grade esophagitis. Male, advanced age, Barrett’s esophagus, duodenal ulcer, gastroesophageal tumors and a history of gastroesophageal surgery are the risk factors of esophagitis. Antrum hyperemia may reduce the severity of RE.

Heterologous expression in transgenic mosquitoes

Arthropod-borne diseases such as malaria and dengue virus afflict billions of people worldwide imposing major economic and social burdens.Control of such pathogens is mainly performed by vector management and treatment of affected individuals with drugs.The failure of these conventional approaches due to emergence of insecticide-resistant insects and drug-resistant parasites demonstrate the need of novel and efficacious control strategies to combat these diseases.Genetic modification(GM) of mosquito vectors to impair their ability to be infected and transmit pathogens has emerged as a new strategy to reduce transmission of many vector-borne diseases and deliver public health gains.Several advances in developing transgenic mosquitoes unable to transmit pathogens have gained support,some of them attempt to manipulate the naturally occurring endogenous refractory mechanisms,while others initiate the identification of an exogenous foreign gene which disrupt the pathogen development in insect vectors. Heterologous expression of transgenes under a native or heterologous promoter is important for the screening and effecting of the transgenic mosquitoes.The effect of the transgene on mosquito fitness is a crucial parameter influencing the success of this transgenic approach.This review examines these two aspects and describes the basic research work that has been accomplished towards understanding the complex relation between the parasite and its vector and focuses on recent advances and perspectives towards construction of transgenic mosquitoes refractory to vector-borne disease transmission.

Purification in entanglement distribution with deep quantum neural network

Entanglement distribution is important in quantum communication. Since there is no information with value in this process, purification is a good choice to solve channel noise. In this paper, we simulate the purification circuit under true environment on Cirq, which is a noisy intermediate-scale quantum(NISQ) platform. Besides, we apply quantum neural network(QNN) to the state after purification. We find that combining purification and quantum neural network has good robustness towards quantum noise. After general purification, quantum neural network can improve fidelity significantly without consuming extra states. It also helps to obtain the advantage of entangled states with higher dimension under amplitude damping noise. Thus, the combination can bring further benefits to purification in entanglement distribution.

Target fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid

Chlorogenic acid(CGA)is a natural product that effectively inhibits tumor growth,demonstrated in many preclinical models,and phase II clinical trials for patients with glioma.However,its direct proteomic targets and anticancer molecular mechanisms remain unknown.Herein,we developed a novel bi-functional photo-affinity probe PAL/CGA and discovered mitochondrial acetyl-CoA acetyltransferase 1(ACAT1)was one of the main target proteins of CGA by using affinity-based protein profiling(AfBPP)chemical proteomic approach.We performed in-depth studies on ACAT1/CGA interactions via multiple assays including SPR,ITC,and cryo-EM.Importantly,we demonstrated that CGA impaired cancer cell proliferation by inhibiting the phosphorylation of tetrameric ACAT1 on Y407 residue through a novel mode of action in vitro and in vivo.Our study highlights the use of AfBPP platforms in uncovering unique druggable modalities accessed by natural products.And identifying the molecular target of CGA sheds light on the future clinical application of CGA for cancer therapy.

TCP-1,a novel peptide to diagnose early colon cancer

A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.In tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

Heat shock protein 90(Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin(GA) is the first identified Hsp90 inhibitor that exhibited potent anticancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1(C6-ethyl) and 2(C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds1 and 2 bind to Hsp90 protein with the IC_(50) of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.

Long non-coding RNAs: From disease code to drug role

Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development of tumors,cardiovascular diseases,nervous system disorders,nephropathy,and other diseases.The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases.This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of IncRNAs from the role of disease coding to acting as drug candidates,including the current status and progress in preclinical research.Cutting-edge strategies for lncRNA modulation have been summarized,including the sources of LncRNA-related drugs,such as genetic technology and small-molecule compounds,and related delivery methods.The current progress of clinical trials of lncRNA-targeting drugs is also discussed.This information will form a latest updated reference for research and development of lncRNA-based drugs.

A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models

Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.

Targeted delivery of chlorogenic acid by mannosylated liposomes to effectively promote the polarization of TAMs for the treatment of glioblastoma

Tumor-associated macrophages(TAMs)generally display an immunosuppressive M2 phenotype and promote tumor progression and metastasis,suggesting their potential value as a target in cancer immunotherapy.Chlorogenic acid(CHA)has been identified as a potent immunomodulator that promotes the polarization of TAMs from an M2 to an M1 phenotype.However,rapid clearance in vivo and low tumor accumulation have compromised the immunotherapeutic efficacy of CHA in clinical trials.In this study,mannosylated liposomes are developed for targeted delivery of CHA to TAMs.The immunoregulatory effects of CHA,along with the overall antitumor efficacy of CHA-encapsulated mannosylated liposomes,are investigated through in vitro and in vivo experiments.The prepared CHA-encapsulated mannosylated liposomes exhibit an ideal particle size,favorable stability,and preferential accumulation in tumors via the mannose receptor-mediated TAMs-targeting effects.Further,CHA-encapsulated mannosylated liposomes inhibit G422 glioma tumor growth by efficiently promoting the polarization of the pro-tumorigenic M2 phenotype to the anti-tumorigenic M1 phenotype.Overall,these findings indicate that CHA-encapsulated mannosylated liposomes have great potential to enhance the immunotherapeutic efficacy of CHA by inducing a shift from the M2 to the M1 phenotype.

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding incessantly.Currently,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer patients.Herein,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human PD-L1.Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune checkpoints.Mechanistically,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro.YDP-29B was modified as the YPD-30 prodrug to improve druggability.Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo.Taken together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

Ferroptosis:An emerging therapeutic opportunity for cancer

Ferroptosis,a new form of non-apoptotic,regulated cell death characterized by iron dependency and lipid peroxidation,is involved in many pathological conditions such as neurodegenerative diseases,heart ischemia/reperfusion injury,acute renal failure,and cancer.While metabolic dysfunctions can lead to excessive lipid peroxidation culminating in ferroptotic cell death,glutathione peroxidase 4(GPX4)resides in the center of a network that functions to prevent lipid hydroperoxides from accumulation,thereby suppressing ferroptosis.Indeed,RSL3 and other small-molecule GPX4 inhibitors can induce ferroptosis in not only cultured cancer cells but also tumor xenografts implanted in mice.Similarly,erastin and other system Xc−inhibitors can deplete intracellular glutathione required for GPX4 function,leading to lipid peroxidation and ferroptosis.As therapy-resistant cancer cells are sensitive to GPX4-targeted therapeutic regimens,the agents capable of inducing ferroptosis hold great promises to improve current cancer therapy.This review will outline the molecular basis of ferroptosis,but focus on the strategies and the agents developed in recent years for therapeutic induction of ferroptosis.The potentials of these ferroptosis-inducing agents,which include system Xc−inhibitors,GPX4 inhibitors,and iron-based nanoparticles,in cancer therapy will be subsequently discussed.

Construction of chlorogenic acid-containing liposomes with prolonged antitumor immunity based on T cell regulation

As a potential cancer immunotherapeutic agent,chlorogenic acid(CHA)has entered phase II clinical trials in China as a lyophilized powder formulation for treating glioma.However,the in vivo instability of CHA necessitates daily intramuscular injections,resulting in patient noncompliance.In this study,CHA-phospholipid complex(PC)-containing PEGylated liposomes(CHA-PC PEG-Lipo,named as CPPL),with CHA-PC as the drug intermediate,were prepared to lower the administration frequency.CPPL demonstrated excellent physicochemical properties,enhanced tumor accumulation,and inhibited tumor growth even when the administration interval was prolonged to 4 days when compared to a CHA solution and CHA-PC loaded liposomes(CHA-PC Lipo,labeled as CPL),both of which only demonstrated antitumor efficacy with once-daily administration.Further evaluation of the in vivo antitumor immune mechanism suggested that the extended antitumor immune efficacy of CPPL could be attributed to its distinct immune-stimulating mechanism when compared with CHA solution and CPL,such as stimulating both CD4+and CD8+T cell infiltration,inhibiting myeloid-derived suppressor cell expression,reducing the expression of Th2 related factors,and notably,increasing the memory T cells in tumor tissues.This CHA-containing formulation could reduce the frequency of in vivo CHA administration during cancer treatment via T cells,especially memory T cell regulation.

Coordinated dispatching strategy of multiple energy sources for wind power consumption

Heat storage systems with multiple heat sources play an important role in consuming extra wind power.A reasonable scheduling strategy for a hybrid system with multiple heat and electric sources could provide greater economic benefits.However,the present scheduling methods primarily focus on extra wind power consumption alone.This paper aims to develop a coordinated dispatching method that targets the maximum extra wind power consumed and highest economic benefit of the hybrid energy system as the optimization objective.A two-step coordinated dispatching method is proposed,where the first step focuses on optimizing the extra wind power consumed by coordinating the consumption quota for different types of energy sources at the system level and distributes the consumption share for every unit within each type of energy source,thereby maximizing fuel savings and economic benefits in the second step.The effectiveness of the approach is demonstrated using simulation results for an electric-heat hybrid system.Compared with two existing dispatching methods,the scheduling strategy presented in this paper could consume more extra wind power and provide higher fuel savings and economic benefits.

Ultrasound-Assisted Transient Liquid Phase Bonding of Magnesium Alloy Using Brass Interlayer in Air

The microstructure evolution and oxide film behavior in ultrasound-assisted transient liquid phase（U-TLP） bonding of Mg alloy were investigated by applying different ultrasonic time at 460？C with brass interlayer in air. The results indicated that with increasing ultrasonic time, brass interlayer disappeared gradually and the Mg-Cu-Zn eutectic compounds were formed. The eutectic compounds in the joint decreased as the ultrasonic time increased further. The oxide removal process was divided into four steps. Continuous oxide film at the interface was partially fractured by ultrasonic vibration,and then suspended into liquid by undermining eutectic reaction. After that, the suspended oxide film was broken into small oxide fragments by ultrasonic cavitation effect, which was finally squeezed out of the joint by ultrasonic squeeze action. In addition, the mechanical properties of the joints were investigated. The maximum shear strength of the joint reached 105 MPa, which was 100% of base metal.