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Abstract Background The long-term impacts of COVID-19 on human health are a major concern, yet comprehensive evaluations of its effects on various health conditions are lacking. Methods This study aims to evaluate the role of various diseases in relation to COVID-19 by analyzing genetic data from a large-scale population over 2,000,000 individuals. A bidirectional two-sample Mendelian randomization approach was used, with exposures including COVID-19 susceptibility, hospitalization, and severity, and outcomes encompassing 86 different diseases or traits. A reverse Mendelian randomization analysis was performed to assess the impact of these diseases on COVID-19. Results Our analysis identified causal relationships between COVID-19 susceptibility and several conditions, including breast cancer (OR = 1.0073, 95% CI = 1.0032–1.0114, p = 5 × 10 − 4), ER + breast cancer (OR = 0.5252, 95% CI = 0.3589–0.7685, p = 9 × 10 − 4), and heart failure (OR = 1.0026, 95% CI = 1.001–1.0042, p = 0.002). COVID-19 hospitalization was causally linked to heart failure (OR = 1.0017, 95% CI = 1.0006–1.0028, p = 0.002) and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). COVID-19 severity had causal effects on primary biliary cirrhosis (OR = 2.6333, 95% CI = 1.8274–3.7948, p = 2.059 × 10 − 7), celiac disease (OR = 0.0708, 95% CI = 0.0538–0.0932, p = 9.438 × 10–80), and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). Reverse MR analysis indicated that rheumatoid arthritis, diabetic nephropathy, multiple sclerosis, and total testosterone (female) influence COVID-19 outcomes. We assessed heterogeneity and horizontal pleiotropy to ensure result reliability and employed the Steiger directionality test to confirm the direction of causality. Conclusions This study provides a comprehensive analysis of the causal relationships between COVID-19 and diverse health conditions. Our findings highlight the long-term impacts of COVID-19 on human health, emphasizing the need for continuous monitoring and targeted interventions for affected individuals. Future research should explore these relationships to develop comprehensive healthcare strategies.

Summary: Pulmonary arterial hypertension (PAH) is a life-threatening disease induced by abnormal activation of pulmonary adventitial fibroblasts (PAFs) in the early stage. The association between selenium deficiency and PAH is not yet fully understood. In this study, we found that the serum selenium content of PAH patients was significantly lower than that of healthy volunteers in two independent cohorts. Moreover, PAH patients with lower selenium levels may present poorer prognosis. Prophylactic selenium supplementation could effectively improve hemodynamics and pulmonary vascular remodeling in monocrotaline-induced pulmonary hypertension rat models. Mechanistically, selenium supplementation restored the level of selenium binding protein 1 (SELENBP1) which could exert an antagonistic effect on PAF activation. The rescue assay further proved that selenium supplementation worked in a SELENBP1-dependent manner. These findings demonstrated that selenium deficiency is an important risk factor in PAH, and the selenium-SELENBP1 axis represents a promising target for PAH prevention.

Origami structures with morphing behaviours and unique mechanical properties are useful in aerospace deployable structures, soft robots and mechanical metamaterials. Curved-crease origami, as one of the variants in the origami family, has a curve that connects two vertices as a crease compared to the straight crease counterpart. This feature couples the crease folding and facet bending during the folding process, providing versatile design space of mechanical metamaterials with tunable stiffness, multi-stability properties and morphing behaviours. However, current design techniques are mostly for simple geometries with intuitive construction, the modelling technique focuses on using the conventional finite element method, and the intrinsically complex geometries make specimens difficult to manufacture, which further hinders the development of curved-crease origami structures. Thus, it is valuable to review the state-of-the-art in curved-crease origami. This paper presents a review on the design methodology, analytical methods, and applications of curved-crease origami over the years, discusses their strengths, identifies future challenges and provides an outlook for the future development of the curved-crease origami concept.

ObjectiveAcupuncture has certain effects to improve myopia visual function, but its neural mechanism is unclear. In this study, we acupunctured at the right Taiyang acupoint of myopic patients to analyze the effects of acupuncture on visual function and electroencephalographic activity and to investigate the correlation between improvements in visual function and changes in the brain.MethodsIn this study, a total of 18 myopic patients were recruited. The contrast sensitivity (CS) of the subjects was examined before and after acupuncture, and electroencephalography (EEG) data of the entire acupuncture process were recorded.ResultsThe study found that compared with before acupuncture, the CS of both eyes in myopic patients at each spatial frequency was increased after acupuncture; compared with the resting state, the contribution of microstate C was decreased during the post-acupuncture state, and the transition probability between microstate A and microstate C was reduced; in addition, the contribution of microstate C was negatively correlated with CS at both 12 and 18 cpd.ConclusionThe contrast sensitivity of myopic patients was improved after acupuncture at the Taiyang acupoint (20 min), which may be related to microstate C.

Abstract Multi‐stable structures and metamaterials with more than two stable states are widely applied in diversified engineering applications. Non‐rigid foldable origami patterns have provided an effective way of designing multi‐stable structures. But most of them have only two stable states and therefore require a combination of many units to achieve multi‐stability. Here, a series of extensible origami structures are proposed with generic multi‐stability based on non‐rigid wrapping origami. Through a kinematic analysis and experiments, it is demonstrate that a sequential folding among different layers of the structures is created to generate a continuous rigid origami range and several discrete rigid origami states, which consequently leads to the multi‐stability of the extensible origami structures. Moreover, the effects of design parameters on the mechanical properties of the structures are investigated by numerical simulation, enabling properties programmability upon specific needs. This study thus paves a new pathway for the development of novel multi‐stable origami structures.

Summary: Bladder cancer (BLCA) is one of the most prevalent and heterogeneous urinary malignant tumors. Previous researches have reported a significant association between cancer-associated fibroblasts (CAFs) and poor prognosis of tumor patients. However, uncertainty surrounds the role of CAFs in the BLCA tumor microenvironment, necessitating further investigation into the CAFs-related gene signatures in BLCA. In this study, we identified three CAF subtypes in BLCA according to single-cell RNA-seq data and constructed CAFs-related risk score (CRRS) by screening 102,714 signatures. The survival analysis, ROC curves, and nomogram suggested that CRRS was a valuable predictor in 2,042 patients from 9 available public datasets and Xiangya real-world cohort. We further revealed the significant correlation between CRRS and clinicopathological characteristics, genome alterations, and epithelial-mesenchymal transition (EMT). A high CRRS indicated a non-inflamed phenotype and a lower remission rate of immunotherapy in BLCA. In conclusion, the CRRS had the potential to predict the prognosis and immunotherapy response of BLCA patients.

Metamaterials constructed from origami units of different types and behaviors could potentially offer a broader scope of mechanical properties than those formed from identical unit types. However, the geometric design rules and property programming methods for such metamaterials have yet to be extensively explored. In this paper, we propose a new kind of origami metasheet by incorporating a family of different square-twist units. The tessellation rule of these metasheets is established to allow compatible mountain–valley crease assignments and geometric parameters among neighboring units. We demonstrate through experiments that the energy, initial peak force, and maximum stiffness of the metasheets can be obtained by a summation of the properties of the constitutional units. Based on this, we are able to program the mechanical properties of the metasheets over a wide range by varying the types and proportions of the units, as well as their geometric and material parameters. Furthermore, for a metasheet with a fixed number of units, all the geometrically compatible tessellations can be folded out of the same pre-creased sheet material by simply changing the mountain–valley assignments, thereby allowing the properties of the metasheet to be re-programmed based on specific requirements. This work could inspire a new class of programmable origami metamaterials for current and future mechanical and other engineering applications.

BackgroundRas guanine nucleotide-releasing protein 2 (RASGRP2), one of the guanine nucleotide exchange factors (GEFs), has attracted much attention in recent years. However, the correlation between RASGRP2 and immune infiltration and malignant features in lung adenocarcinoma (LUAD) has rarely been mentioned.MethodsThe Limma package and the LASSO regression model were performed to screen for differentially expressed genes. Data from the TCGA and 5 GEO databases were used to explore the expression level of RASGRP2 in LUAD patients. A weighted co-expression network and LinkFinder module were established to find the related genes of RASGRP2. The ESTIMATE algorithm was used to analyze the correlation between RASGRP2 and immune infiltration in LUAD. Tumor-infiltrating immune cells were sorted and sequenced at the single-cell level to analyze differences in RASGRP2. Real-time PCR and immunohistochemistry were performed in the real-world cohort to verify the expression of RASGRP2 and its correlation with immune-related genes. Clone formation and EdU assays were used to verify the proliferation ability. The proportion of apoptotic cells was analyzed by flow cytometry. Observation of mitochondrial membrane potential (MMP) changes by fluorescence microscopy.ResultsOur results suggested that decreased RASGRP2 was associated with worse clinical parameters and prognosis in LUAD patients. And we constructed a FLI1-HSA-miR-1976-RASGRP2 transcriptional network to support the role of RASGRP2. Enrichment analysis revealed that RASGRP2 was involved in lymphocyte activation and leukocyte adhesion. RASGRP2 was found to be positively correlated with the infiltration of most immune cells, immunoregulators, and chemokines in a subsequent study. Meanwhile, the real-world cohort confirmed that the expression levels of PDCD1, CTLA4, CD40LG, CCL14, CXCR5, and CCR7 were higher in the high-RASGRP2 expression group. Cytological experiments proved that RASGRP2 inhibited cell proliferation in LUAD by regulating mitochondrial-dependent apoptosis.ConclusionRASGRP2 was a potential immune-related biomarker of LUAD. In addition, RASGRP2 was involved in the malignant progression of LUAD through the regulation of mitochondrial-dependent apoptosis.

Abstract The efficacy of cancer immunotherapy largely depends on the tumor microenvironment, especially the tumor immune microenvironment. Emerging studies have claimed that microbes reside within tumor cells and immune cells, suggesting that these microbes can impact the state of the tumor immune microenvironment. For the first time, this review delineates the landscape of intra-tumoral microbes and their products, herein defined as the tumor microbe microenvironment. The role of the tumor microbe microenvironment in the tumor immune microenvironment is multifaceted: either as an immune activator, inhibitor, or bystander. The underlying mechanisms include: (I) the presentation of microbial antigens by cancer cells and immune cells, (II) microbial antigens mimicry shared with tumor antigens, (III) microbe-induced immunogenic cell death, (IV) microbial adjuvanticity mediated by pattern recognition receptors, (V) microbe-derived metabolites, and (VI) microbial stimulation of inhibitory checkpoints. The review further suggests the use of potential modulation strategies of the tumor microbe microenvironment to enhance the efficacy and reduce the adverse effects of checkpoint inhibitors. Lastly, the review highlights some critical questions awaiting to be answered in this field and provides possible solutions. Overall, the tumor microbe microenvironment modulates the tumor immune microenvironment, making it a potential target for improving immunotherapy. It is a novel field facing major challenges and deserves further exploration.

BackgroundImmunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified.MethodsIn this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models.ResultsThe 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis.ConclusionIn conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.

A range of soft robotic systems have recently been developed that use soft, flexible materials and respond to environmental stimulus. The greatest challenge in their design is the integration of the actuator, energy sources, and body of robots while achieving fast locomotion and well-defined programmable trajectories. This work presents such a design that operates under constant conditions without the need for an externally modulated stimulus. By using a humidity-sensitive agarose film and overcoming the isotropic and random bending of the film, the robot, which we call the Hydrollbot, harnesses energy from evaporation for spontaneous and continuous fast self-rolling locomotion with a programmable trajectory in a constant-humidity environment. Moreover, the geometric parameters of the film were fine-tuned to maximize the rolling speed, and the optimised hydrollbot is capable of carrying a payload up to 100% of its own weight. The ability to self-propel fast under constant conditions with programmable trajectories will confer practical advantages to this robot in the applications for sensors, medical robots, actuation, etc.

Origami and kirigami inspired foldcores have recently seen a surge in research and engineering applications mainly due to their open channel configuration to avoid moisture accumulation and diversification of design parameters to meet customized requirements. In this paper, a new kirigami-inspired pyramid foldcore was proposed, and the performance of the corresponding sandwich structure subjected to quasi-static out-of-plane compression and shear, respectively, were studied experimentally, numerically, and analytically. The deformation mechanism of the new sandwich in each loading scenario was revealed, and the effects of geometric parameters were obtained through parametric analysis. Moreover, a theoretical model was established to estimate the average shear stress of the sandwich. In comparison with the commonly adopted square honeycomb, Miura-ori, and eggbox sandwiches, the average compressive stress of the new sandwich was respectively increased by 73%, 342%, and 130%. Upon shear loading, the average shear stress of the new sandwich outperformed the Miura-ori by 34%, and was comparable with that of the square honeycomb by a difference of 11%. To summarize, the new foldcore shows great promise in the design of high-performance sandwich structures.

Origami-inspired metamaterials are receiving increasing attention because they can provide unusual and favorable mechanical properties that are determined by their unique patterned geometry. In this paper, a novel design based on Miura-ori pattern, with varying geometries throughout its volume, is proposed and analyzed under quasi-static compression. Both experiments and numerical simulations indicate that the new design, both two-dimensional graded (2DG) and three-dimensional graded (3DG), can generate periodically graded stiffness as well as superior energy absorption. The sensitivity of the graded behavior to various parameters of the problem is studied. It appears that both in-plane and out-of-plane graded stiffness can be accomplished with an appropriate introduction of the geometric gradients. As to the coupling effect, when the 3DG model is compressed in the z-direction, the existence of the x-directional gradient tends to reduce the stress level and specific energy absorption (SEA), whereas when compressed in the x-direction, the opposite trend is observed regarding the z-directional gradient. Comparing with the conventional design, the proposed design can achieve an increase of 129.68% in SEA in the optimal case. In general, the proposed origami metamaterial, whose behavior can be customized and programmed, shows great potential in engineering applications where a non-uniform response is needed. Keywords: Origami structure, Compressive property, Three-dimensional graded stiffness, Self-locking, Energy absorption, Mechanical metamaterial

Morphing wing skin can greatly improve the performance of aircraft by adjusting the shape of the wings according to different flight conditions. However, it is a challenge to maintain a smooth aerodynamic wing skin surface during the deformation process. Here, we propose an angled morphing wing skin module based on a silicon rubber matrix reinforced by carbon-fiber-reinforced polymer rods, which takes advantage of the tensile stress generated during shear to prevent it from wrinkling under large shear deformation. Experiments conducted on a series of wing skin modules with varying initial angles indicate that by starting from an angled configuration, the skin module can withstand a pure shear deformation of 92° without wrinkling, 53% larger than existing designs. A parametric analysis was also conducted to analyze the effects of geometric and material parameters on the wrinkle-free deformation range. Finally, a theoretical model based on the energy method was developed to unveil the underlying wrinkle prevention mechanism and to estimate the critical wrinkling angle of the skin. The proposed design can potentially greatly expand the shear morphing capability of aircraft wings, leading to larger variation in sweepback angle and therefore superior aerodynamic performance.

Origami has recently emerged as a promising building block of mechanical metamaterials because it offers a purely geometric design approach independent of scale and constituent material. The folding mechanics of origami-inspired metamaterials, i.e., whether the deformation involves only rotation of crease lines (rigid origami) or both crease rotation and facet distortion (nonrigid origami), is critical for fine-tuning their mechanical properties yet very difficult to determine for origami patterns with complex behaviors. Here, we characterize the folding of tubular waterbomb using a combined kinematic and structural analysis. We for the first time uncover that a waterbomb tube can undergo a mixed mode involving both rigid origami motion and nonrigid structural deformation, and the transition between them can lead to a substantial change in the stiffness. Furthermore, we derive theoretically the range of geometric parameters for the transition to occur, which paves the road to program the mechanical properties of the waterbomb pattern. We expect that such analysis and design approach will be applicable to more general origami patterns to create innovative programmable metamaterials, serving for a wide range of applications including aerospace systems, soft robotics, morphing structures, and medical devices.

Using Complete Coverage Path Planning (CCPP), a cleaning robot could visit every accessible area in the workspace. The dynamic environment requires the higher computation of the CCPP algorithm because the path needs to be replanned when the path might become invalid. In previous CCPP methods, when the neighbours of the current position are obstacles or have been visited, it is challenging for the robot to escape from the deadlocks with the least extra time cost. In this study, a novel CCPP algorithm is proposed to deal with deadlock problems in a dynamic environment. A priority template inspired by the short memory model could reduce the number of deadlocks by giving the priority of directions. Simultaneously, a global backtracking mechanism guides the robot to move to the next unvisited area quickly, taking the use of the explored global environmental information. What's more, the authors extend their CCPP algorithm to a multi-robot system with a market-based bidding process which could deploy the coverage time. Experiments of apartment-like scenes show that the authors’ proposed algorithm can guarantee an efficient collision-free coverage in dynamic environments. The proposed method performs better than related approaches on coverage rate and overlap length.

Objective: Acupuncture has certain effects to improve myopia visual function, but its neural mechanism is unclear. In this study, we acupunctured at the right Taiyang acupoint of myopic patients to analyze the effects of acupuncture on visual function and electroencephalographic activity and to investigate the correlation between improvements in visual function and changes in the brain. Methods: In this study, a total of 18 myopic patients were recruited. The contrast sensitivity (CS) of the subjects was examined before and after acupuncture, and electroencephalography (EEG) data of the entire acupuncture process were recorded. Results: The study found that compared with before acupuncture, the CS of both eyes in myopic patients at each spatial frequency was increased after acupuncture; compared with the resting state, the contribution of microstate C was decreased during the post-acupuncture state, and the transition probability between microstate A and microstate C was reduced; in addition, the contribution of microstate C was negatively correlated with CS at both 12 and 18 cpd. Conclusion: The contrast sensitivity of myopic patients was improved after acupuncture at the Taiyang acupoint (20min), which may be related to microstate C. [ABSTRACT FROM AUTHOR]

Multistability plays an important role in advanced engineering applications such as metastructures, deployable structures, and reconfigurable robotics. However, most existing multistability design is based on the two-dimensional (2D)/3D series or parallel combinations of bistable unit cells, which are derived from snap-through instability, nonrigid foldable origami structures, and compliant mechanism, due to the lack of a generic multistable unit cell. Here, we develop a tristable kirigami cuboid by creating a set of elastic joints only effective in a specific motion range which integrates the elastic sheets and switchable hinge axes inspired by the kinematic behaviors of a kirigami cuboid with thick facets. The energy barriers between the stable states can be programmed by the geometric design parameters and material properties of the elastic joints. Taking the tristable cuboid as a unit cell, we construct a family of metastructures with multiple stable states. The number of stable states, the combination of unit stable states, and their transform sequences can be programmed by the number of unit cells, unit design parameters, and loading modes and loading sequences. We also apply this tristable cuboid to the design of frequency reconfigurable antenna with three programmable working frequencies, which demonstrates that such versatile multistability and structural diversity facilitate the development of multifunctional materials and devices. [ABSTRACT FROM AUTHOR]