A Statistical Model for Phase Difference Spectrum of Ground-Motion and Its Application in Generating Non-Stationary Seismic Waves

The intensity non-stationarity is one of the most important features of earthquake records.Modeling of this feature is significant to the generation of artificial earthquake waves.Based on the theory of phase difference spectrum,an intensity non-stationary envelope function with log-normal form is proposed.Through a tremendous amount of earthquake records downloaded on Kik-net,a parameter fitting procedure using the genetic algorithm is conducted to obtain the value of model parameters under different magnitudes,epicenter distances and site conditions.A numerical example is presented to describe the procedure of generating fully non-stationary ground motions via spectral representation,and the mean EPSD(evolutionary power spectral density)of simulated waves is proved to agree well with the target EPSD.The results show that the proposed model is capable of describing the intensity non-stationary features of ground motions,and it can be used in structural anti-seismic analysis and ground motion simulation.

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy.Targeted radionuclide therapy delivers radiation directly to tumor sites.LNC1004 is a fibroblast activation protein(FAP)-targeting radiopharmaceutical,conjugated with the albumin binder Evans Blue,which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies.Herein,we demonstrate that^(68)Ga/^(177)Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts.Radionuclide therapy with^(177)Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells.The combination of^(177)Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice,with mice showing 100%tumor rejection upon rechallenge.Immunohistochemistry,single-cell RNA sequencing(scRNA-seq),and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication,CD8^(+)T-cell activation and expansion,M1 macrophage counts,antitumor activity of neutrophils,and T-cell receptor diversity.A preliminary clinical study demonstrated that^(177)Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers.Further,scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment.This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation.In conclusion,our data supported the efficacy of immunotherapy combined with^(177)Lu-LNC1004 for cancer patients with FAP-positive tumors.

CBP-mediated Slug acetylation stabilizes Slug and promotes EMT and migration of breast cancer cells

Slug,a member of the Snail family of transcriptional repressors,plays a key role in cancer progression,cellular plasticity,and epithelial to mesenchymal transition(EMT).Slug is a fast-turnover protein and its stability is controlled by post-translational modifications.Here,we identified that Slug is acetylated by acetyltransferase CREB-binding protein(CBP)in breast cancer cells.CBP directly interacts with the C-terminal domain of Slug through its catalytic histone acetyltransferase(HAT)domain,leading to acetylation of Slug at lysines 166 and 211.Analysis with acetylation-specific antibodies revealed that Slug is highly acetylated in metastatic breast cancer cells.Notably,Slug acetylation,mediated by CBP at lysines 166 and 211,doubles its halflife and increases its stability.Further,acetylated Slug downregulates the expression of E-cadherin,the epithelial marker,and upregulates the expression of N-cadherin and vimentin,thereby promoting breast cancer cell migration.In conclusion,the present study demonstrates that CBP-mediated Slug acetylation increases its stability,promoting EMT and migration of breast cancer cells.

C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision

Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.

LATS1 K751 acetylation blocks activation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein

Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.

Memory bandwidth optimization of SpMV on GPGPUs

It is an important task to improve performance for sparse matrix vector multiplication （SpMV）, and it is a difficult task because of its irregular memory access. Gen- eral purpose GPU （GPGPU） provides high computing abil- ity and substantial bandwidth that cannot be fully exploited by SpMV due to its irregularity. In this paper, we propose two novel methods to optimize the memory bandwidth for SpMV on GPGPU. First, a new storage format is proposed to exploit memory bandwidth of GPU architecture more effi- ciently. The new storage format can ensure that there are as many non-zeros as possible in the format which is suitable to exploit the memory bandwidth of the GPU. Second, we pro- pose a cache blocking method to improve the performance of SpMV on GPU architecture. The sparse matrix is partitioned into sub-blocks that are stored in CSR format. With the block- ing method, the corresponding part of vector x can be reused in the GPU cache, so the time to access the global memory for vector x is reduced heavily. Experiments are carried out on three GPU platforms, GeForce 9800 GX2, GeForce GTX 480, and Tesla K40. Experimental results show that both new methods can efficiently improve the utilization of GPU mem- ory bandwidth and the performance of the GPU.