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Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake. Loss of LILRB1 impairs cholesterol uptake but activates the de novo cholesterol synthesis pathway to maintain cellular cholesterol homeostasis, leading to the decrease of anti-ferroptotic metabolite squalene. Our study uncovers the function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis, implicating LILRB1 as a promising therapeutic target for MM patients.

The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression.

Summary: Neuromodulation is pivotal in modifying neuronal properties and motor states. CKR-1, a homolog of the cholecystokinin receptor, modulates robust escape steering and undulation body bending in C. elegans. Nevertheless, the mechanisms through which CKR-1 governs these motor states remain elusive. We elucidate the head motoneuron SMD as the orchestrator of both motor states. This regulation involves two neuropeptides: NLP-12 from DVA enhances undulation body curvature, while NLP-18 from ASI amplifies Ω-turn head curvature. Moreover, synthetic NLP-12 and NLP-18 peptides elicit CKR-1-dependent currents in Xenopus oocytes and Ca2+ transients in SMD neurons. Notably, CKR-1 shows higher sensitivity to NLP-18 compared to NLP-12. In situ patch-clamp recordings reveal CKR-1, NLP-12, and NLP-18 are not essential for neurotransmission at C. elegans neuromuscular junction, suggesting that SMD independently regulates head and body bending. Our studies illustrate that a single motoneuron SMD utilizes a cholecystokinin receptor CKR-1 to integrate two motor states.

Background Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development of mAbs with improved cytotoxicity, targeting new and known tumor-associated antigens, therefore continues to be an active research area. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo.Methods The specificity and antibody-binding capacity of DKK1-A2 mAbs were determined using indirect ELISA, confocal imaging, QIFIKIT antibody-binding capacity and cell surface binding assays. The affinity of mAbs was determined using a surface plasmon resonance biosensor. A flow cytometry-based cell death was performed to detect tumor cell apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays were used to evaluate the ability of DKK1-A2 mAbs to mediate ADCC and CDC activities against tumor cells in vitro. Flow cytometry data were collected with an FACSymphony A3 cell analyzer and analyzed with FlowJo V.10.1 software. Human cancer xenograft mouse models were used to determine the in vivo therapeutic efficacy and the potential safety and toxicity of DKK1-A2 mAbs. In situ TUNEL assay was performed to detect apoptosis in tumors and mouse organs.Results We generated novel DKK1-A2 mAbs that recognize the DKK1 P20 peptide presented by human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+ cancer cells. These mAbs directly induced apoptosis in HLA-A2+DKK1+ hematologic and solid cancer cells by activating the caspase-9 cascade, effectively lysed the cancer cells in vitro by mediating CDC and ADCC and were therapeutic against established cancers in their xenograft mouse models. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs neither bound to or killed HLA-A2+ blood cells in vitro nor caused tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice.Conclusion Our study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers.

The controllable pitch propeller hydraulic system has high constraints and nonlinearity. Due to these inherent deficiencies, the proportional–integral–derivative (PID) control algorithm cannot meet the control accuracy requirements of nonlinear systems. A control law based on a model predictive control (MPC) algorithm is designed in this paper. The gain parameters of the predictive control are optimized. The MPC and PID control systems are compared and simulated to verify the MPC controller’s effectiveness. Subsequently, the embedded controller of a controllable pitch propeller is developed. The support package for the embedded circuit board target containing an underlying driver for each interface is written by introducing the C-MEX S-Function and TLC programming language. A semi-physical simulation experiment is performed. The results show that the established controllable pitch propeller with an embedded controller displays reliable running performance, good anti-interference, and the capacity to fulfill the control function of the pitch propeller under various working conditions.

Objective The objective of this article is to explore the effect of formononetin (FMN) on depressive-like behaviors and neuroinflammation in lipopolysaccharide (LPS)-induced mice.

Abstract Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that regulates cell proliferation, survival, and migration. However, its role on human multiple myeloma (MM) cells is largely unknown. In this study, we show that LPA, which is highly elevated in MM patients, plays an important role in protecting human MM cells against proteasome inhibitor (PI)-induced apoptosis. LPA bound to its receptor LPAR2 activated its downstream MEK1/2-ERK1/2 signaling pathway and enhanced oxidative phosphorylation (OXPHOS) in mitochondria in MM cells. Increased OXPHOS activity produced more NAD+ and ATP, reduced proteasome activity, and enhanced protein folding and refolding in endoplasmic reticulum (ER), leading to induction of MM resistance to PIs. Importantly, inhibiting LPAR2 activity or knocking out LPAR2 in MM cells significantly enhanced MM sensitivity to PI-induced apoptosis in vitro and in vivo. Interestingly, primary MM cells from LPA-high patients were more resistant to PI-induced apoptosis than MM cells from LPA-low patients. Thus, our study indicates that LPA-LPAR2-mediated signaling pathways play an important role in MM sensitivity to PIs and targeting LPA or LPAR2 may potentially be used to (re)sensitize patients to PI-based therapy.

The leakage of the ship’s pipeline system will bring great risks to the engine equipment and seriously threaten the vitality of the ship. In this paper, the pipeline leakage detection and localization research are carried out based on the vibration signal generated by pipeline leakage. First, the finite element model of the pipeline is constructed to obtain the variation law of the vibration signal when the pipeline leaks are carried out. Second, the vibration signal is processed based on the variational mode decomposition (VMD) and radial basis function (RBF) neural networks. The wavelet packet threshold noise reduction is conducted before signal decomposition to improve the signal-to-noise ratio. Then, the denoised signal is decomposed by VMD. The effective component is identified by analyzing the correlation coefficient between the component and the denoised signal. The center frequency and energy of the effective component are used as feature vector to train the RBF neural network to identify and locate leakage. Finally, a pipeline leakage test platform is built under laboratory conditions. After processing the data samples collected from the test, the RBF neural network is trained to identify and locate leaks. The test sample identification results show that the leak identification and localization method based on VMD-RBF has a high accuracy.

This paper presents a shallow architecture based on Convolutional Neural Networks (CNN) for detecting Micro-cracks in Photovoltaic (PV) cells within the manufacturing environment. Based on Electro Luminescence (EL) imaging principles, this research presents a mechanism for determining the number of filters within the convolutional blocks, gradient guided filter tuning (GGFT). Observing the similarity between the original EL images and the filter output images obtained via GGFT, the research further introduces a mechanism for generating PV cell images based on EL Modelling, termed Filter Fused Data Scaling (FFDS). The effectiveness of both techniques is presented by benchmarking our developed architecture against ‘off the shelf’ augmentations and State-of-the-Art (SOTA) networks. The performance criteria was widened to include accuracy, computational, architectural, and post-deployment metrics. The high performance of our architecture in an intensive and wide-scoped evaluation demonstrates the high efficacy of our proposed mechanisms for developing PV-specific architectures and addressing the issue of data scarcity, particularly the difficulty in the procurement of quality EL images from the manufacturing site.

Morphological changes of the choroid have been proved to be associated with the occurrence and pathological mechanism of many ophthalmic diseases. Optical Coherence Tomography (OCT) is a non-invasive technique for imaging of ocular biological tissues, that can reveal the structure of the retinal and choroidal layers in micron-scale resolution. However, unlike the retinal layer, the interface between the choroidal layer and the sclera is ambiguous in OCT, which makes it difficult for ophthalmologists to identify with certainty. In this paper, we propose a novel boundary-enhanced encoder-decoder architecture for choroid segmentation in retinal OCT images, in which a Boundary Enhancement Module (BEM) forms the backbone of each encoder-decoder layer. The BEM consists of three parallel branches: 1) a Feature Extraction Branch (FEB) to obtain feature maps with different receptive fields; 2) a Channel Enhancement Branch (CEB) to extract the boundary information of different channels; and 3) a Boundary Activation Branch (BAB) to enhance the boundary information via a novel activation function. In addition, in order to incorporate expert knowledge into the segmentation network, soft key point maps are generated on the choroidal boundary, and are combined with the predicted images to facilitate precise choroidal boundary segmentation. In order to validate the effectiveness and superiority of the proposed method, both qualitative and quantitative evaluations are employed on three retinal OCT datasets for choroid segmentation. The experimental results demonstrate that the proposed method yields better choroid segmentation performance than other deep learning approaches. Moreover, both 2D and 3D features are extracted for statistical analysis from normal and highly myopic subjects based on the choroid segmentation results, which is helpful in revealing the pathology of high myopia. Code is available at https://github.com/iMED-Lab/Choroid-segmentation.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that includes symptoms such as inattentiveness, hyperactivity and impulsiveness. It is considered as an important public health issue, and prevalence of diagnosis has increased as awareness of the disease grew over the past years. Supply of specialist medical experts has not kept pace with the increasing demand for assessment, both due to financial pressures on health systems and the difficulty to train new experts, resulting in growing waiting lists. Patients are not being treated quickly enough causing problems in other areas of health systems (e.g. increased GP visits, increased risk of self-harm and accidents) and more broadly (e.g. time off work, relationship problems). Advances in machine learning make it possible to attempt to diagnose ADHD based on the analysis of relevant data, and this could inform clinical practice. This paper reports on findings related to the mental health services of a specialist Trust within the UK’s National Health Service (NHS). The analysis studied data of adult patients who underwent diagnosis over the past few years, and developed a diagnostic model for ADHD in adults. The results demonstrate that it is indeed possible to correctly diagnose ADHD patients with promising statistical accuracy.

Dementia is an incurable neurodegenerative disease primarily affecting the older population, for which the World Health Organisation has set to promoting early diagnosis and timely management as one of the primary goals for dementia care. While a range of popular machine learning algorithms and their variants have been applied for dementia diagnosis, fuzzy systems, which have been known effective in dealing with uncertainty and offer to explicitly reason how a diagnosis can be inferred, sporadically appear in recent literature. Given the advantages of a fuzzy rule-based model, which could potentially result in a clinical decision support system that offers understandable rules and a transparent inference process to support dementia diagnosis, this paper proposes a novel fuzzy inference system by adapting the concept of dominant sets that arise from the study of graph theory. A peeling-off strategy is used to iteratively extract from the constructed edge-weighted graph a collection of dominant sets. Each dominant set is further converted into a parameterized fuzzy rule, which is finally optimized in a supervised adaptive network-based fuzzy inference framework. An illustrative example is provided that demonstrates the interpretable rules and the transparent reasoning process of reaching a decision. Further systematic experiments conducted on data from the Open Access Series of Imaging Studies (OASIS) repository, also validate its superior performance over alternative methods.

CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro–polarized, transferred IL-9–secreting CD8+ Tc9 (cytotoxic T lymphocyte subset 9) cells exert greater persistence and antitumor efficacy than Tc1 cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell–derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis in the tumor microenvironment. IL-9 signaling deficiency, inhibiting STAT3, or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also exhibited lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL9 and higher lipid peroxidation– and ferroptosis-related genes than circulating CD8+ T cells in patients with melanoma. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via the IL-9/STAT3/fatty acid oxidation pathway and regulating T cell lipid peroxidation can be used to enhance T cell–based immunotherapy in human cancer.

Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.

Summary: Escape is an evolutionarily conserved and essential avoidance response. Considered to be innate, most studies on escape responses focused on hard-wired circuits. We report here that a neuropeptide NLP-18 and its cholecystokinin receptor CKR-1 enable the escape circuit to execute a full omega (Ω) turn. We demonstrate in vivo NLP-18 is mainly secreted by the gustatory sensory neuron (ASI) to activate CKR-1 in the head motor neuron (SMD) and the turn-initiating interneuron (AIB). Removal of NLP-18 or CKR-1 or specific knockdown of CKR-1 in SMD or AIB neurons leads to shallower turns, hence less robust escape steering. Consistently, elevation of head motor neuron (SMD)'s Ca2+ transients during escape steering is attenuated upon the removal of NLP-18 or CKR-1. In vitro, synthetic NLP-18 directly evokes CKR-1-dependent currents in oocytes and CKR-1-dependent Ca2+ transients in SMD. Thus, cholecystokinin peptidergic signaling modulates an escape circuit to generate robust escape steering.

The tortuosity assessment of vessels and nerve fibres in ophthalmic images has drawn substantial attention, for its potentials in assisting various medical diagnoses. Numerous morphological tortuosity measures have been leveraged to quantify tortuosity from various perspectives, which warrants the simultaneous use of multiple measures with an aim to produce a robust and accurate assessment. This paper proposes an approach for the automated assessment of curvilinear structures' tortuosity. Starting with the generation of clusters of tortuosity density for each individual measure, labelled fuzzy sets are then extracted that enhances the readability of subsequent operations. Finally, results from multiple measures are aggregated by a nearest neighbour guided approach where weights are generated in a data-driven manner to explain the derived aggregations. Experimental results on both ophthalmic vessel and nerve images demonstrate the superior performance of the proposed method over those where measurements are used independently or aggregated using conventional averaging operators.

In the conventional electromagnetic tube expansion, the end effects generated by the conventional helix coil may lead to inhomogeneous tube deformation in the axial direction. This paper is aimed at overcoming this issue by proposing a new concave coil structure to replace the helix coil currently used by the industry practice to generate a radial electromagnetic force on the tube. The proposed concave coil is expected to reinforce the electromagnetic force distribution profile and, hence, improving the axial inhomogeneous deformation of the tube. In this context, a new R-L criterion of deformation uniformity is first proposed. Second, an electromagnetic-structural coupling finite element model is established to investigate the relationship between the distribution of electromagnetic force generated by the concave coil and the uniformity of the tube under various voltage levels. The effectiveness of the proposed method is validated through a series of experimental and simulation analyses. Furthermore, based on the characteristics of the electromagnetic tube expansion, a modified multilayer concave coil structure is proposed to overcome the axial inhomogeneous deformation of long tubes.

Objectives: This study aims to investigate the environmental and individual factors contributing to male nurses' psychological well-being and to explore the psychological mechanisms that may explain the links between nurses' practice environment and work engagement, thereby presenting the implications for nurse managers. Methods: A total of 161 male nurses from three tertiary first-class hospitals in Changsha City in China participated in the study. We collected the data using the Practice Environment Scale of the Nursing Work Index, the Psychological Capital Questionnaire, and the Utrecht Work Engagement Scale. Results: Scores of male nurses' practice environment (2.88 ± 0.31), psychological capital (4.42 ± 0.62), and work engagement (3.17 ± 1.39) were all above the midpoint; however, the subscales âthe nursing staffing and resources adequacyâ (2.72 ± 0.48), âhopeâ (4.33 ± 0.72), and âdedicationâ (2.96 ± 1.61)scored lowest. Nurses' practice environment and psychological capital positively predicted nurses' work engagement; psychological capital fully mediated the influence of nurses' practice environment on work engagement. Conclusions: Creating a supportive nursing practice environment can increase male nurses' work engagement by developing their psychological capital. Nurse managers can then provide reasonable workload and pathways for male nurses to achieve goals, thereby fostering their hope. Keywords: Male nurses, Nurses' practice environment, Psychological capital, Work engagement

Three alloys with different microstructure characteristics were prepared, which microstructures were characterized as enriched with eutectics, supersaturated solid solution and coarse precipitates. Combined isothermal hot compression test and microstructure observation, the hot deformation behaviors of three alloys were studied in the temperature range of 340-490℃ and strain rate range of 0.001-10s-1. The results show initial microstructure characteristics have significant influences on the hot deformation of alloys. Among three alloys, the alloy enriched with coarse precipitates has the largest peak stress value while the alloy enriched with eutectics has the smallest one. The flow behaviors of three alloys were described by the hyperbolic sine constitutive equations. The deformation activation energy for three alloys calculated to be 178.6, 222.1, 154.9kJ/mol, respectively. The processing maps were calculated and analyzed according to the dynamic materials model. Among three alloys, the alloy enriched with coarse precipitates has the widest processing range while the alloy enriched with eutectics has the narrowest one.

The coal as fired, with unidentified characteristics of the coal gangue, was burned on a 300MW circulating fluidized bed unit. The equipment of the coal conveying system was damaged and the boiler operation was unstable. In response to the problems, the coal quality data and storage conditions of the coal were examined and the site was spot-checked to evaluate the coal quality characteristics. At the same time, the typical representative parameters of the coal handling system and boiler operation were selected. According to the analysis of coal quality and coal storage, the coal quality fluctuates greatly and the uniformity of particle size distribution is poor. There is actually the coal gangue with hard texture and hard to grind in the coal pile. The coal gangue will have adverse effects on the fine screening machine, fine crusher and other equipment. After burned this type of coal, the fluidized quality of the boiler bed is degraded to make an impact on the safe and stable operation of the boiler. It is recommended that the coal should be screened and then burned into the furnace to ensure safe and stable operation of the boiler.

In order to solve the problem of abnormal rise of the differential pressure of the revolving air preheater on 300MW unit, we analysed the causes of abnormal rise of the differential pressure of the air preheater and evaluated performances of control measures, through historical data mining and on-site inspection of the unit. The results show that, with the gradual decrease of environment temperature with the decrease of the exhaust gas temperature, the ashes in flue gas are bound by acid liquid produced by condensation of flue gas, and the adhesion areas of the ammonium bisulfate produced in the denitration process are enlarged. However the original set ash blowing pressure can no longer satisfy the requirements of the air preheater, giving rise to the differential pressure of the air preheater on both sides to rise. The reason of the higher differential pressure of the unilateral air preheater is that the large ammonia injection amount, leading to the increases of ammonia escape of the denitrification system. So the side of the air on preheater ammonium bisulfate type blockage is more serious. After the Measures of Adjusting distribution coefficient of ammonia supply valve on both sides, increasing the dust blowing frequency and pressure of the air preheater, the differential pressure of air preheater on both sides are close to the consistent. The decrease amplitude of the differential pressure of the air preheater on 280MW is about 300-500Pa.