Search

Organoids, characterized by their high physiological attributes, effectively preserve the genetic characteristics, physiological structure, and function of the simulated organs. Since the inception of small intestine organoids, other organoids for organs including the liver, lungs, stomach, and pancreas have subsequently been developed. However, a comprehensive summary and discussion of research findings on gastrointestinal tract (GIT) organoids as disease models and drug screening platforms is currently lacking. Herein, in this review, we address diseases related to GIT organoid simulation and highlight the notable advancements that have been made in drug screening and pharmacokinetics, as well as in disease research and treatment using GIT organoids. Organoids of GIT diseases, including inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and Helicobacter pylori infection, have been successfully constructed. These models have facilitated the study of the mechanisms and effects of various drugs, such as metformin, Schisandrin C, and prednisolone, in these diseases. Furthermore, GIT organoids have been used to investigate viruses that elicit GIT reactions, including Norovirus, SARS-CoV-2, and rotavirus. Previous studies by using GIT organoids have shown that dasabuvir, gemcitabine, and imatinib possess the capability to inhibit viral replication. Notably, GIT organoids can mimic GIT responses to therapeutic drugs at the onset of disease. The GIT toxicities of compounds like gefitinib, doxorubicin, and sunset yellow have also been evaluated. Additionally, these organoids are instrumental for the study of immune regulation, post-radiation intestinal epithelial repair, treatment for cystic fibrosis and diabetes, the development of novel drug delivery systems, and research into the GIT microbiome. The recent use of conditioned media as a culture method for replacing recombinant hepatocyte growth factor has significantly reduced the cost associated with human GIT organoid culture. This advancement paves the way for large-scale culture and compound screening of GIT organoids. Despite the ongoing challenges in GIT organoid development (e.g., their inability to exist in pairs, limited cell types, and singular drug exposure mode), these organoids hold considerable potential for drug screening. The use of GIT organoids in this context holds great promises to enhance the precision of medical treatments for patients living with GIT diseases.

Peptide-functionalized hydrogel is one of commonly used biomaterials to introduce hydrogel-induced vessel regeneration. Despite many reports about the discoveries of high-active peptides (or ligands) for regeneration, the study on the conjugating methods for the hydrogel functionalization with peptides is limited. Here, we compared the vasculogenic efficacy of the peptide-functionalized hydrogels prepared by two commonly used conjugating methods, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) and Click methods, through cell models, organ-on-chips models, animal models, and RNA sequencing analysis. Two vascular-related cell types, the human umbilical vein endothelial cells (HUVECs) and the adipose-derived stem cells (ADSCs), have been cultured on the hydrogel surfaces prepared by EDC/Click methods. It showed that the hydrogels prepared by Click method supported the higher vasculogenic activities while the ones made by EDC method compromised the peptide activities on hydrogels. The vasculogenesis assays further revealed that hydrogels prepared by Click method promoted a better vascular network formation. In a critical ischemic hindlimb model, only the peptide-functionalized hydrogels prepared by Click method successfully salvaged the ischemic limb, significantly improved blood perfusion, and enhanced the functional recoveries (through gait analysis and animal behavior studies). RNA sequencing studies revealed that the hydrogels prepared by Click method significantly promoted the PI3K-AKT pathway activation compared to the hydrogels prepared by EDC method. All the results suggested that EDC method compromised the functions of the peptides, while Click method preserved the vascular regenerating capacities of the peptides on the hydrogels, illustrating the importance of the conjugating method during the preparation of the peptide-functionalized hydrogels.

Abstract During the Cold War era, translation constituted an integral part of the ideological confrontations of US cultural diplomacy. Scholarly discussions on US-associated cultural products have provided insights from the perspective of American patronage, yet have not adequately addressed the diverse role of unofficial agencies in their cultural practices with multiple intentions. This study analyzes Chinese translations in the magazine Children’s Paradise (CP) operated by the Union, an entity involved in the network of American covert cultural diplomatic activities. It delves into the Union’s agenda of furthering a progressive Chinese nation that continues and revitalizes Chinese civilization by analyzing three marked characteristics of the translated texts and their underlying rationales. It finds that, through deliberate omissions, substitutions, and additions, CP demonstrated a relentless commitment to the Union’s China-centric agendas in its domesticated and adapted translations. Despite sharing the anti-communist conviction associated with American interests, CP leveraged localized practices to engage with the social-political issues of the British-ruled Hong Kong of the 1970s. As a result, it generated cultural outcomes exceeding the Cold War polarities, and left a lasting legacy on the younger generation of Hong Kong.

Abstract Age is a significant contributing factor to the occurrence and progression of cardiovascular disease (CVD). Pharmacological treatment can effectively alleviate CVD symptoms caused by aging. However, 90% of the drugs have failed in clinics because of the loss of drug effects or the occurrence of the side effects. One of the reasons is the disparity between animal models used and the actual physiological levels in humans. Therefore, we integrated multiple datasets from single‐cell and bulk‐seq RNA‐sequencing data in rats, monkeys, and humans to identify genes and pathways with consistent/differential expression patterns across these three species. An approach called “Cross‐species signaling pathway analysis” was developed to select suitable animal models for drug screening. The effectiveness of this method was validated through the analysis of the pharmacological predictions of four known anti‐vascular aging drugs used in animal/clinical experiments. The effectiveness of drugs was consistently observed between the models and clinics when they targeted pathways with the same trend in our analysis. However, drugs might have exhibited adverse effects if they targeted pathways with opposite trends between the models and the clinics. Additionally, through our approach, we discovered four targets for anti‐vascular aging drugs, which were consistent with their pharmaceutical effects in literatures, showing the value of this approach. In the end, software was established to facilitate the use of “Cross‐species signaling pathway analysis.” In sum, our study suggests utilizing bioinformatics analysis based on disease characteristics can help in choosing more appropriate animal models.

Familial dilated cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, dilated cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPβ signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of dilated cardiomyopathy. Displacement of PP2A from mAKAPβ, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPβ-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing dilated cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo. Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in dilated cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for dilated cardiomyopathy.

Abstract Background Serum exosomes play important roles in intercellular communication and are promising biomarkers of several autoimmune diseases. However, the biological functions and potential clinical importance of long non-coding RNAs (lncRNAs) and mRNAs from serum exosomes in rheumatoid arthritis (RA) have not yet been studied. Methods Serum exosomal lncRNAs and mRNAs were isolated from patients with RA and osteoarthritis (OA) and healthy controls. The differentially expressed lncRNAs (DE-lncRNAs) and mRNA profiles in the serum exosomes of patients with RA were analysed using high-throughput sequencing, and their functions were predicted using Gene Ontologyenrichment, Kyoto Encyclopedia of Genes and Genomes pathway, and gene set enrichment analysis. We constructed a DE-lncRNA-mRNA network and a protein–protein interaction network of differentially expressed mRNAs (DE-mRNAs) in RA using the Cytoscape software. The expression of several candidate a DE-lncRNAs and DE-mRNAs in the serum of patients with RA, patients with OA, and healthy controls was confirmed by qRT-PCR. We assessed the diagnostic ability of DE-lncRNAs and DE-mRNAs in patients with RA using receiver operating characteristic analysis. Furthermore, we analysed the characteristics of immune cell infiltration in RA by digital cytometry using the CIBERSORT algorithm and determined the correlation between immune cells and several DE-lncRNAs or DE-mRNAs in RA. Results The profiles of serum exosomal lncRNAs and mRNAs in patients with RA were different from those in healthy controls and patients with OA. The functions of both DE-lncRNAs and DE-mRNAs in RA are associated with the immune response and cellular metabolic processes. The RT-PCR results show that NONHSAT193357.1, CCL5, and MPIG6B were downregulated in patients with RA. The combination of three DE-mRNAs, CCL5, MPIG6B, and PFKP, had an area under the curve of 0.845 for differentiating RA from OA. Digital cytometry using the CIBERSORT algorithm showed that the neutrophil counts were higher in patients with RA than those in healthy controls and patients with OA. Conclusions These findings help to elucidate the role of serum exosomal lncRNAs and mRNAs in the specific mechanisms underlying RA.

3D bioprinting technology is widely used to fabricate various tissue structures. However, the absence of vessels hampers the ability of bioprinted tissues to receive oxygen and nutrients as well as to remove wastes, leading to a significant reduction in their survival rate. Despite the advancements in bioinks and bioprinting technologies, bioprinted vascular structures continue to be unsuitable for transplantation compared to natural blood vessels. In addition, a complete assessment index system for evaluating the structure and function of bioprinted vessels in vitro has not yet been established. Therefore, in this review, we firstly highlight the significance of selecting suitable bioinks and bioprinting techniques as they two synergize with each other. Subsequently, focusing on both vascular-associated cells and vascular tissues, we provide a relatively thorough assessment of the functions of bioprinted vascular tissue based on the physiological functions that natural blood vessels possess. We end with a review of the applications of vascular models, such as vessel-on-a-chip, in simulating pathological processes and conducting drug screening at the organ level. We believe that the development of fully functional blood vessels will soon make great contributions to tissue engineering and regenerative medicine.

Coal will occupy the main position in China's energy structure for a long time, and the negative externalities of its exploitation have a serious impact on the ground surface and its appurtenances. With the proposal of the dual carbon strategy, the coal-based energy determines that green and safe coal mining should be the priority direction of China's energy development. Taking Xinyi coalmine, which is mined in unstable coal seams with large mining depth, as the research area, the surface response characteristic and subsidence law under the different mining degrees were clarified. Meanwhile, the damage mechanism of buildings was revealed, which was from no obvious damage to Grade Ⅳ under the extremely insufficient mining to subcritical mining. Based on the sustainable development and green production in coalmines, the overburden grout injection technique under buildings that does not affect the normal production was proposed, and its technical principle was described. A weighted grey relational analysis model was established, and obtained that the panel width was the main factor affecting the overburden failure height under subcritical mining. According to the definition of overburden failure degree proposed by the author, the feasibility of overburden grout injection technique under buildings was analyzed and the key parameters, such as slurry diffusion radius, borehole position and depth, grouting system and technology, were determined and successfully applied. The engineering application shows that the maximum surface subsidence after grouting is 253 mm, and the building damage is within the Grade I. Meanwhile, 5.82 Mt of coal resources under the buildings have been liberated, which realizes high quality coal mining, low environmental damage, green and low-carbon, and also provides a reference for the sustainable development of coal enterprises, especially for the exhausted coalmines that recover coal pillars.

Abstract The latest research on hybrid networks of decode‐and‐forward (DF) relay and intelligent reflecting surface (IRS) is limited to just a single relay. To harvest multiple relay gains, this paper proposes a hybrid communication networks that combines multiple DF relays with an IRS. The authors formulate and address the joint optimization problem to maximize the end‐to‐end transmission rate by jointly optimizing the reflect beam forming, the best relay selection and the power allocation, subject to total transmit power constraint. Moreover, to better exploit the degrees of freedom, it is proposed that the source also transmits signals in the second time slot. While the optimization problem is difficult to solve, the authors propose some efficient approaches to make the problem tractable. First, power allocation problem is simplified by applying Cauchy‐Schwarz inequality and introducing equivalent channel gain, second, non‐convex rank‐one constraint is overcome by utilizing semidefinite relaxation (SDR) approach, then the slacked non‐convex constraint is overcome by applying first‐order Taylor expansion approximation. The simulation results demonstrate that our proposed joint optimization scheme for hybrid networks of multiple DF relays with an IRS has significant performance improvement over the other optimization schemes, such as the optimization scheme for hybrid networks of single DF relay and an IRS.

BackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune disease involving multiple organs throughout the body. The health care–seeking behaviors, disease progression of SLE, and patients' knowledge of and attitudes toward SLE have not been characterized in China. ObjectiveThe aim of this study was to depict the health care–seeking behaviors, disease progression, and medications in patients with SLE and to examine the factors associated with their disease flares, knowledge, and attitudes toward SLE in China. MethodsWe conducted a cross-sectional survey in 27 provinces in China. Descriptive statistical methods were used to depict the demographic characteristics, health care–seeking behaviors, medications, and health status. Multivariable logistic regression models were used to identify the factors associated with disease flares, medication changes, and attitudes toward SLE. An ordinal regression model was used to examine the factors associated with the knowledge of the treatment guidelines. ResultsWe recruited 1509 patients with SLE, and 715 had lupus nephritis (LN). Approximately 39.96% (603/1509) of the patients with SLE were primarily diagnosed with LN, and 12.4% (112/906) developed LN (mean time 5.2 years) from non-LN. Patients whose registered permanent residences or workplaces in other cities from the same province and adjacent provinces seeking health care accounted for 66.9% (569/850) and 48.8% (479/981) of the patients with SLE in the provincial capital cities, respectively. Mycophenolate mofetil was the most commonly used immunosuppressive drug in patients without LN (185/794, 23.3%) and patients with LN (307/715, 42.9%). Femoral head necrosis (71/228, 31.1%) and hypertension (99/229, 43.2%) were the most common adverse event (AE) and chronic disease during treatment, respectively. Change of hospitals for medical consultation (odds ratio [OR] 1.90, 95% CI 1.24-2.90) and development of 1 chronic disease (OR 3.60, 95% CI 2.04-6.24) and AE (OR 2.06, 95% CI 1.46-2.92) and more were associated with disease flares. A pregnancy plan (OR 1.58, 95% CI 1.18-2.13) was associated with changes in medication. Only 242 (16.03%) patients with SLE were familiar with the treatment guidelines, and patients with LN tended to be more familiar with the disease (OR 2.20, 95% CI 1.81-2.68). After receiving treatment, 891 (59.04%) patients changed their attitudes toward SLE from fear to acceptance, and patients with college education or higher (OR 2.09, 95% CI 1.10-4.04) were associated with a positive attitude toward SLE. ConclusionsA large proportion of patients seeking health care in the provincial capital cities of China migrated from other cities. Persistent monitoring of potential AEs and chronic diseases during SLE treatment and managing patients who changed hospitals for medical consultation are essential for controlling disease flares. Patients had insufficient knowledge about SLE treatment guidelines and would benefit from health education to maintain a positive attitude toward SLE.

Abstract Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.

The propagation of secondary surges can lead to unexpected interaction events with navigation ships and downstream hydraulic structures; hence, they may cause navigation accidents and structural damage. In the present study, physical experiments were performed in a long water wave tank to study the evolution of breaking undular and breaking surges advancing in still water. Both free-surface and velocity measurements were conducted. It was observed that the transition from a breaking undular surge to a breaking surge occurred as the ratio of the mean water depth behind the surge to the still water depth equal to 1.68–1.71. Empirical expressions based on the experimental data were proposed to predict the wave amplitude and wave steepness of breaking undular surges. The unsteady flow results demonstrated that the normalized longitudinal velocity component beneath the surge front was governed mainly by the normalized free-surface elevation, independently of the surge type. Moreover, the maximum vertical velocity component during the surge front passage had a linear dependence on the vertical location. The present result provided new quantitative information on breaking undular and breaking surges advancing in still water.

Abstract Dopamine receptors are involved in several immunological diseases. We previously found that dopamine D3 receptor (D3R) on mast cells showed a high correlation with disease activity in patients with rheumatoid arthritis, but the mechanism remains largely elusive. In this study, a murine collagen-induced arthritis (CIA) model was employed in both DBA/1 mice and D3R knockout mice. Here, we revealed that D3R-deficient mice developed more severe arthritis than wild-type mice. D3R suppressed mast cell activation in vivo and in vitro via a Toll-like receptor 4 (TLR4)-dependent pathway. Importantly, D3R promoted LC3 conversion to accelerate ubiquitin-labeled TLR4 degradation. Mechanistically, D3R inhibited mTOR and AKT phosphorylation while enhancing AMPK phosphorylation in activated mast cells, which was followed by autophagy-dependent protein degradation of TLR4. In total, we found that D3R on mast cells alleviated inflammation in mouse rheumatoid arthritis through the mTOR/AKT/AMPK-LC3-ubiquitin-TLR4 signaling axis. These findings identify a protective function of D3R against excessive inflammation in mast cells, expanding significant insight into the pathogenesis of rheumatoid arthritis and providing a possible target for future treatment.

KAT6A syndrome is an autosomal dominant genetic disorder associated with intellectual disability due to mutations in the lysine acetyltransferase 6A ( KAT6A ) gene. There are some differences in phenotype between KAT6A gene variants. This current case report describes a 1-month-old male infant that had a nonsense mutation in the KAT6A gene. Neither of his parents had the mutation. The proband had feeding difficulties and a physical examination revealed the following: moderate dysphagia, hypoplastic laryngeal cartilage, poor audio-visual response, poor head-up ability, no active grasping awareness, microcephaly, high arched palate and he was significantly behind other children of the same age. Echocardiography showed that the foramen ovale was not closed. He was diagnosed with atrial septal defect (ASD) when 2 years old. The patient received ASD repair at 32 months of age. Head colour Doppler ultrasonography and brain magnetic resonance imaging showed cysts in the right ventricle and choroid plexus, which returned to normal at 2 years of age. This current case demonstrates that immediate surgery should be considered in newborns with KAT6A syndrome presenting with a heart malformation. A new KAT6A syndrome phenotype is described in this current case report, which requires early diagnosis and treatment.

Citrus Huanglongbing (HLB), known as the most economically devastating disease in citrus industry, is mainly caused by phloem-restricted Gram-negative bacterium “Candidatus Liberibacter asiaticus” (CLas). To date, CLas is still unculturable in vitro, which has been dramatically delaying the research on its pathogenesis, and only few Sec-dependent effectors (SDEs) have been identified to elucidate the pathogenesis of CLas. Here, we confirmed that a CLas-secreted Sec-dependent polypeptide, namely SECP8 (CLIBASIA_05330), localized in nucleus, cytoplasm and cytoplasmic membrane, and showed remarkably higher transcript abundance in citrus than in psyllids. Potato virus X (PVX)-mediated transient expression assays indicated that mSECP8 (the mature form of SECP8) suppressed pro-apoptotic mouse protein BAX and Phytophthora infestans elicitin INF1-triggered hypersensitive response (HR) associated phenotypes, including cell death, H2O2 accumulation and callose deposition. Intriguingly, mSECP8 also inhibited SDE1 (CLIBASIA_05315)-induced water-soaked and dwarfing symptoms in Nicotiana benthamiana. In addition, mSECP8 can promote the susceptibility of transgenic Wanjincheng orange (Citrus sinensis) to CLas invasion and further HLB symptom development, and it contributes to the proliferation of Xanthomonas citri subsp. citri (Xcc). Moreover, the expression of ten immunity-related genes were significantly down-regulated in mSECP8 transgenic citrus than those in wide-type (WT) plants. Overall, we propose that mSECP8 may serve as a novel broad-spectrum suppressor of plant immunity, and provide the first evidence counteractive effect among CLas effectors. This study will enrich and provide new evidences for elucidating the pathogenic mechanisms of CLas in citrus host.

Abstract This study aimed to assess the association of coagulation-related indicators such as plasma fibrinogen (FIB), d-dimer, and fibrin degradation product (FDP) in rheumatoid arthritis (RA) with the disease activity. Data from 105 RA patients and 102 age- and gender-matched healthy controls were collected in the retrospective study. Disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) was used to divide RA patients into low activity group (DAS28-CRP ≤ 2.7) and active group (DAS28-CRP > 2.7). Receiver operating characteristic (ROC) curve was applied to determine area under the curve (AUC). The association between plasma FIB, d-dimer, and FDP and DAS28-CRP was evaluated by spearman correlation. Logistical regression analysis was used to identify the independent variables associated with RA disease activity. RA patients showed higher levels of plasma FIB, d-dimer, and FDP than the controls (P

Abstract X‐linked intellectual disability type Nascimento (XLID) is a rare disease caused by variants in the ubiquitin‐conjugating enzyme E2A gene (UBE2A). Patients with XLID have similar phenotypes, including speech impairments, severe intellectual disability, hearing loss, wide facies, synophrys, generalized hirsutism, and urogenital abnormalities. Till date, only two splice‐site variants of the UBE2A gene have been observed in patients with X‐linked ID type Nascimento. Here, we report the case of a Chinese boy with a syndrome clinically similar to XLID with speech impairment, severe intellectual disability, and moderate hearing loss. However, different characteristics were also present in the patient, including an inability to maintain his head in an upright posture. Both of the patient's palms have a single transverse palmar crease. Subsequent whole‐exome sequencing revealed a novel splice site variant in UBE2A (c.241 + 1 G > A). Our study not only expands the variant spectrum and clinical characteristics of UBE2A deficiency syndrome but also provides clinical evidence for genetic diagnoses.

Tumor cells metastasize from a primary lesion to distant organs mainly through hematogenous dissemination, in which tumor cell re-adhesion to the endothelium is essential before extravasating into the target site. We thus hypothesize that tumor cells with the ability to adhere to the endothelium of a specific organ exhibit enhanced metastatic tropism to this target organ. This study tested this hypothesis and developed an in vitro model to mimic the adhesion between tumor cells and brain endothelium under fluid shear stress, which selected a subpopulation of tumor cells with enhanced adhesion strength. The selected cells up-regulated the genes related to brain metastasis and exhibited an enhanced ability to transmigrate through the blood–brain barrier. In the soft microenvironments that mimicked brain tissue, these cells had elevated adhesion and survival ability. Further, tumor cells selected by brain endothelium adhesion expressed higher levels of MUC1, VCAM1, and VLA-4, which were relevant to breast cancer brain metastasis. In summary, this study provides the first piece of evidence to support that the adhesion of circulating tumor cells to the brain endothelium selects the cells with enhanced brain metastasis potential.

Pitting corrosion of rotating machinery is one of the most common faults in industrial engineering. The convolutional neural network (CNN) is increasingly applied to the fault diagnosis. However, the conventional CNN method will reduce the feature dimension of the collected signal and cause the loss of information during the pooling process. In this paper, a new method based on dilated CNN combined with spatial dropout (DCSD) is proposed to diagnose the early faults of rotating machinery. By filling the convolution kernel, the DCSD method can increase the receptive field of the CNN without increasing the number of parameters while retaining more features of the raw vibration signal of the rotating machine. To avoid the dropout method eliminates the adjacent elements with a strong correlation, the Spatial Dropout method is adopted to reduce the overfitting problem of deep networks. The early pitting gears experiment was designed to verify the DCSD method in this paper. The raw vibration signal data of 6 different healthy states were collected to verify the effectiveness of the method. The experimental results show that the DCSD method proposed can effectively distinguish the different early gears pitting, and the diagnostic accuracy is better than other popular deep learning methods.

Water-exit is a hydraulic phenomenon induced when an object exists in a body of water. In the case of ship lifts, the hydrodynamic forces induced by the water-exit of the chamber’s support beam may result in unsafe and unstable operating conditions and may even cause a loss of structural integrity. In this study, the water-exit process of a simplified beam was investigated using an experimental–numerical approach. The experimental results revealed that three major stages occur during water-exit: start-up, flow-around, and exit-moment. Moreover, the maximum additional hydrodynamic load exerted on the beam during water-exit occurred in the exit-moment phase. Based on these results, a calibrated numerical method was employed to analyse the main factors affecting the maximum additional hydrodynamic load. The numerical results indicated that the additional load can be accurately predicted using two dimensionless parameters. These results may help evaluate the negative impacts of suction on a ship lift chamber and improve the technical support and operation of ship lifts.

As the total mileage of natural gas pipeline network continues to increase, the topological structure of natural gas pipeline network will become more and more complex. The complicated topological structure of natural gas pipeline network is likely to cause inherent structural defects, which have serious impacts on the safe operation of natural gas pipeline network. At present, related researches mainly focused on the safe and reliable operation of natural gas pipeline network, which has become a research hotspot, but few of them considered the complexity of natural gas pipeline network and its potential impacts. In order to understand the complexity of natural gas pipeline network and its behaviors when facing structural changes, this paper studied the robustness of natural gas pipeline network based on complex network theory. This paper drew on the methods and experience of robustness researches in other related fields, and proposed a robustness evaluation method for natural gas pipeline network which is combined with its operation characteristics. The robustness evaluation method of natural gas pipeline network is helpful to identify the key components of the pipeline network and understand the response of the pipeline network to structural changes. Furthermore, it can provide a theoretical reference for the safe and stable operation of natural gas pipeline network. The evaluation results show that natural gas pipeline network shows strong robustness when faced with random disturbances represented by pipeline accidents or component failures caused by natural disasters, and when faced with targeted disturbances represented by terrorist disturbances, the robustness of natural gas pipeline network is very weak. Natural gas pipeline network behaves differently in the face of different types of random disturbances. Natural gas pipeline network is more robust when faced with component failures than pipeline accidents caused by natural disasters.

Ultrasonic guided wave has received significant attention in the field of nondestructive testing because of their advantages in detecting the entire wall thickness. Since pipe elbows are an important component of the piping system, it is desirable to study the propagation behavior of the guided wave in the elbows. In this paper, instead of using the traditional method of a ring of transducers to generate guided wave at the same time, the propagation behavior of the guided wave in the elbows under the action of a single excitation source is simulated. Using the chirp excitation signal, the transmission signals of the guided wave at different excitation central frequencies are extracted with high efficiency, and the behavior of the guided wave in the elbow under different excitation frequencies is studied. In addition, it is proposed to use the flight time quantity to characterize the complete information of the structure, and the influence of the defects on the flight time is also studied. The results prove that the flight time feature has good detection sensitivity to the defects with varying depth in different locations of the elbow.

Accurate and timely prediction of remaining useful life (RUL) of a machine enables the machine to have an appropriate operation and maintenance decision. Data-driven RUL prediction methods are more attractive to researchers because they can be deployed quicker and cheaper compared to other approaches. The existing deep neural network (DNN) models proposed for the applications of RUL prediction are mostly single-path and top-down propagation. In order to improve the prognostic accuracy of the network, this paper proposes a directed acyclic graph (DAG) network that combines long short term memory (LSTM) and a convolutional neural network (CNN) to predict the RUL. Different from the existing prediction models combined with CNN and LSTM, the method proposed in this paper combines CNN and LSTM organically instead of just using CNN for feature extraction. Moreover, when a single timestamp is used as an input, padding the signals in the same training batch would affect the prediction ability of the developed model. To overcome this drawback, the proposed method generates a short-term sequence by sliding the time window (TW) with one step size. In addition, based on the degradation mechanism, the piece-wise RUL function is used instead of the traditional linear function. In the experimental test, the turbofan engine degradation simulation dataset provided by NASA is used to validate the proposed RUL prediction model. By comparing with the existing methods using the same dataset, it can be concluded that the prediction method proposed in this paper has better prediction capability.

Benzo[a]pyrene (BaP), a carcinogen, leads to the severe liver injury. Isoorientin (ISO), a natural flavonoid, is known for its bioactivities, including anti-oxidation, anti-inflammation, and so on. However, there is no report on the effects of ISO on liver injury induced by BaP. The present study demonstrated that ISO treatment could relieve BaP-caused autophagic and pyroptotic injury in HL-7702 human hepatocyte and male BALB/c mice by down-regulating the numbers of autophagosomes, the mRNA expression of LC3 II and Beclin-1, and the levels of pyroptotic characteristic indices. Histopathology stained also confirmed that ISO could suppress the BaP-induced liver injury. Meanwhile, ISO was able to improve the liver function, and remarkably (p

Genetic mutations of trappc9 cause intellectual disability with the atrophy of brain structures and variable obesity by poorly understood mechanisms. Trappc9-deficient mice develop phenotypes resembling pathological changes in humans and appear overweight shortly after weaning, and thus are useful for studying the pathogenesis of obesity. Here, we investigated the effects of trappc9 deficiency on the proliferation and differentiation capacity of adipose-derived stem cells (ASCs). We isolated ASCs from mice before overweight was developed and found that trappc9-null ASCs exhibited signs of premature senescence and cell death. While the lineage commitment was retained, trappc9-null ASCs preferred adipogenic differentiation. We observed a profound accumulation of lipid droplets in adipogenic cells derived from trappc9-deficient ASCs and marked differences in the distribution patterns and levels of calcium deposited in osteoblasts obtained from trappc9-null ASCs. Biochemical studies revealed that trappc9 deficiency resulted in an upregulated expression of rab1, rab11, and rab18, and agitated autophagy in ASCs. Moreover, we found that the content of neural stem cells in both the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus vastly declined in trappc9-null mice. Collectively, our results suggest that obesity, as well as brain structure hypoplasia induced by the deficiency of trappc9, involves an impairment in the plasticity of stem cells.

Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington’s disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.

Isoorientin (Iso), a natural bioactive flavonoid, possesses significant anti-tumor and anti-oxidant activities. Benzo[a]pyrene (BaP) is a food processing injurant with carcinogenicity, teratogenicity, and genotoxicity. Our preliminary study demonstrates that Iso attenuated the pyroptotic hepatocyte damage induced by BaP; however, the molecular mechanism remains unknown. The present study showed that Iso reduced the increase caused by BaP in the overflow of LDH, NO, and the electrical conductivity and the protein expressions of GSDMD-N, IL-18, and IL-1β, further showing that Iso could reduced the pyroptotic damage in HL-7702 cells induced by BaP. Caspase-1 inhibitor (Z-VAD-FMK) inhibited the characteristic pyroptosis protein expressions of Caspase-1, GSDMD-N, IL-18, and IL-1β, showing that the classic pyroptosis pathway depending on Caspase-1 was caused by BaP in HL-7702 cells. Consistent with the effects of the NLRP3 inhibitor (MCC950), NF-κB inhibitor (PDTC), ROS, and mtROS inhibitor (NAC and Mito-TEMPO), Iso weakened the stimulatory effects of BaP on the levels of ROS, the nuclear localization of NF-κB, and the activation of NLRP3 inflammasome and the characteristic indices of pyroptosis, demonstrating that Iso could alleviate the BaP-induced pyroptotic hepatocytes injury through inhibiting the ROS/NF-κB/NLRP3/Caspase-1 signaling pathway, which provides a new perspective and strategy to prevent liver injury induced by BaP.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.

Optical microcavity configuration is one optical strategy to enhance light trapping in devices using planar electrodes. In this work, the potential application of optical microcavity configuration with ultrathin metal electrodes in highly efficient perovskite solar cells (PSCs) was investigated. By comparing with the device with conventional indium-tin-oxide (ITO) electrodes, it is shown that by carefully designing the Ag/dielectric planar electrode, a device with an optical microcavity structure can achieve comparable—or even higher—power conversion efficiency than a conventional device. Moreover, there is a relative high tolerance for the Ag film thickness in the optical microcavity structure. When the thickness of the Ag film is increased from 8 to 12 nm, the device still can attain the performance level of a conventional device. This gives a process tolerance to fabricate devices with an optical microcavity structure and reduces process difficulty. This work indicates the great application potential of optical microcavities with ultrathin metal electrodes in PSCs; more research attention should be paid in this field.

Coordinated actions of Rab and Rho are necessary for numerous essential cellular processes ranging from vesicle budding to whole cell movement. How Rab and Rho are choreographed is poorly understood. Here, we report a protein complex comprised of kalirin, a Rho guanine nucleotide exchange factor (GEF) activating Rac1, and RabGEF transport protein particle (TRAPP). Kalirin was identified in a mass spectrometry analysis of proteins precipitated by trappc4 and detected on membranous organelles containing trappc4. Acute knockdown of kalirin did not affect trappc4, but significantly reduced overall and membrane-bound levels of trappc9, which specifies TRAPP toward activating Rab11. Trappc9 deficiency led to elevated expression of kalirin in neurons. Co-localization of kalirin and Rab11 occurred at a low frequency in NRK cells under steady state and was enhanced upon expressing an inactive Rab11 mutant to prohibit the dissociation of Rab11 from the kalirin-TRAPP complex. The small RNA-mediated depletion of kalirin diminished activities in cellular membranes for activating Rab11 and resulted in a shift in size of Rab11 positive structures from small to larger ones and tubulation of recycling endosomes. Our study suggests that kalirin and TRAPP form a dual GEF complex to choreograph actions of Rab11 and Rac1 at recycling endosomes.

Continuous monitoring for defects in oil and gas pipelines is important for leakage prevention. This paper proposes a new kind of pipe elbow damage identification technique, which consists of three processes. First, piezoelectric sensors evenly arranged along the circumference of the pipeline in the turn generated ultrasonic guided wave signals in the elbow. Then, the wavefront flight time at each grid node in the known sound field were computed using the fast-marching algorithm. Finally, an elbow wall thickness map reconstruction technique based on the sparse inversion method was proposed to identify elbow defects. Compared with the traditional elbow defect identification technology, this technology can not only detect the existence of the defect but also accurately locate the defect position.

In the indoor location field, the quality of received-signal-strength-indicator (RSSI) fingerprints plays a key role in the performance of indoor location services. However, changes in an indoor environment may lead to the decline of location accuracy. This paper presents a localization method employing a Hybrid Wireless fingerprint (HW-fingerprint) based on a convolutional neural network (CNN). In the proposed scheme, the Ratio fingerprint was constructed by calculating the ratio of different RSSIs from important contribution access points (APs). The HW-fingerprint combined the Ratio fingerprint and the RSSI to enhance the expression of indoor environment characteristics. Moreover, a CNN architecture was constructed to learn important features from the complex HW-fingerprint for indoor locations. In the experiment, the HW-fingerprint was tested in an actual indoor scene for 15 days. Results showed that the average daily location accuracy of the K-Nearest Neighbor (KNN), Support Vector Machines (SVMs), and CNN was improved by 3.39%, 8.03% and 9.03%, respectively, when using the HW-fingerprint. In addition, the deep-learning method was 4.19% and 16.37% higher than SVM and KNN in average daily location accuracy, respectively.

Pneumonia is a leading cause of death in children and the elderly worldwide, accounting for 15% of all deaths of children under 5 years old. Streptococcus pneumoniae is a common and aggressive cause of pneumonia and can also contribute to meningitis and sepsis. Despite the widespread use of antibiotics, mortality rates for pneumonia remain unacceptably high in part due to the release of bacterial toxins. Pneumolysin (PLY) is a cholesterol-dependent toxin that is produced by Streptococcus, and it is both necessary and sufficient for the development of the extensive pulmonary permeability edema that underlies acute lung injury. The mechanisms by which PLY disrupts the pulmonary endothelial barrier are not fully understood. Previously, we found that reactive oxygen species (ROS) contribute to the barrier destructive effects of PLY and identified an unexpected but potent role of Hsp70 in suppressing ROS production. The ability of Hsp70 to influence PLY-induced barrier dysfunction is not yet described, and the goal of the current study was to identify whether Hsp70 upregulation is an effective strategy to protect the lung microvascular endothelial barrier from G+ bacterial toxins. Overexpression of Hsp70 via adenovirus-mediated gene transfer attenuated PLY-induced increases in permeability in human lung microvascular endothelial cells (HLMVEC) with no evidence of cytotoxicity. To adopt a more translational approach, we employed a pharmacological approach using geranylgeranylacetone (GGA) to acutely upregulate endogenous Hsp70 expression. Following acute treatment (6 h) with GGA, HLMVECs exposed to PLY displayed improved cell viability and enhanced endothelial barrier function as measured by both Electric Cell-substrate Impedance Sensing (ECIS) and transwell permeability assays compared to control treated cells. PLY promoted increased mitochondrial ROS, decreased mitochondrial oxygen consumption, and increased caspase 3 cleavage and cell death, which were collectively improved in cells pretreated with GGA. In mice, IP pretreatment with GGA 24 h prior to IT administration of PLY resulted in significantly less Evans Blue Dye extravasation compared to vehicle, indicating preserved endothelial barrier integrity and suggesting that the acute upregulation of Hsp70 may be an effective therapeutic approach in the treatment of lung injury associated with pneumonia.

There are some issues that should be solved like load shock, vibration, and uneven load distribution during transmission of involute spur gears. However, common modification methods such as axial modification as well as profile modification could not solve these problems once for all. Hence, a novel method of comprehensive modification was proposed, and the evaluation methodology of transmission performance was drawn up too. Changing modification parameters can control transmission performance of gear unit, which can generate many different modification ways. Besides, based on the orthogonal experiment method and evaluation methodology, optimal modification ways can be chosen for gear pairs working in different conditions. Taking a set of spur gear pair as an example, an ideal modification way was obtained. In addition, analysis results verified that conducting comprehensive modification could enhance the meshing performance once for all.

This paper deals with gear pitting fault diagnosis problem and presents a method by integrating convolutional neural network (CNN) and gated recurrent unit (GRU) networks with vibration and acoustic emission signals to solve the problem. The presented method first trains a one-dimensional CNN with acoustic emission signals and a GRU network with vibration signals. Then the gear pitting fault features obtained by the two networks are concatenated to form a deep learning structure for gear pitting fault diagnosis. Seven different gear pitting conditions are used to test the feasibility of the presented method. The diagnosis result of the gear pitting fault shows that the accuracy of the presented method reaches above 98% with only a relatively small number of training samples. In comparison with the results using CNN or GRU network alone, the presented method gives more accurate diagnosis results. By comparing the results of different loads and learning rates, the robustness of the presented method for gear pitting fault diagnosis is proved. Moreover, the presented deep structure can be easily extended to more other sensor input signals for gear pitting fault diagnosis in the future.

Research on data-driven fault diagnosis methods has received much attention in recent years. The deep belief network (DBN) is a commonly used deep learning method for fault diagnosis. In the past, when people used DBN to diagnose gear pitting faults, it was found that the diagnosis result was not good with continuous time domain vibration signals as direct inputs into DBN. Therefore, most researchers extracted features from time domain vibration signals as inputs into DBN. However, it is desirable to use raw vibration signals as direct inputs to achieve good fault diagnosis results. Therefore, this paper proposes a novel method by stacking spare autoencoder (SAE) and Gauss-Binary restricted Boltzmann machine (GBRBM) for early gear pitting faults diagnosis with raw vibration signals as direct inputs. The SAE layer is used to compress the raw vibration data and the GBRBM layer is used to effectively process continuous time domain vibration signals. Vibration signals of seven early gear pitting faults collected from a gear test rig are used to validate the proposed method. The validation results show that the proposed method maintains a good diagnosis performance under different working conditions and gives higher diagnosis accuracy compared to other traditional methods.

The Huntington's disease (HD) mutation causes polyglutamine expansion in huntingtin (Htt) and neurodegeneration. Htt interacts with a complex containing Rab11GDP and is involved in activation of Rab11, which functions in endosomal recycling and neurite growth and long-term potentiation. Like other Rab proteins, Rab11GDP undergoes nucleotide exchange to Rab11GTP for its activation. Here we show that striatal membranes of HD140Q/140Q knock-in mice are impaired in supporting conversion of Rab11GDP to Rab11GTP. Dominant negative Rab11 expressed in the striatum and cortex of normal mice caused neuropathology and motor dysfunction, suggesting that a deficiency in Rab11 activity is pathogenic in vivo. Primary cortical neurons from HD140Q/140Q mice were delayed in recycling transferrin receptors back to the plasma membrane. Partial rescue from glutamate-induced cell death occurred in HD neurons expressing dominant active Rab11. We propose a novel mechanism of HD pathogenesis arising from diminished Rab11 activity at recycling endosomes.

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases pulmonary blood pressure. Elevated pressures in the pulmonary artery imparts a chronic stress on the right ventricle which undergoes compensatory hypertrophy but eventually fails. How PAH develops remains incompletely understood and evidence for the altered production of reactive oxygen and nitrogen species (ROS, RNS respectively) in the pulmonary circulation has been well documented. There are many different types of ROS and RNS, multiple sources, and collective actions and interactions. This review summarizes past and current knowledge of the sources of ROS and RNS and how they may contribute to the loss of endothelial function and changes in smooth muscle proliferation in the pulmonary circulation.

The mechanism of cutting process of roadheader with cutting head was researched, and the influences of properties of coal and rock on cutting load were deeply analyzed. Aimed at the defects of traditional calculation method of cutting load on fully expressing the complex cutting process of cutting head, the method of finite element simulation was proposed to simulate the dynamic cutting process. Aimed at the characteristics of coal and rock which affect the cutting load, several simulations with different firmness coefficient were taken repeatedly, and the relationship between three-axis force and firmness coefficient was derived. A comparative analysis of cutting pick load between simulation results and theoretical formula was carried out, and a consistency was achieved. Then cutting process with a total cutting head was carried out on this basis. The results show that the simulation analysis not only provides a reliable guarantee for the accurate calculation of the cutting head load and improves the efficiency of the cutting head cutting test but also offers a basis for selection of cutting head with different geological conditions of coal or rock.