Erratum: PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer: Erratum.

[This corrects the article DOI: 10.7150/jca.66773.].

Building Coarse to Fine Convex Hulls with Auxiliary Vertices for Palette-based Image Recoloring.

Constructing a convex hull for the pixel colors of an image by viewing them as 3D points can extract a set of palette colors for the image, then image recoloring can be achieved by modifying the palette colors. For better recoloring effect, the convex hull should contain more pixels (inclusive) and be more compact. Otherwise, reconstruction error would occur or the extracted palette color would be less representative, yielding wrong recoloring results or less effective edit. We observe that convex hulls constructed by prior methods can contain all the image pixels, but are far from compact. Efforts have been made to optimize the vertices of convex hull to increase the compactness but are still not perfect. In this paper, we propose a novel coarse to fine convex hull construction scheme with auxiliary vertices. We start by constructing a coarse convex hull whose vertices are directly image pixels which is thus the most compact but cannot contain all pixels. We then make a remedy by adding auxiliary vertices into the coarse convex hull to obtain a fine convex hull. More auxiliary vertices are added, more image pixels will be contained into the fine convex hull. The auxiliary vertices are image pixels too so that the compactness can still be maintained. During editing, the auxiliary vertices are not allowed to be edited for edit convenience, but deformed as-rigid-as-possible with the adjusting of other vertices. Our convex hull is both inclusive and compact. Extensive experiments validate the effectiveness of the proposed method.

Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment.

The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung cancer (NSCLC). In this study, we identified a potent and oral EGFRL858R/T790M/C797S tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFRL858R/T790M/C797S mutant with IC50 value as 0.010 µM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFRL858R/T790M/C797S and induced tumor cell cycle arrest and cell apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics.

Injection of YiQiFuMai powder protects against heart failure via inhibiting p38 and ERK1/2 MAPKs activation.

CONTEXT: Injection of YiQiFuMai (YQFM) powder, a modern Chinese plant-derived medical preparation, has a therapeutic effect in heart failure (HF). However, its therapeutic mechanism remains largely unknown. OBJECTIVE: To investigate the molecular mechanisms of YQFM in HF. MATERIALS AND METHODS: Kinase inhibition profiling assays with 2 mg/mL YQFM were performed against a series of 408 kinases. In addition, the effects of kinase inhibition were validated in cardiomyocyte cell line H9c2. In vivo, HF with reduced ejection fraction (HFrEF) was induced by permanent left anterior descending (LAD) coronary artery ligation for 6 weeks in male Sprague-Dawley rats. Then, HFrEF mice were treated with 0.46 g/kg YQFM or placebo once a day for 2 weeks. Echocardiography, immunohistochemistry, histological staining and Western blotting analysis were performed to assess the myocardial damage and molecular mechanisms. RESULTS: Kinase inhibition profiling analysis demonstrated that mitogen-activated protein kinases (MAPKs) mediated the signalling cascades of YQFM during HF therapy. Meanwhile, p38 and extracellular signal-regulated kinases (ERK1/2) were inhibited after YQFM treatment in H9c2 cells. In rats, the control group had lower left ventricular ejection fraction (LVEF) at 37 ± 1.7% compared with the YQFM group at 54 ± 1.1% (p < 0.0001). Cardiac fibrosis levels in control group rats were significantly higher than YQFM group (30.5 ± 3.0 vs. 14.1 ± 1.0, p < 0.0001). CONCLUSIONS: Our collective in vitro and in vivo experiments demonstrated that YQFM improves left ventricular (LV) function and inhibits fibrosis in HFrEF rats by inhibiting MAPK signalling pathways.

PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer.

Breast cancer has become the most newly-diagnosed cancer and the 5th leading cause of cancer death worldwide. The 5-year survival rate of breast cancer is about 90%. However, the 5-year survival rate drops to <30% when metastasis to distant sites occurs. The blood vessel formation (i.e., angiogenesis) plays a crucial role during the metastatic process. In this study, we investigated the role of PFKFB4 in angiogenesis of breast cancer. Employing in vitro HUVEC tube formation or in vivo orthotopic mouse model, and gene editing or specific small inhibitors strategy, and utilizing qPCR, western blot, ELISA, or immunofluorescent/immunohistochemistry staining methods, we found the following: 1) PFKFB4 upregulates IL-6 expression via NF-κB signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-κB activation in breast cancer cells; 3) IL-6 elicits angiogenesis via STAT5A/P-STAT5 in HUVEC; 4) 5-MPN (a specific PFKFB4 inhibitor) suppresses angiogenesis in vitro and in vivo. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.

Design, synthesis and biological assessment of novel CDK4 inhibitor with potent anticancer activity.

Efforts toward finding potent CDK4 inhibitor for cancer therapy, a series of fluorine substituted pyrrolo[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated. Among them, the optimal lead compound 18i was discovered with potent activity against CDK4 at the nanomolar level (IC50 = 2.5 nM) and exquisite selectivity which demonstrated only modest activity against 3 out of the 394 protein kinases. 18i exhibited a much greater in vitro antiproliferative activity against several human cancer cell lines than that of the approved drug ribociclib. Further mechanism studies revealed that 18i effectively stimulated cancer cell cycle arrest in G1 phase and induced tumor cell apoptosis. In the comparison of in vivo therapeutic effects in xenograft mouse models of breast cancer, oral administration of 18i showed a significantly better degree of inhibitory effect to ribociclib without obvious toxicity. All of the results indicated that 18i could be a promising CDK4 inhibitor for treating malignancies.

Cleavage of FNDC5 and insights into its maturation process.

FNDC5 corresponds to an irisin precursor that increases with exercise. Studies suggest that irisin mediates beneficial effects in adipose tissues, skeletal muscle, bone, and brain. However, the cleavage and maturation processes of FNDC5 have not been clearly identified. This study aimed to show that the signal peptide and transmembrane domain of FNDC5 were associated with the secretion of its ectodomain. Localization studies identified the signal peptide that was responsible for endoplasmic reticulum targeting activity of nascent FNDC5 and showed that the FNDC5 ectodomain corresponding to irisin could be transported across the membrane by a transmembrane domain. Analysis of cleavage constructs revealed that the ectodomain of FNDC5 could be cleaved from its signal peptide and transmembrane attachment. Genetic ablation of the signal peptide cleavage site blocked N-glycosylation of FNDC5. Identification of the FNDC5 maturation process should facilitate our understanding of irisin secretion.

Effective Video Stabilization via Joint Trajectory Smoothing and Frame Warping.

Video stabilization is usually composed of three stages: feature trajectory extraction, trajectory smoothing, and frame warping. Most previous approaches view them as three separate stages. This paper proposes a method combining the last two stages, namely the trajectory smoothing and frame warping stages, into a single optimization framework. The novelty exists in the way of how we combine them: the trajectory smoothing part plays a major role while the frame warping part plays an auxiliary role. With this kind of design, we can conveniently increase the strength of the trajectory smoothing part by a robust first-order derivative term, which makes it possible to produce very aggressive stabilization effects. On the other hand, we adopt adaptive weighting mechanisms in the frame warping part, to follow the smoothed trajectories as much as possible while regularizing other places as similar as possible. Our method is robust to utilize both foreground and background features, and very short trajectories. The utilization of all these information in turn increases the accuracy of the proposed method. We also provide a simplified implementation of our method, which is less accurate but more efficient. Experiments on various kinds of videos demonstrate the effectiveness of our method.

Collision-Free Video Synopsis Incorporating Object Speed and Size Changes.

This paper presents a new surveillance video synopsis method which performs much better than previous approaches in terms of both compression ratio and artifact. Previously, a surveillance video was usually compressed by shifting the moving objects of that video forward along the time axis, which inevitably yielded serious collision and chronological disorder artifacts between the shifted objects. The main observation of this paper is that these artifacts can be alleviated by changing the speed or size of the objects, since with varied speed and size the objects can move more flexibly to avoid collision points or to keep chronological relationships. Based on this observation, we propose a video synopsis method that performs object shifting, speed changing, and size scaling simultaneously. We show how to integrate the three heterogeneous operations into a single optimization framework and achieve high-quality synopsis results. Unlike previous approaches that usually use alternative optimization strategies to solve synopsis optimizations, we develop a Metropolis sampling algorithm to find the solution for our three-variable optimization problem. A variety of experiments demonstrate the effectiveness of our method.

Multi-View Video Synopsis via Simultaneous Object-Shifting and View-Switching Optimization.

We present a method for synopsizing multiple videos captured by a set of surveillance cameras with some overlapped field-of-views. Currently, object-based approaches that directly shift objects along the time axis are already able to compute compact synopsis results for multiple surveillance videos. The challenge is how to present the multiple synopsis results in a more compact and understandable way. Previous approaches show them side by side on the screen, which however is difficult for user to comprehend. In this paper, we solve the problem by joint object-shifting and camera view-switching. Firstly, we synchronize the input videos, and group the same object in different videos together. Then we shift the groups of objects along the time axis to obtain multiple synopsis videos. Instead of showing them simultaneously, we just show one of them at each time, and allow to switch among the views of different synopsis videos. In this view switching way, we obtain just a single synopsis results consisting of content from all the input videos, which is much easier for user to follow and understand. To obtain the best synopsis result, we construct a simultaneous object-shifting and view-switching optimization framework instead of solving them separately. We also present an alternative optimization strategy composed of graph cuts and dynamic programming to solve the unified optimization. Experiments demonstrate that our single synopsis video generated from multiple input videos is compact, complete, and easy to understand.

CRISPR/Cas9-mediated specific integration of fat-1 at the goat MSTN locus.

Recent advances in understanding the CRISPR/Cas9 system have provided a precise and versatile approach for genome editing in various species. However, no study has reported simultaneous knockout of endogenous genes and site-specific knockin of exogenous genes in large animal models. Using the CRISPR/Cas9 system, this study specifically inserted the fat-1 gene into the goat MSTN locus, thereby achieving simultaneous fat-1 insertion and MSTN mutation. We introduced the Cas9, MSTN knockout small guide RNA and fat-1 knockin vectors into goat fetal fibroblasts by electroporation, and obtained a total of 156 positive clonal cell lines. PCR and sequencing were performed for identification. Of the 156 clonal strains, 40 (25.6%) had simultaneous MSTN knockout and fat-1 insertion at the MSTN locus without drug selection, and 55 (35.25%) and 101 (67.3%) had MSTN mutations and fat-1 insertions, respectively. We generated a site-specific knockin Arbas cashmere goat model using a combination of CRISPR/Cas9 and somatic cell nuclear transfer for the first time. For biosafety, we mainly focused on unmarked and non-resistant gene screening, and point-specific gene editing. The results showed that simultaneous editing of the two genes (simultaneous knockout and knockin) was achieved in large animals, demonstrating that the CRISPR/Cas9 system has the potential to become an important and applicable gene engineering tool in safe animal breeding.

Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide as a Novel Inhibitor Targeting Cyclin-dependent Kinase 4/9 (CDK4/9) and Histone Deacetlyase1 (HDAC1) against Malignant Cancer.

A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7 H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)phenyl)- N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8, 12, and 2.2 nM, respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity. Compound 6e induces G2/M arrest in high concentration and G0/G1 arrest in low concentration to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with 6e showed significant antitumor efficacy. The insight into mechanisms of 6e indicated that it could induce cancer cell death via cell apoptosis based on CDK4/9 and HDAC1 repression and phosphorylation of p53. Our data demonstrated the novel compound 6e could be a promising drug candidate for cancer therapy.

Highly Selective, Potent, and Oral mTOR Inhibitor for Treatment of Cancer as Autophagy Inducer.

On the basis of novel pyrazino[2,3-c]quinolin-2(1H)-one scaffold, we designed and identified a highly selective, potent and oral mTOR inhibitor, 9m. Compound 9m showed low nanomolar activity against mTOR (IC50 = 7 nM) and greater selectivity over the related PIKK family kinases, which demonstrated only modest activity against 3 out of the 409 protein kinases. In vitro assays, compound 9m exhibited high potency against human breast and cervical cancer cells and induced tumor cell cycle arrest and autophagy. 9m inhibited cellular phosphorylation of mTORC1 (pS6 and p4E-BP1) and mTORC2 (pAKT (S473)) substrates. In T-47D xenograft mouse model, oral administration of compound 9m led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics. Collectively, due to its high potency and selectivity, compound 9m could be used as a mTOR drug candidate.

Dynamic Video Stitching via Shakiness Removing.

Stitching videos captured by hand-held mobile cameras can essentially enhance entertainment experience of ordinary users. However, such videos usually contain heavy shakiness and large parallax, which are challenging to stitch. In this paper, we propose a novel approach of video stitching and stabilization for videos captured by mobile devices. The main component of our method is a unified video stitching and stabilization optimization that computes stitching and stabilization simultaneously rather than does each one individually. In this way, we can obtain the best stitching and stabilization results relative to each other without any bias to one of them. To make the optimization robust, we propose a method to identify background of input videos, and also common background of them. This allows us to apply our optimization on background regions only, which is the key to handle large parallax problem. Since stitching relies on feature matches between input videos, and there inevitably exist false matches, we thus propose a method to distinguish between right and false matches, and encapsulate the false match elimination scheme and our optimization into a loop, to prevent the optimization from being affected by bad feature matches. We test the proposed approach on videos that are causally captured by smartphones when walking along busy streets, and use stitching and stability scores to evaluate the produced panoramic videos quantitatively. Experiments on a diverse of examples show that our results are much better than (challenging cases) or at least on par with (simple cases) the results of previous approaches.Stitching videos captured by hand-held mobile cameras can essentially enhance entertainment experience of ordinary users. However, such videos usually contain heavy shakiness and large parallax, which are challenging to stitch. In this paper, we propose a novel approach of video stitching and stabilization for videos captured by mobile devices. The main component of our method is a unified video stitching and stabilization optimization that computes stitching and stabilization simultaneously rather than does each one individually. In this way, we can obtain the best stitching and stabilization results relative to each other without any bias to one of them. To make the optimization robust, we propose a method to identify background of input videos, and also common background of them. This allows us to apply our optimization on background regions only, which is the key to handle large parallax problem. Since stitching relies on feature matches between input videos, and there inevitably exist false matches, we thus propose a method to distinguish between right and false matches, and encapsulate the false match elimination scheme and our optimization into a loop, to prevent the optimization from being affected by bad feature matches. We test the proposed approach on videos that are causally captured by smartphones when walking along busy streets, and use stitching and stability scores to evaluate the produced panoramic videos quantitatively. Experiments on a diverse of examples show that our results are much better than (challenging cases) or at least on par with (simple cases) the results of previous approaches.

N-Glycosylation is required for FDNC5 stabilization and irisin secretion.

Irisin, a myokine derived from the extracellular domain of FNDC5, has been shown to mediate thermogenesis of white adipose tissue. Biochemical data have shown that N-glycosylation of FNDC5 is unlikely to affect ligand or receptor activation of irisin. The N-glycosylation of FNDC5 remains poorly understood. In the present study, we analysed N-glycosylation sites of FNDC5 and found that two potential N-glycosylation sites (Asn36 and Asn81) could indeed be occupied by N-glycan. Furthermore we showed that the lack of N-glycosylation decreases the secretion of irisin, which is relevant to the instability of FNDC5 and the deficiency of cleavage of the signal peptide. We also found that the expression level of N-glycosylated FNDC5 was elevated after myoblast differentiation. These findings show that the secretion of irisin is modulated by N-glycosylation, which in turn enhances our understanding of the secretion of glycosylated irisin.

Homography Propagation and Optimization for Wide-Baseline Street Image Interpolation.

Wide-baseline street image interpolation is useful but very challenging. Existing approaches either rely on heavyweight 3D reconstruction or computationally intensive deep networks. We present a lightweight and efficient method which uses simple homography computing and refining operators to estimate piecewise smooth homographies between input views. To achieve the goal, we show how to combine homography fitting and homography propagation together based on reliable and unreliable superpixel discrimination. Such a combination, other than using homography fitting only, dramatically increases the accuracy and robustness of the estimated homographies. Then, we integrate the concepts of homography and mesh warping, and propose a novel homography-constrained warping formulation which enforces smoothness between neighboring homographies by utilizing the first-order continuity of the warped mesh. This further eliminates small artifacts of overlapping, stretching, etc. The proposed method is lightweight and flexible, allows wide-baseline interpolation. It improves the state of the art and demonstrates that homography computation suffices for interpolation. Experiments on city and rural datasets validate the efficiency and effectiveness of our method.

Identification and characterization of an endoplasmic reticulum localization motif.

Sorting motifs are involved in the transport of diverse proteins. In the present study, we identified a hydrophobic peptide (WRPWRNFWWSIRVPWRRN) that was able to target enhanced green fluorescent protein- or DsRed2-enriched vesicular-like sub-compartments of the endoplasmic reticulum (ER). Analysis of mutation constructs revealed that the sequence WRPWRNFWW was responsible for the ER-targeting activity, and the arginine residue of the peptide is a critical determinant of ER localization. Results from co-immunoprecipitation, glutathione S-transferase pull-down, liquid chromatography-tandem mass spectrometry, and western blotting analyses demonstrated that this motif could bind with the γ2-COP subcomplex of coat protein complex I (COPI), which is involved in the retrieval and transport of ER-resident proteins from the Golgi apparatus to the ER. Overall, we report a new hydrophobic peptide that possesses an arginine-based ER localization motif, which can help elucidate the mechanisms of ER sorting mediated by COPI.

Object Movements Synopsis via Part Assembling and Stitching.

Video synopsis aims at removing video's less important information, while preserving its key content for fast browsing, retrieving, or efficient storing. Previous video synopsis methods, including frame-based and object-based approaches that remove valueless whole frames or combine objects from time shots, cannot handle videos with redundancies existing in the movements of video object. In this paper, we present a novel part-based object movements synopsis method, which can effectively compress the redundant information of a moving video object and represent the synopsized object seamlessly. Our method works by part-based assembling and stitching. The object movement sequence is first divided into several part movement sequences. Then, we optimally assemble moving parts from different part sequences together to produce an initial synopsis result. The optimal assembling is formulated as a part movement assignment problem on a Markov Random Field (MRF), which guarantees the most important moving parts are selected while preserving both the spatial compatibility between assembled parts and the chronological order of parts. Finally, we present a non-linear spatiotemporal optimization formulation to stitch the assembled parts seamlessly, and achieve the final compact video object synopsis. The experiments on a variety of input video objects have demonstrated the effectiveness of the presented synopsis method.

Compact video synopsis via global spatiotemporal optimization.

Video synopsis aims at providing condensed representations of video data sets that can be easily captured from digital cameras nowadays, especially for daily surveillance videos. Previous work in video synopsis usually moves active objects along the time axis, which inevitably causes collisions among the moving objects if compressed much. In this paper, we propose a novel approach for compact video synopsis using a unified spatiotemporal optimization. Our approach globally shifts moving objects in both spatial and temporal domains, which shifting objects temporally to reduce the length of the video and shifting colliding objects spatially to avoid visible collision artifacts. Furthermore, using a multilevel patch relocation (MPR) method, the moving space of the original video is expanded into a compact background based on environmental content to fit with the shifted objects. The shifted objects are finally composited with the expanded moving space to obtain the high-quality video synopsis, which is more condensed while remaining free of collision artifacts. Our experimental results have shown that the compact video synopsis we produced can be browsed quickly, preserves relative spatiotemporal relationships, and avoids motion collisions.

Fast exact nearest patch matching for patch-based image editing and processing.

This paper presents an efficient exact nearest patch matching algorithm which can accurately find the most similar patch-pairs between source and target image. Traditional match matching algorithms treat each pixel/patch as an independent sample and build a hierarchical data structure, such as kd-tree, to accelerate nearest patch finding. However, most of these approaches can only find approximate nearest patch and do not explore the sequential overlap between patches. Hence, they are neither accurate in quality nor optimal in speed. By eliminating redundant similarity computation of sequential overlap between patches, our method finds the exact nearest patch in brute-force style but reduces its running time complexity to be linear on the patch size. Furthermore, relying on recent multicore graphics hardware, our method can be further accelerated by at least an order of magnitude (≥10×). This greatly improves performance and ensures that our method can be efficiently applied in an interactive editing framework for moderate-sized image even video. To our knowledge, this approach is the fastest exact nearest patch matching method for high-dimensional patch and also its extra memory requirement is minimal. Comparisons with the popular nearest patch matching methods in the experimental results demonstrate the merits of our algorithm.