Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were de...Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were developed. In PFV method, the mass fluxes of across the cell faces of the control volume (CV) were expanded into power series of the grid spacing and the coefficients of the power series were determined by means of the conservation equation itself. The UPFV and CPFV scheme respectively uses the same nodes and expressions as those of the normal first-order upwind and second-order central scheme, which is apt to programming. The results of numerical experiments about the flow in a lid-driven cavity and the problem of transport of a scalar quantity in a known velocity field show that compared to the first-order UFV and second-order CFV schemes, upwind PFV scheme is higher accuracy and resolution, especially better robustness. The numerical computation to flow in a lid-driven cavity shows that the under-relaxation factor can be arbitrarily selected ranging from (0.3) to (0.8) and convergence perform excellent with Reynolds number variation from 10~2 to 10~4.展开更多
An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing ...An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing the transmitter and receiver into two sparse subarrays,noncircular property of source can be used to construct new extended received signal model for two sparse subarrays.The new received model can double the virtual array aperture due to the elliptic covariance of imping sources is nonzero.To further exploit the multidimensional structure of the noncircular received model,we stack the subarray output and its conjugation according to mode-1 unfolding and mode-2 unfolding of a third-order tensor,respectively.Thus,the corresponding extended tensor model consisted of noncircular information for DOA and DOD can be obtained.Then,the higher-order singular value decomposition technique is utilized to estimate the accurate signal subspace and angular parameter can be automatically paired via the rotational invariance relationship.Specifically,the ambiguous angle can be eliminated and the true targets can be achieved with the aid of the coprime property.Furthermore,a closed-form expression for the deterministic CRB under the NC sources scenario is also derived.Simulation results verify the superiority of the proposed estimator.展开更多
To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The...To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The tip positioning error consists of the coupled tip residual vibration and linear motor tracking error.Given the influence of nonlinear friction and load flexibility,the topology of COMFF is designed as decoupled structures so that COMFF can suppress the tip residual vibration and compensate for the linear motor tracking error compatibly.Furthermore,Bi-Loop IFFT is built to improve the robustness of COMFF in high-precision motor tracking performance.In the state space of the linear motor tracking error based on the projection theorem,two loops are performed in parallel along the iteration direction.One is the P-type iteration loop that drives linear motor tracking errors to converge to the zero state.The other is the observation loop constructed by the recursive least square with forgetting factors to accelerate the P-type iteration loop.Driven by the P-type iteration loop with the aid of the observation loop,the proposed COMFF is integrated with fast convergence and high robustness when confronted with model disturbances.The effectiveness of the proposed COMFF combined with Bi-Loop IFFT is validated by experiments.展开更多
In order to suppress the influence of symmetrical noise component on multiple-input multiple-output(MIMO)sonar’s direction of arrival(DOA)estimation under the condition of low signal-to-noise ratio,we propose a DOA e...In order to suppress the influence of symmetrical noise component on multiple-input multiple-output(MIMO)sonar’s direction of arrival(DOA)estimation under the condition of low signal-to-noise ratio,we propose a DOA estimation algorithm based on covariance matrix reconstruction method.Firstly,the noise field can be decomposed into symmetrical noise field and asymmetrical noise field.We utilize symmetry property of colored noise matrix and the feature that the imaginary part of covariance matrix has no relation with the symmetry noise to remove the real part of covariance matrix.This operation helps to suppress the influence of colored noise on DOA estimation accuracy.Based on the principle of the imaginary matrix part displacement and the dimension reduction transformation method,the real part of covariance matrix is reconstructed,which helps to suppress the bilateral spectrum interference.Thereafter,Toeplitz method is applied for the covariance matrix decorrelation amendment,and a noise subspace is formed by singular value decomposition(SVD).Finally,we can estimate the DOA of target signals.Both theoretical analysis results and numerical simulation results verify the symmetrical noise suppression performance of this algorithm,and the estimation performance of target azimuth is improved obviously.This method has the characteristics of lower operational complexity,higher degrees of freedom and stronger target resolution.展开更多
Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency...Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency,and growth rate,while overlooking the genetic improvement of reproductive traits.This study employs advanced multi-omics approaches,such as transcriptome-wide association studies(TWAS)and colocalization between genome-wide association studies(GWAS)and expression quantitative trait loci(eQTLs),to provide a comprehensive understanding of the genetic mechanisms governing semen quality traits in boars.Results Here,we collected 190,000 ejaculate records across 11 semen quality traits from 3,604 Duroc boars.The heritability of semen quality traits ranged from 0.095 to 0.343.Genetic correlations between semen quality traits varied from−0.802 to 0.661,and phenotypic correlations ranged from−0.833 to 0.776.Single-trait GWAS identified 19 independent variants,corresponding to 13 quantitative trait loci(QTLs).By integrating PigGTEx and FAANG resources,we combined TWAS and colocalization analyses to reveal genetic regulation of semen quality traits.Notably,both GWAS and colocalization analyses pinpointed the DCAF12 as a crucial gene associated with multiple semen quality traits.Additionally,the ZSCAN9 gene and the variant rs322211455 were found to significantly affect sperm motility(SPMOT),possibly through hypothalamic-pituitary-gonadal axis.PheWAS further highlighted an association between rs322211455 and sperm abnormality rate,demonstrating the crucial role of ZSCAN9 in male fertility.Conclusion This study reveals the genetic basis and regulatory mechanisms underlying semen quality traits in Duroc boars,identifying key candidate genes such as DCAF12 and ZSCAN9.These findings provide important insight into the genetic regulation of semen quality in boars.展开更多
Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear....Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.展开更多
Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate t...Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate their genetic associations.Using data from the UK Biobank(n=457871),cross-sectional analyses demonstrated that osteoporosis was significantly associated with an increased risk of RCTs(adjusted OR[95%CI]=1.38[1.25–1.52]).A longitudinal analysis of a subset of patients(n=268117)over 11 years revealed that osteoporosis increased the risk of RCTs(adjusted HR[95%CI]=1.56[1.29–1.87]),which is notably varied between sexes in sex-stratified analysis.Causal inference methods,including propensity score matching,inverse probability weighting,causal random forest and survival random forest models further confirmed the causal effect,both from cross-sectional and longitudinal perspectives.展开更多
Our aim in this article is to improve the understanding of the colocated finite volume schemes for the incompressible Navier-Stokes equations.When all the variables are colocated,that means here when the velocities an...Our aim in this article is to improve the understanding of the colocated finite volume schemes for the incompressible Navier-Stokes equations.When all the variables are colocated,that means here when the velocities and the pressure are computed at the same place(at the centers of the control volumes),these unknowns must be properly coupled.Consequently,the choice of the time discretization and the method used to interpolate the fluxes at the edges of the control volumes are essentials.In the first and second parts of this article,two different time discretization schemes are considered with a colocated space discretization and we explain how the unknowns can be correctly coupled.Numerical simulations are presented in the last part of the article.This paper is not a comparison between staggered grid schemes and colocated schemes(for this,see,e.g.,[15,22]).We plan,in the future,to use a colocated space discretization and the multilevel method of[4]initially applied to the two dimensional Burgers problem,in order to solve the incompressible Navier-Stokes equations.One advantage of colocated schemes is that all variables share the same location,hence,the possibility to use hierarchical space discretizations more easily when multilevel methods are used.For this reason,we think that it is important to study this family of schemes.展开更多
Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel tar...Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.展开更多
Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the path...Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.展开更多
Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ra...Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.展开更多
AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion c...AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot.RESULTS: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species(ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins(HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins(caspase 6, 9 and 12).Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein.CONCLUSION: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.展开更多
High-grade colonic neuroendocrine carcinomas (NECs) are uncommon but extremely aggressive. Their co-existence with tubular adenoma (TA) has rarely been reported. We present a 68-year-old man who was found on routine c...High-grade colonic neuroendocrine carcinomas (NECs) are uncommon but extremely aggressive. Their co-existence with tubular adenoma (TA) has rarely been reported. We present a 68-year-old man who was found on routine colonoscopy to have multiple colorectal TAs and an ulcerated lesion in the ascending colon. Microscopically, a poorly-differentiated invasive carcinoma juxtaposed with a TA was identified. Differential diagnosis included a poorly-differentiated adenocarcinoma, medullary carcinoma, high-grade NEC and lymphoma. The immunohistochemical profile showed positive staining for keratins, synaptophysin and chromogranin but negative for LCA, CDX2, CK7, CK20, TTF-1 and PSA, supporting the NEC diagnosis. Upon subsequent laparoscopic right hemicolectomy, the tumor was identified as a 3.0 cm umbilicated and ulcerated mass with an adjacent TA. Both TA and NEC showed positive staining for β-catenin indicating a shared colonic origin. The mitotic counts (77/10 high power fields) and a high proliferation rate (75% by Ki-67) corroborated a high-grade stratification. Mutational analysis indicated a wild-type BRAF and KRAS with mismatch repair proficiency. The AJCC (7<sup>th</sup> edition) pathologic stage is pT3, pN0, pMx. The patient received adjuvant chemotherapy with cisplatin/etoposides for three cycles and will be followed up for a year to detect recurrence. In conclusion, the co-existence of TA with high grade-NEC in our case allowed early identification and intervention of the otherwise asymptomatic but aggressive tumor. In addition, the finding of a high-grade NEC within a large TA in this case suggests a link between the two lesions and could represent a shared stem cell origin.展开更多
Mitochondrial division inhibitor 1（Mdivi-1） is a selective cell-permeable inhibitor of dynamin-related protein-1（Drp1） and mitochondrial division.To investigate the effect of Mdivi-1 on cells treated with glutamat...Mitochondrial division inhibitor 1（Mdivi-1） is a selective cell-permeable inhibitor of dynamin-related protein-1（Drp1） and mitochondrial division.To investigate the effect of Mdivi-1 on cells treated with glutamate,cerebral cortex neurons isolated from neonatal rats were treated with 10 m M glutamate for 24 hours.Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls.Apoptotic cells were detected by flow cytometry.Changes in mitochondrial morphology were examined by electron microscopy.Drp1,Bax,and casp ase-3 expression was evaluated by western blot assays and immunocytochemistry.Mitochondrial membrane potential was detected using the JC-1 probe.Twenty-four hours after 10 m M glutamate treatment,Drp1,Bax and caspase-3 expression was upregulated,Drp1 and Bax were translocated to mitochondria,mitochondrial membrane potential was decreased and the rate of apoptosis was increased.These effects were inhibited by treatment with 50 μM Mdivi-1 for 2 hours.This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity.展开更多
Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years.Despite reports of a wide range of effects of adolescent intermittent ethanol(AIE)exposure o...Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years.Despite reports of a wide range of effects of adolescent intermittent ethanol(AIE)exposure on brain and behavior,little is known about the mechanisms that may underlie those effects,and even less about treatments that might reverse them.Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation,suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function.We utilized astrocyte-specific,membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging,three-dimensional reconstruction,and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE.Additionally,we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)glutamate receptor 1,an AMPA receptor subunit and established neuronal marker of excitatory synapses,as a metric of astrocyte-synapse proximity.AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood.This is striking in that it suggests not only an alteration of the physical association of astrocytes with synapses by AIE,but one that lasts into adulthood-well after the termination of alcohol exposure.Perhaps even more notable,the AIE-induced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent,gabapentin(Neurontin),in adulthood.This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function.All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee(Protocol Registry Number A159-18-07)on July 27,2018.展开更多
文摘Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were developed. In PFV method, the mass fluxes of across the cell faces of the control volume (CV) were expanded into power series of the grid spacing and the coefficients of the power series were determined by means of the conservation equation itself. The UPFV and CPFV scheme respectively uses the same nodes and expressions as those of the normal first-order upwind and second-order central scheme, which is apt to programming. The results of numerical experiments about the flow in a lid-driven cavity and the problem of transport of a scalar quantity in a known velocity field show that compared to the first-order UFV and second-order CFV schemes, upwind PFV scheme is higher accuracy and resolution, especially better robustness. The numerical computation to flow in a lid-driven cavity shows that the under-relaxation factor can be arbitrarily selected ranging from (0.3) to (0.8) and convergence perform excellent with Reynolds number variation from 10~2 to 10~4.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.61701507,61890542,and 61890540).
文摘An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing the transmitter and receiver into two sparse subarrays,noncircular property of source can be used to construct new extended received signal model for two sparse subarrays.The new received model can double the virtual array aperture due to the elliptic covariance of imping sources is nonzero.To further exploit the multidimensional structure of the noncircular received model,we stack the subarray output and its conjugation according to mode-1 unfolding and mode-2 unfolding of a third-order tensor,respectively.Thus,the corresponding extended tensor model consisted of noncircular information for DOA and DOD can be obtained.Then,the higher-order singular value decomposition technique is utilized to estimate the accurate signal subspace and angular parameter can be automatically paired via the rotational invariance relationship.Specifically,the ambiguous angle can be eliminated and the true targets can be achieved with the aid of the coprime property.Furthermore,a closed-form expression for the deterministic CRB under the NC sources scenario is also derived.Simulation results verify the superiority of the proposed estimator.
基金supported by the National Natural Science Foundation Regional Innovation and Development Joint Fund Integrated Project(Grant No.U23A6017)the Central Guidance on Local Science and Technology Development Fund of Hebei Province(Grant No.226Z1805G).
文摘To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The tip positioning error consists of the coupled tip residual vibration and linear motor tracking error.Given the influence of nonlinear friction and load flexibility,the topology of COMFF is designed as decoupled structures so that COMFF can suppress the tip residual vibration and compensate for the linear motor tracking error compatibly.Furthermore,Bi-Loop IFFT is built to improve the robustness of COMFF in high-precision motor tracking performance.In the state space of the linear motor tracking error based on the projection theorem,two loops are performed in parallel along the iteration direction.One is the P-type iteration loop that drives linear motor tracking errors to converge to the zero state.The other is the observation loop constructed by the recursive least square with forgetting factors to accelerate the P-type iteration loop.Driven by the P-type iteration loop with the aid of the observation loop,the proposed COMFF is integrated with fast convergence and high robustness when confronted with model disturbances.The effectiveness of the proposed COMFF combined with Bi-Loop IFFT is validated by experiments.
基金supported by the National Natural Science Foundation for Young Scientists of China(51309191)the National Natural Science Foundation for Young Scientists of China(11704313)the National Natural Science Foundation for Young Scientists of China(61701405)
文摘In order to suppress the influence of symmetrical noise component on multiple-input multiple-output(MIMO)sonar’s direction of arrival(DOA)estimation under the condition of low signal-to-noise ratio,we propose a DOA estimation algorithm based on covariance matrix reconstruction method.Firstly,the noise field can be decomposed into symmetrical noise field and asymmetrical noise field.We utilize symmetry property of colored noise matrix and the feature that the imaginary part of covariance matrix has no relation with the symmetry noise to remove the real part of covariance matrix.This operation helps to suppress the influence of colored noise on DOA estimation accuracy.Based on the principle of the imaginary matrix part displacement and the dimension reduction transformation method,the real part of covariance matrix is reconstructed,which helps to suppress the bilateral spectrum interference.Thereafter,Toeplitz method is applied for the covariance matrix decorrelation amendment,and a noise subspace is formed by singular value decomposition(SVD).Finally,we can estimate the DOA of target signals.Both theoretical analysis results and numerical simulation results verify the symmetrical noise suppression performance of this algorithm,and the estimation performance of target azimuth is improved obviously.This method has the characteristics of lower operational complexity,higher degrees of freedom and stronger target resolution.
基金supported by grants from The Sci-Tech Innovation 2030 Agenda(2023ZD04045)Guangxi Key Research and Development Program(AB241484033).
文摘Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency,and growth rate,while overlooking the genetic improvement of reproductive traits.This study employs advanced multi-omics approaches,such as transcriptome-wide association studies(TWAS)and colocalization between genome-wide association studies(GWAS)and expression quantitative trait loci(eQTLs),to provide a comprehensive understanding of the genetic mechanisms governing semen quality traits in boars.Results Here,we collected 190,000 ejaculate records across 11 semen quality traits from 3,604 Duroc boars.The heritability of semen quality traits ranged from 0.095 to 0.343.Genetic correlations between semen quality traits varied from−0.802 to 0.661,and phenotypic correlations ranged from−0.833 to 0.776.Single-trait GWAS identified 19 independent variants,corresponding to 13 quantitative trait loci(QTLs).By integrating PigGTEx and FAANG resources,we combined TWAS and colocalization analyses to reveal genetic regulation of semen quality traits.Notably,both GWAS and colocalization analyses pinpointed the DCAF12 as a crucial gene associated with multiple semen quality traits.Additionally,the ZSCAN9 gene and the variant rs322211455 were found to significantly affect sperm motility(SPMOT),possibly through hypothalamic-pituitary-gonadal axis.PheWAS further highlighted an association between rs322211455 and sperm abnormality rate,demonstrating the crucial role of ZSCAN9 in male fertility.Conclusion This study reveals the genetic basis and regulatory mechanisms underlying semen quality traits in Duroc boars,identifying key candidate genes such as DCAF12 and ZSCAN9.These findings provide important insight into the genetic regulation of semen quality in boars.
基金supported by the National Natural Science Foundation of China(82002432 to J.W.,82302068 to M.Z.,and 32300568 to T.W.)the Natural Science Foundation of Shandong Province(ZR2024MH159 to Y.Z.,ZR2020QH179 to J.W.,ZR2022QH057 to M.Z.,and ZR2021QH005 to T.W.)the China Postdoctoral Science Foundation(2024M752006 to S.M.)。
文摘Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.
基金the Scientific Research Innovation Capability Support Project for Young Faculty(ZYGXQNJSKYCXNLZCXM-H8)Fundamental Research Funds for the Central Universities(2024ZYGXZR077)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2023B1515120006)Guangzhou Basic and Applied Basic Research Foundation(2024A04J5776)the Research Fund(2023QN10Y421)Guangzhou Talent Recruitment Team Program(2024D03J0004),all related to this study.
文摘Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate their genetic associations.Using data from the UK Biobank(n=457871),cross-sectional analyses demonstrated that osteoporosis was significantly associated with an increased risk of RCTs(adjusted OR[95%CI]=1.38[1.25–1.52]).A longitudinal analysis of a subset of patients(n=268117)over 11 years revealed that osteoporosis increased the risk of RCTs(adjusted HR[95%CI]=1.56[1.29–1.87]),which is notably varied between sexes in sex-stratified analysis.Causal inference methods,including propensity score matching,inverse probability weighting,causal random forest and survival random forest models further confirmed the causal effect,both from cross-sectional and longitudinal perspectives.
基金the National Science Foundation under the grant NSF-DMS-0604235,and by the Research Fund of Indiana University。
文摘Our aim in this article is to improve the understanding of the colocated finite volume schemes for the incompressible Navier-Stokes equations.When all the variables are colocated,that means here when the velocities and the pressure are computed at the same place(at the centers of the control volumes),these unknowns must be properly coupled.Consequently,the choice of the time discretization and the method used to interpolate the fluxes at the edges of the control volumes are essentials.In the first and second parts of this article,two different time discretization schemes are considered with a colocated space discretization and we explain how the unknowns can be correctly coupled.Numerical simulations are presented in the last part of the article.This paper is not a comparison between staggered grid schemes and colocated schemes(for this,see,e.g.,[15,22]).We plan,in the future,to use a colocated space discretization and the multilevel method of[4]initially applied to the two dimensional Burgers problem,in order to solve the incompressible Navier-Stokes equations.One advantage of colocated schemes is that all variables share the same location,hence,the possibility to use hierarchical space discretizations more easily when multilevel methods are used.For this reason,we think that it is important to study this family of schemes.
基金funded by the Hainan Province Clinical Medical Center(82171084)the National Natural Science Foundation of China(82371086).
文摘Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.
基金supported by The Medical Engineering Cross Research Funding of Shanghai Jiaotong University"Star of Jiaotong University"Program(24X010301595).
文摘Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.
基金supported by grants from the Central Public-interest Scientific Institution Basal Research Fund(2020-YWF-YB-02)the Young Scientists Fund of the National Natural Science Foundation of China(32202652)+1 种基金China Agriculture Research System of MOF and MARA(CARS-37)the Science and Technology Project of Inner Mongolia Autonomous Region(2020GG0210).
文摘Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.
基金Supported by National Research Foundation of Korea grant funded by the Korea government(MEST),No.2013-005810
文摘AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot.RESULTS: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species(ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins(HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins(caspase 6, 9 and 12).Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein.CONCLUSION: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.
文摘High-grade colonic neuroendocrine carcinomas (NECs) are uncommon but extremely aggressive. Their co-existence with tubular adenoma (TA) has rarely been reported. We present a 68-year-old man who was found on routine colonoscopy to have multiple colorectal TAs and an ulcerated lesion in the ascending colon. Microscopically, a poorly-differentiated invasive carcinoma juxtaposed with a TA was identified. Differential diagnosis included a poorly-differentiated adenocarcinoma, medullary carcinoma, high-grade NEC and lymphoma. The immunohistochemical profile showed positive staining for keratins, synaptophysin and chromogranin but negative for LCA, CDX2, CK7, CK20, TTF-1 and PSA, supporting the NEC diagnosis. Upon subsequent laparoscopic right hemicolectomy, the tumor was identified as a 3.0 cm umbilicated and ulcerated mass with an adjacent TA. Both TA and NEC showed positive staining for β-catenin indicating a shared colonic origin. The mitotic counts (77/10 high power fields) and a high proliferation rate (75% by Ki-67) corroborated a high-grade stratification. Mutational analysis indicated a wild-type BRAF and KRAS with mismatch repair proficiency. The AJCC (7<sup>th</sup> edition) pathologic stage is pT3, pN0, pMx. The patient received adjuvant chemotherapy with cisplatin/etoposides for three cycles and will be followed up for a year to detect recurrence. In conclusion, the co-existence of TA with high grade-NEC in our case allowed early identification and intervention of the otherwise asymptomatic but aggressive tumor. In addition, the finding of a high-grade NEC within a large TA in this case suggests a link between the two lesions and could represent a shared stem cell origin.
基金supported by the National Natural Science Foundation of China,No.81371967 and 81401807a grant from the 5th Phase of "Project 333"of Jiangsu Province of China,No.BRA2016512a grant from the Six Talent Peaks Project of Jiangsu Province of China,No.2014-WSN-012
文摘Mitochondrial division inhibitor 1（Mdivi-1） is a selective cell-permeable inhibitor of dynamin-related protein-1（Drp1） and mitochondrial division.To investigate the effect of Mdivi-1 on cells treated with glutamate,cerebral cortex neurons isolated from neonatal rats were treated with 10 m M glutamate for 24 hours.Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls.Apoptotic cells were detected by flow cytometry.Changes in mitochondrial morphology were examined by electron microscopy.Drp1,Bax,and casp ase-3 expression was evaluated by western blot assays and immunocytochemistry.Mitochondrial membrane potential was detected using the JC-1 probe.Twenty-four hours after 10 m M glutamate treatment,Drp1,Bax and caspase-3 expression was upregulated,Drp1 and Bax were translocated to mitochondria,mitochondrial membrane potential was decreased and the rate of apoptosis was increased.These effects were inhibited by treatment with 50 μM Mdivi-1 for 2 hours.This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity.
基金supported by the National Institute on Alcohol Abuse and Alcoholism(NIAAA)Neurobiology of Adolescent Drinking In Adulthood(NADIA)Grant#2U01AA019925(to HSS)the National Institute on Alcohol Abuse and Alcoholism(NIAAA)R00AA022651(to TAW)the National Institute on Drug Abuse(NIDA)R01DA041455(to KJR)
文摘Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years.Despite reports of a wide range of effects of adolescent intermittent ethanol(AIE)exposure on brain and behavior,little is known about the mechanisms that may underlie those effects,and even less about treatments that might reverse them.Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation,suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function.We utilized astrocyte-specific,membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging,three-dimensional reconstruction,and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE.Additionally,we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)glutamate receptor 1,an AMPA receptor subunit and established neuronal marker of excitatory synapses,as a metric of astrocyte-synapse proximity.AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood.This is striking in that it suggests not only an alteration of the physical association of astrocytes with synapses by AIE,but one that lasts into adulthood-well after the termination of alcohol exposure.Perhaps even more notable,the AIE-induced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent,gabapentin(Neurontin),in adulthood.This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function.All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee(Protocol Registry Number A159-18-07)on July 27,2018.
