Optically Non-Contact Cross-Country Skiing Action Recognition Based on Key-Point Collaborative Estimation and Motion Feature Extraction.

Technical motion recognition in cross-country skiing can effectively help athletes to improve their skiing movements and optimize their skiing strategies. The non-contact acquisition method of the visual sensor has a bright future in ski training. The changing posture of the athletes, the environment of the ski resort, and the limited field of view have posed great challenges for motion recognition. To improve the applicability of monocular optical sensor-based motion recognition in skiing, we propose a monocular posture detection method based on cooperative detection and feature extraction. Our method uses four feature layers of different sizes to simultaneously detect human posture and key points and takes the position deviation loss and rotation compensation loss of key points as the loss function to implement the three-dimensional estimation of key points. Then, according to the typical characteristics of cross-country skiing movement stages and major sub-movements, the key points are divided and the features are extracted to implement the ski movement recognition. The experimental results show that our method is 90% accurate for cross-country skiing movements, which is equivalent to the recognition method based on wearable sensors. Therefore, our algorithm has application value in the scientific training of cross-country skiing.

Adaptive Data Fusion Method of Multisensors Based on LSTM-GWFA Hybrid Model for Tracking Dynamic Targets.

In preparation for the battlefields of the future, using unmanned aerial vehicles (UAV) loaded with multisensors to track dynamic targets has become the research focus in recent years. According to the air combat tracking scenarios and traditional multisensor weighted fusion algorithms, this paper contains designs of a new data fusion method using a global Kalman filter and LSTM prediction measurement variance, which uses an adaptive truncation mechanism to determine the optimal weights. The method considers the temporal correlation of the measured data and introduces a detection mechanism for maneuvering of targets. Numerical simulation results show the accuracy of the algorithm can be improved about 66% by training 871 flight data. Based on a mature refitted civil wing UAV platform, the field experiments verified the data fusion method for tracking dynamic target is effective, stable, and has generalization ability.

An artificial intelligence deep learning platform achieves high diagnostic accuracy for Covid-19 pneumonia by reading chest X-ray images.

The coronavirus disease of 2019 (Covid-19) causes deadly lung infections (pneumonia). Accurate clinical diagnosis of Covid-19 is essential for guiding treatment. Covid-19 RNA test does not reflect clinical features and severity of the disease. Pneumonia in Covid-19 patients could be caused by non-Covid-19 organisms and distinguishing Covid-19 pneumonia from non-Covid-19 pneumonia is critical. Chest X-ray detects pneumonia, but a high diagnostic accuracy is difficult to achieve. We develop an artificial intelligence-based (AI) deep learning method with a high diagnostic accuracy for Covid-19 pneumonia. We analyzed 10,182 chest X-ray images of healthy individuals, bacterial pneumonia. and viral pneumonia (Covid-19 and non-Covid-19) to build and test AI models. Among viral pneumonia, diagnostic accuracy for Covid-19 reaches 99.95%. High diagnostic accuracy is also achieved for distinguishing Covid-19 pneumonia from bacterial pneumonia (99.85% accuracy) or normal lung images (100% accuracy). Our AI models are accurate for clinical diagnosis of Covid-19 pneumonia by reading solely chest X-ray images.

Infrared Small Target Detection Method with Trajectory Correction Fuze Based on Infrared Image Sensor.

Due to the complexity of background and diversity of small targets, robust detection of infrared small targets for the trajectory correction fuze has become a challenge. To solve this problem, different from the traditional method, a state-of-the-art detection method based on density-distance space is proposed to apply to the trajectory correction fuze. First, parameters of the infrared image sensor on the fuze are calculated to set the boundary limitations for the target detection method. Second, the density-distance space method is proposed to detect the candidate targets. Finally, the adaptive pixel growth (APG) algorithm is used to suppress the clutter so as to detect the real targets. Three experiments, including equivalent detection, simulation and hardware-in-loop, were implemented to verify the effectiveness of this method. Results illustrated that the infrared image sensor on the fuze has a stable field of view under rotation of the projectile, and could clearly observe the infrared small target. The proposed method has superior anti-noise, different size target detection, multi-target detection and various clutter suppression capability. Compared with six novel algorithms, our algorithm shows a perfect detection performance and acceptable time consumption.

A deep learning diagnostic platform for diffuse large B-cell lymphoma with high accuracy across multiple hospitals.

Diagnostic histopathology is a gold standard for diagnosing hematopoietic malignancies. Pathologic diagnosis requires labor-intensive reading of a large number of tissue slides with high diagnostic accuracy equal or close to 100 percent to guide treatment options, but this requirement is difficult to meet. Although artificial intelligence (AI) helps to reduce the labor of reading pathologic slides, diagnostic accuracy has not reached a clinically usable level. Establishment of an AI model often demands big datasets and an ability to handle large variations in sample preparation and image collection. Here, we establish a highly accurate deep learning platform, consisting of multiple convolutional neural networks, to classify pathologic images by using smaller datasets. We analyze human diffuse large B-cell lymphoma (DLBCL) and non-DLBCL pathologic images from three hospitals separately using AI models, and obtain a diagnostic rate of close to 100 percent (100% for hospital A, 99.71% for hospital B and 100% for hospital C). The technical variability introduced by slide preparation and image collection reduces AI model performance in cross-hospital tests, but the 100% diagnostic accuracy is maintained after its elimination. It is now clinically practical to utilize deep learning models for diagnosis of DLBCL and ultimately other human hematopoietic malignancies.

Mechanical and Electronic Video Stabilization Strategy of Mortars with Trajectory Correction Fuze Based on Infrared Image Sensor.

For a higher attack accuracy of projectiles, a novel mechanical and electronic video stabilization strategy is proposed for trajectory correction fuze. In this design, the complexity of sensors and actuators were reduced. To cope with complex combat environments, an infrared image sensor was used to provide video output. Following the introduction of the fuze's workflow, the limitation of sensors for mechanical video stabilization on fuze was proposed. Particularly, the parameters of the infrared image sensor that strapdown with fuze were calculated. Then, the transformation relation between the projectile's motion and the shaky video was investigated so that the electronic video stabilization method could be determined. Correspondingly, a novel method of dividing sub-blocks by adaptive global gray threshold was proposed for the image pre-processing. In addition, the gray projection algorithm was used to estimate the global motion vector by calculating the correlation between the curves of the adjacent frames. An example simulation and experiment were implemented to verify the effectiveness of this strategy. The results illustrated that the proposed algorithm significantly reduced the computational cost without affecting the accuracy of the motion estimation. This research provides theoretical and experimental basis for the intelligent application of sensor systems on fuze.

Correction Strategy of Mortars with Trajectory Correction Fuze Based on Image Sensor.

For a higher accuracy of projectiles, a novel trajectory correction fuze is proposed. In this design, the sensor and actuator were reduced to achieve a balance between performance and affordability. Following introduction of the fuze concept, the flight model was presented and the crossrange and downrange components of trajectory response under control were investigated. The relationship between the inertial coordinate system and the detector coordinate system was studied so that the imager feedback could be used to derive the actual miss distance. The deployment time of canards and roll angle of the forward fuze were derived and used as the inputs of the control system in this strategy. Example closed-loop simulations were implemented to verify the effectiveness of the strategy. The results illustrate that the accuracy increase is evident and the proposed correction concept is applicable for terminal correction of mortars.

Hydroxychloroquine protects melanocytes from autoantibody-induced injury by reducing the binding of antigen-antibody complexes.

Vitiligo is a polygenic autoimmune disorder characterized by loss of pigmentation due to melanocyte destruction. Hydroxychloroquine (HCQ) is an effective immunosuppressant widely used in the treatment of autoimmune disorders. As generalized vitiligo (GV) is commonly considered to be a T cell and autoantibody-induced immune disorder, the present study aimed to determine whether HCQ protects melanocytes from autoantibody­induced disruption. Anti­melanocyte antibodies were obtained from the serum of patients with progressive GV and the effects of HCQ on prevent the autoantibody­induced disruption of melanocytes was observed. Cell­based ELISA, indirect immunofluorescence and western blotting were used to analyze the autoantibody content of sera samples obtained from 32 patients with progressive GV. The cytotoxicity of HCQ was detected by MTT assay, and 1 µg/ml HCQ was applied to human primary melanocytes (HMCs) to examine whether it could exert protective effects against autoantibody­induced immune injury. Flow cytometry was used to measure autoantibody binding to the surface of HMCs. Complement­dependent cytotoxicity (CDC) and antibody­dependent cell­mediated cytotoxicity (ADCC) were monitored by MTT and lactate dehydrogenase­releasing assays. The concentration of autoantibodies in sera samples taken from GV patients was significantly higher than in controls, particularly in patients who had >10% of their body surface affected by vitiligo. The majority of the autoantibodies presented in the HMCs and human keratinocytes (HKCs) and were predominantly localized to the cell surface and cytoplasm. The molecular weights of the autoantigens were identified as 30, 37­39, 42, 53, 60­75, 90, 100, 110, and 126 kDa; the 30 kDa protein was observed only in HMCs. The addition of HCQ at a concentration of 1 µg/ml produced no significant cytotoxicity in HMCs and was demonstrated to reduce the binding of GV immunoglobulin G (IgG) to the surface of HMCs. HCQ also significantly decreased the effects of ADCC and CDC that were mediated by GV IgG. The present study provides evidence that HCQ dissociates autoantibody-antigen complexes on the surface of HMCs and reverses ADCC and CDC activity in vitro. Thus, in addition to its effectiveness as an antimalarial therapeutic agent, HCQ may also be a promising potential treatment for patients with vitiligo.

Curcumin improves the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cells via the NF-κB-p53-caspase-3 pathway.

Paclitaxel, isolated from Taxus brevifolia, is considered to be an efficacious agent against a wide spectrum of human cancers, including human cervical cancer. However, dose-limiting toxicity and high cost limit its clinical application. Curcumin, a nontoxic food additive, has been reported to improve paclitaxel chemotherapy in mouse models of cervical cancer. However, the underlying mechanisms remain unclear. In this study, two human cervical cancer cell lines, CaSki [human papilloma virus (HPV)16-positive] and HeLa (HPV18-positive), were selected in which to investigate the effect of curcumin on the anticancer action of paclitaxel and further clarify the mechanisms. Flow cytometry and MTT analysis demonstrated that curcumin significantly promoted paclitaxel-induced apoptosis and cytotoxicity in the two cervical cell lines compared with that observed with paclitaxel alone (P<0.05). Reverse transcription-polymerase chain reaction indicated that the decline of HPV E6 and E7 gene expression induced by paclitaxel was also assisted by curcumin. The expression levels of p53 protein and cleaved caspase-3 were increased significantly in the curcumin plus paclitaxel-treated HeLa and CaSki cells compared with those in the cells treated with paclitaxel alone (P<0.01). Significant reductions in the levels of phosphorylation of IκBα and the p65-NF-κB subunit in CaSki cells treated with curcumin and paclitaxel were observed compared with those in cells treated with paclitaxel alone (P<0.05). This suggests that the combined effect of curcumin and paclitaxel was associated with the NF-κB-p53-caspase-3 pathway. In conclusion, curcumin has the ability to improve the paclitaxel-induced apoptosis of HPV-positive human cervical cancer cell lines via the NF-κB-p53-caspase-3 pathway. Curcumin in combination with paclitaxel may provide a superior therapeutic effect on human cervical cancer.

Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival.

Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.

A monoclonal antibody against GPNMB.

As a melanosome-associated transmembrane glycoprotein, GPNMB plays an important role in numerous cell types, as well as in tumors. Producing a high specificity and affinity monoclonal antibody against human GPNMB provides an important tool to study the function of GPNMB protein. In this study, monoclonal antibodies to GPNMB were obtained by immunizing BALB/c mice with purified GST-GPNMB emulsified in Freund's adjuvant. Three monoclonal antibodies with high specificity and affinity were obtained. The titers of anti-serum were 1:10,000, 1:8000, and 1:3000, respectively. Western blot and immunohistochemistry experiments were used to characterize the antibody. The anti-GPNMB antibodies G203 and F105 had high affinities (G203 around 2.7 × 10(-8) M and F105 around 1.6 × 10(-8) M, respectively) for the GPNMB antigen. However, M306 had a low binding activity to GPNMB. The results of Western blot and immunohistochemistry experiments showed that the antibodies could bind human GPNMB antigen. The monoclonal antibodies provided good tools for further studying functional characterization of GPNMB.

Endothelin-1 enhances the melanogenesis via MITF-GPNMB pathway.

Endothelin-1 (ET-1) plays an indispensable role in epidermal pigmentation in hyperpigmentary disorders due to a central role in melanogenesis. Nevertheless, precise mechanism involved in ET-1-induced hyperpigmentation is still undefined. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB) is a key element in melanosome formation. Therefore, we speculated that GPNMB was correlated with ET-1-induced pigmentation. After culturing with ET-1, melanin synthesis was significantly up-regulated, accompanying with increased expression of GPNMB and microphthalmia- associated transcription factor (MITF). Total number of melanosomes and melanin synthesis were sharply reduced via GPNMB-siRNA transfection, indicating ET-1-induced pigmentation by GPNMB-dependent manner. Furthermore, MITFsiRNA transfection strikingly inhibited GPNMB expression and the melanogenesis, and this suppression failed to be alleviated by ET-1 stimulation. All of these results demonstrated that ET-1 can trigger melanogenesis via the MITF-regulated GPNMB pathway. Taken together, these findings will provide a new explanation of how ET-1 induces hyperpigmentation, and possibly supply a new strategy for cosmetic studies.

Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors.

CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 (Schedule A) or day 8 (Schedule B), repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.

Silencing of GPNMB by siRNA inhibits the formation of melanosomes in melanocytes in a MITF-independent fashion.

BACKGROUND: Melanosomes are specialized membrane-surrounded organelles, which are involved in the synthesis, storage and transport of melanin. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB), a melanosome-specific structural protein, shares significant amino acid sequence homology with Pmel-17. Proteomic analysis demonstrated that GPNMB is present in all stages (I-IV) of melanosomes. However, little is known about the role of GPNMB in melanosomes. METHODOLOGY/PRINCIPAL FINDINGS: Using real-time quantitative PCR, Western blotting and immunofluorescence analysis, we demonstrated that the expression of GPNMB in PIG1 melanocytes was up-regulated by ultraviolet B (UVB) radiation. Transmission electron microscopy analysis showed that the total number of melanosomes in PIG1 melanocytes was sharply reduced by GPNMB-siRNA transfection. Simultaneously, the expression levels of tyrosinase (Tyr), tyrosinase related protein 1 (Trp1), Pmel17/gp100 and ocular albinism type 1 protein (OA1) were all significantly attenuated. But the expression of microphthalmia-associated transcription factor (MITF) was up-regulated. Intriguingly, in GPNMB silenced PIG1 melanocytes, UVB radiation sharply reduced MITF expression. CONCLUSION: Our present work revealed that the GPNMB was critical for the formation of melanosomes. And GPNMB expression down-regulation attenuated melanosome formation in a MITF-independent fashion.

The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells.

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.

LSK derived LSK- cells have a high apoptotic rate related to survival regulation of hematopoietic and leukemic stem cells.

A balanced pool of hematopoietic stem cells (HSCs) in bone marrow is tightly regulated, and this regulation is disturbed in hematopoietic malignancies such as chronic myeloid leukemia (CML). The underlying mechanisms are largely unknown. Here we show that the Lin(-)Sca-1(+)c-Kit(-) (LSK(-)) cell population derived from HSC-containing Lin(-)Sca-1(+)c-Kit(+) (LSK) cells has significantly higher numbers of apoptotic cells. Depletion of LSK cells by radiation or the cytotoxic chemical 5-fluorouracil results in an expansion of the LSK(-) population. In contrast, the LSK(-) population is reduced in CML mice, and depletion of leukemia stem cells (LSCs; BCR-ABL-expressing HSCs) by deleting Alox5 or by inhibiting heat shock protein 90 causes an increase in this LSK(-) population. The transition of LSK to LSK(-) cells is controlled by the Icsbp gene and its downstream gene Lyn, and regulation of this cellular transition is critical for the survival of normal LSK cells and LSCs. These results indicate a potential function of the LSK(-) cells in the regulation of LSK cells and LSCs.

Scd1 plays a tumor-suppressive role in survival of leukemia stem cells and the development of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is derived from a stem cell, and it is widely accepted that the existence of leukemia stem cells (LSCs) is one of the major reasons for the relapse of CML treated with kinase inhibitors. Key to eradicating LSCs is to identify genes that play a critical role in survival regulation of these stem cells. Using BCR-ABL-induced CML mouse model, here we show that expression of the stearoyl-CoA desaturase 1 (Scd1) gene is downregulated in LSCs and that Scd1 plays a tumor-suppressive role in LSCs with no effect on the function of normal hematopoietic stem cells. Deletion of Scd1 causes acceleration of CML development and conversely overexpression of Scd1 delays CML development. In addition, using genetic approaches, we show that Pten, p53, and Bcl2 are regulated by Scd1 in LSCs. Furthermore, we find that induction of Scd1 expression by a PPARγ agonist suppresses LSCs and delays CML development. Our results demonstrate a critical role for Scd1 in functional regulation of LSCs, providing a new anti-LSC strategy through enhancing Scd1 activity.

A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia.

We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and ß-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.

CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.

Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

Targeted therapy of chronic myeloid leukemia.

Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs.