Exploration of the potential common pathogenic mechanisms in COVID-19 and silicosis by using bioinformatics and system biology.

Silicosis is an occupational lung disease that is common worldwide. In recent years, coronavirus disease 2019 (COVID-19) has provided daunting challenges to public healthcare systems globally. Although multiple studies have shown a close link between COVID-19 and other respiratory diseases, the inter-relational mechanisms between COVID-19 and silicosis remain unclear. This study aimed to explore the shared molecular mechanisms and drug targets of COVID-19 and silicosis. Gene expression profiling identified four modules that were most closely associated with both diseases. Furthermore, we performed functional analysis and constructed a protein-protein interaction network. Seven hub genes (budding uninhibited by benzimidazoles 1 [BUB1], protein regulator of cytokinesis 1 [PRC1], kinesin family member C1 [KIFC1], ribonucleotide reductase regulatory subunit M2 [RRM2], cyclin-dependent kinase inhibitor 3 [CDKN3], Cyclin B2 [CCNB2], and minichromosome maintenance complex component 6 [MCM6]) were involved in the interaction between COVID-19 and silicosis. We investigated how diverse microRNAs and transcription factors regulate these seven genes. Subsequently, the correlation between the hub genes and infiltrating immune cells was explored. Further in-depth analyses were performed based on single-cell transcriptomic data from COVID-19, and the expression of hub-shared genes was characterized and located in multiple cell clusters. Finally, molecular docking results reveal small molecular compounds that may improve COVID-19 and silicosis. The current study reveals the common pathogenesis of COVID-19 and silicosis, which may provide a novel reference for further research.

Schistosome infection promotes osteoclast-mediated bone loss.

Infection with schistosome results in immunological changes that might influence the skeletal system by inducing immunological states affecting bone metabolism. We investigated the relationships between chronic schistosome infection and bone metabolism by using a mouse model of chronic schistosomiasis, affecting millions of humans worldwide. Results showed that schistosome infection resulted in aberrant osteoclast-mediated bone loss, which was accompanied with an increased level of receptor activator of nuclear factor-κB (NF-κB) Ligand (RANKL) and decreased level of osteoprotegerin (OPG). The blockade of RANKL by the anti-RANKL antibody could prevent bone loss in the context of schistosome infection. Meanwhile, both B cells and CD4+ T cells, particularly follicular helper T (Tfh) cell subset, were the important cellular sources of RANKL during schistosome infection. These results highlight the risk of bone loss in schistosome-infected patients and the potential benefit of coupling bone therapy with anti-schistosome treatment.

Mangasese doped polypyrole nanoparticels for photothermal/chemodynamic therapy and immune activation.

Photothermal therapy (PTT) is a promising treatment that efficiently suppresses local cancer, but fails to induce a robust antitumor immune response against tumor metastasis and recurrence. In this study, a NIR responsive nano-immunostimulant (Mn/A-HP NI) is fabricated by entrapping manganese and azo-initiator (AIPH) into hyaluronic acid-based polypyrrole nanoparticle. The as-prepared Mn/A-HP NIs with a high photothermal conversion efficiencey of 20.17% dramatically induced the imunogenic cell death of tumor cells and triggered the release ATP and HMGB1. Meanwhile, the hyperthermia induced AIPH decomposition to produce alkyl radicals which further destroyed cancer cells. Furthermore, the Mn/A-HP NIs were capable of promoting the maturation and antigen cross-presentation ability of dendritic cells. Consequently, the multifunctional Mn/A-HP NIs provided a combined treatment via integrating PTT/chemo-dynamic therapy and immune activation for tumor therapy.

Recent advances in nanoplatforms for the treatment of neuropathic pain.

STUDY DESIGN: Narrative review. OBJECTIVES: The objective was to summarize the literature on nanoplatforms in spinal cord injury (SCI) and describe their effect in facilitating experiments for SCI. Currently, the primary clinical treatment for neuropathic pain (NP) is drug therapy, but these traditional drugs have many disadvantages, such as high dose, rapid clearance from the circulatory system, off-target side effects, and cytotoxicity. Moreover, the treatment for NP is complicated by the existence of blood-brain barrier. In recent years, nanomedicine has been receiving increased attention; this novel modality could help deliver drugs to treat NP via nanoplatforms, making it a promising alternative therapy. The use of nanoplatforms can enhance pharmaceutic effectiveness by either avoiding rapid clearance from the blood or ensuring adequate concentration in the lesion. METHODS: A literature review was conducted, with a focus on nanoplatforms that have been described in the experimental studies of neuropathic pain. RESULTS: We provide a brief description of the roles of liposomes, polymeric nanoparticles, metal nanoparticles, micelles, and dendrimers in the treatment of NP and discuss the prospective development of the nanoplatform system for NP. CONCLUSION: The emergence of various nanoplatform drug delivery systems can provide an advantageous resource tool for real-time diagnosis and effective treatment of SCI-related NP.

Hepatocyte CD1d protects against liver immunopathology in mice with schistosomiasis japonica.

Schistosomiasis is a neglected tropical disease with over 250 million people infected worldwide. The main clinically important species Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum) cause inflammatory responses against tissue-trapped eggs, resulting in formation of granulomas mainly in host liver. Persistent granulomatous response results in severe fibrosis in the liver, leading to irreversible impairment of the liver and even death of the host. CD1d, a highly conserved MHC class I-like molecule, is expressed by both haematopoietic and non-haematopoietic cells. CD1d on antigen-presenting cells (APCs) of haematopoietic origin presents pathogen-derived lipid antigens to natural killer T (NKT) cells, which enables them to rapidly produce large amounts of various cytokines and facilitate CD4+ T helper (Th) cell differentiation upon invading pathogens. Noteworthy, hepatocytes of non-haematopoietic origin have recently been shown to be involved in maintaining liver NKT cell homeostasis through a CD1d-dependent manner. However, whether hepatocyte CD1d-dependent regulation of NKT cell homeostasis also modulates CD4+ Th cell responses and liver immunopathology in murine schistosomiasis remains to be addressed. Here, we show in mice that CD1d expression on hepatocytes was decreased dramatically upon S. japonicum infection, accompanied by increased NKT cells, as well as upregulated Th1 and Th2 responses. Overexpression of CD1d in hepatocytes significantly decreased local NKT numbers and cytokines (IFN-γ, IL-4, IL-13), concomitantly with downregulation of both Th1 and Th2 responses and alleviation in pathological damage in livers of S. japonicum-infected mice. These findings highlight the potential of hepatocyte CD1d-targeted therapies for liver immunopathology control in schistosomiasis.

A rare case of atypical spinal neurocytoma with EGFR mutation in a 12-year-old boy.

Spinal neurocytoma (SN), although frequently reportedly as tumors of the central nervous system (CNS), are a distinct class of tumors, which can achieve a better prognosis following subtotal or gross total tumor resection. Nonetheless, even with the premise of successful treatment after tumor resection, poor prognosis after treatment due to the SN high proliferation index (typically known as atypical SN) have been reported. Over the past two decades, atypical SN was only reported in four pediatric cases, amidst the lingering controversy surrounding its postoperative adjuvant therapy. Thus, herein, we report a unique case of atypical SN with epidermal growth factor receptor (EGFR) amplification mutation in a 12-year-old boy. We, however, also highlighted the significance of radiotherapy and target therapy for patients with SN.

[Study on gait symmetry based on simulation and evaluation system of prosthesis gait].

A software and hardware platform for gait simulation and system evaluation for lower limb intelligent prosthesis is proposed and designed, in order that the wearable symmetry effect of the intelligent knee prosthesis can be quantitatively analyzed by machine test instead of human wear test. The whole-body three-dimensional gait and motion analysis system instrument, a device to collect gait data such as joint angle and stride of adults, was used for extracting simulated gait characteristic curve. Then, the gait curve was fitted based on the corresponding joint to verify the feasibility of the test platform in the experiment. Finally, the developed artificial knee prosthesis was worn on the prosthetic evaluation system to quantitatively analyze the gait symmetry effect. The results showed that there was no significant difference in gait symmetry between the developed knee joints at different speeds, which could reach more than 88%. The simulation and evaluation of the prosthetic gait have good effects on the functional simulation and evaluation of the lower limb intelligent prosthesis.

A metabolomics research based on UHPLC-ESI-Q-TOF-MS coupled with metabolic pathway analysis: Treatment effects of stir-frying Xanthii Fructus on allergic rhinitis in mice model.

Xanthii Fructus (XF), a well-known herb in traditional Chinese medicine, has been frequently used for the treatment of allergic rhinitis in the clinic. Its therapeutic metabolic mechanism, however, remains undetermined. In this work, a metabolomics research coupled with metabolic pathway analysis has been employed to screen out the potential mechanism in its effects on allergic rhinitis. Specifically, mouse serum samples containing XF were analyzed based on ultra-high performance liquid chromatography equipped with electrospray ionization quadruple time-of-flight mass spectrometry detection (UHPLC-ESI-Q-TOF-MS) in both positive and negative polarity. In addition, the raw data gained from UHPLC-ESI-Q-TOF-MS were processed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) in order to discover remarkable metabolites. Twenty-seven potential biomarkers in mouse serum were filtered from free databases like HMDB. Interestingly, this study filtered the potential metabolic pathways including glycerophospholipid metabolism and branch-chain amino acid metabolism. We hope that this paper will provide a feasible strategy for revealing the therapeutic mechanism of XF in allergic rhinitis mice model.

Characterization of in vitro effects of microcystin-LR on intestinal epithelial cells.

The intestinal epithelium is a single-cell layer that provides an important barrier against natural toxins. Microcystin-LR (MC-LR), a cyclic heptapeptide, is one of the best known toxins able to alter the functions of intestine. This study evaluated the toxic effects and the possible mechanisms of MC-LR on barrier function of the intestinal epithelial cells. Intestinal epithelial cells (IEC-6) were exposed to 0, 6.25, 12.5, 25 and 50 µM MC-LR. Cell viability significantly decreased, while the ratio of apoptotic cells increased after exposure to 12.5µM and higer concentration of MC-LR. As expected, the integrity of a polarized IEC-6 monolayer was affected by MC-LR exposure, as demonstrated by a decrease in the transepithelial electrical resistance (TEER) values, becoming most pronounced at 50µM, 24 h. No effects were detected on the protein expression levels of the tight junction protein claudin at 50µM. However, the expression of occludin and zonula occludens-1 (ZO-1) declined. Furthermore, MC-LR can immigrate into IEC-6 cells. The activity of protein phosphatases 2A (PP2A) decreased from the concentration of 12.5 µM, showing a dose-dependent decline. These results provide new information that strengthens the concept that the intestinal epithelium is important targets for toxic effects of water contaminants like MC-LR. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1539-1547, 2017.

Protective effects of l-cysteine and N-acetyl-l-cysteine on boar sperm quality during hypothermic liquid storage with bovine serum albumin as a protectant.

Hypothermic liquid storage at 4-5 °C has emerged as a novel approach for preserving boar semen, offering innovative possibilities for semen preservation. However, this method also presents challenges, including cold shock and excessive reactive oxygen species (ROS) production. Therefore, reducing oxidative damage induced by low temperatures becomes essential while supplementing appropriate protectants. In this study, we investigated the efficacy of Bovine Serum Albumin (BSA) compared to Polyvinylpyrrolidone (PVP) and Skim Milk Powder (SMP) in maintaining boar sperm motility and progressive motility using computer-assisted sperm analysis (CASA). Among the tested concentrations, 4 g/L of BSA exhibited the best protective effect. Subsequently, we supplemented different concentrations of l-cysteine (LC) and N-acetyl-l-cysteine (NAC) as additives in the presence of BSA as a protectant. Our results demonstrated that 1 mmol/L of LC and 0.5 mmol/L of NAC exhibited superior protection of sperm quality compared to other concentrations. Furthermore, the 1 mmol/L LC and 0.5 mmol/L NAC groups showed significantly improved plasma membrane integrity and acrosome integrity compared to the control group. These groups also exhibited enhanced antioxidant capacity, evidenced by increased mitochondrial membrane potential (MMP), ATP production, total superoxide dismutase (T-SOD) activity, total antioxidant capacity (T-AOC), glutathione (GSH), glutathione peroxidase (GSH-PX), and GPX-4 levels. Additionally, they demonstrated decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as reduced oxidized glutathione (GSSG) and glutathione reductase (GR) levels. Furthermore, LC and NAC treatment enhanced AMP-activated protein kinase (AMPK) phosphorylation. However, inhibiting AMPK using compound C did not inhibit the protective effects of LC and NAC on low-temperature preserved boar sperm. These findings suggest that 4 g/L BSA can serve as an effective protectant for hypothermic liquid storage of boar semen. Additionally, LC and NAC supplementation reduces oxidative damage by enhancing antioxidant capacity rather than through AMPK-mediated ATP supplementation. These results contribute to advancing the application of LC and NAC in hypothermic liquid storage of boar semen.

Simultaneous and ultrafast detection of pan-SARS-coronaviruses and influenza A/B viruses by a novel multiplex real-time RT-PCR assay.

Here we report an ultrafast quadruplex RT-qPCR assay with robust diagnostic ability to detect and distinguish pan-SARS-CoVs and influenza A/B viruses within 35 min. This quadruplex RT-qPCR assay comprised of one novel RNA-based internal control targeting human ß2-microglobulin (B2M) for process accuracy and three newly-designed primers-probe sets targeting the envelope protein (E) of pan-SARS-CoV, matrix protein (MP) of influenza A virus and non-structural (NS) region of influenza B virus. This quadruplex assay exhibited a sensitivity comparable to its singleplex counterparts and a slightly higher to that of the Centers for Disease Control and Prevention-recommended SARS-CoV-2 and influenza A/B assays. The novel assay showed no false-positive amplifications with other common respiratory viruses, and its 95 % limits of detection for pan-SARS-CoV and influenza A/B virus was 4.26-4.52 copies/reaction. Moreover, the assay was reproducible with less than 1 % coefficient of variation and adaptable testing different clinical and environmental samples. Our ultrafast quadruplex RT-qPCR assay can serve as an attractive tool for effective differentiation of influenza A/B virus and SARS-CoV-2, but more importantly prognose the reemergence/emergence of SARS and novel coronaviruses or influenza viruses from animal spillover.

A Portable, Integrated, Sample-In Result-Out Nucleic Acid Diagnostic Device for Rapid and Sensitive Chikungunya Virus Detection.

Chikungunya virus, a mosquito-borne virus that causes epidemics, is often misdiagnosed due to symptom similarities with other arboviruses. Here, a portable and integrated nucleic acid-based diagnostic device, which combines reverse transcription-loop-mediated isothermal amplification and lateral-flow detection, was developed. The device is simple to use, precise, equipment-free, and highly sensitive, enabling rapid chikungunya virus identification. The result can be obtained by the naked eye within 40 min. The assay can effectively distinguish chikungunya virus from dengue virus, Japanese encephalitis virus, Zika virus, and yellow fever virus with high specificity and sensitivity as low as 598.46 copies mL-1. It has many benefits for the community screening and monitoring of chikungunya virus in resource-limited areas because of its effectiveness and simplicity. The platform has great potential for the rapid nucleic acid detection of other viruses.

The role of serum chloride ion in the prognosis of COPD.

BACKGROUND: As exacerbations of chronic obstructive pulmonary disease (COPD) are one of the leading causes of hospitalization and are associated with significant mortality, it is particularly important to accurately assess the risk of exacerbations in COPD. Most of the current clinical biomarkers are related to inflammation and few consider how ion levels affect COPD. Chloride ion, the second most abundant serum electrolyte, has been shown to be associated with poor prognoses in several diseases, but their relationship with COPD remains unclear. METHODS: In total, 105 patients with acute exacerbations of COPD were recruited. Data on clinical characteristics, lung function, blood count, blood biochemistry, relevant scales including the Clinical COPD Questionnaire (CCQ), BODE (BMI, airflow obstruction, dyspnea, exercise capacity) index and the St. George's Respiratory Questionnaire (SGRQ) were collected from all patients for statistical analysis. RESULT: There were significant differences in lung function indicators and disease severity in the low chloride ion subgroup compared with the high chloride ion subgroup. On multiple logistic regression analysis, chloride ion was an independent factor affecting lung function in COPD patients (OR = 0.808, 95% CI: 0.708 - 0.922, p = 0.002). The sensitivity of chloride ion in predicting COPD severity was 78%, the specificity was 63%, and the area under the curve was 0.734 (p < 0.001). Subgroup analysis showed that chloride ion was a stronger predictor in male and smoking patients. CONCLUSIONS: Chloride ion was a novel prognostic biomarker for COPD, and low levels of chloride ion were independently associated with exacerbations in COPD patients.

A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair.

Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves.

Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants.

The constant emergence of SARS-CoV-2 variants continues to impair the efficacy of existing neutralizing antibodies, especially XBB.1.5 and EG.5, which showed exceptional immune evasion properties. Here, we identify a highly conserved neutralizing epitope targeted by a broad-spectrum neutralizing antibody BA7535, which demonstrates high neutralization potency against not only previous variants, such as Alpha, Beta, Gamma, Delta and Omicron BA.1-BA.5, but also more recently emerged Omicron subvariants, including BF.7, CH.1.1, XBB.1, XBB.1.5, XBB.1.9.1, EG.5. Structural analysis of the Omicron Spike trimer with BA7535-Fab using cryo-EM indicates that BA7535 recognizes a highly conserved cryptic receptor-binding domain (RBD) epitope, avoiding most of the mutational hot spots in RBD. Furthermore, structural simulation based on the interaction of BA7535-Fab/RBD complexes dissects the broadly neutralizing effect of BA7535 against latest variants. Therapeutic and prophylactic treatment with BA7535 alone or in combination with BA7208 protected female mice from the circulating Omicron BA.5 and XBB.1 variant infection, suggesting the highly conserved neutralizing epitope serves as a potential target for developing highly potent therapeutic antibodies and vaccines.

[Optimization of Scutellaria baicalensis extraction process by orthogonal experiment combined with pharmacodynamic index].

To optimize the Scutellaria baicalensis extraction process, the filter paper method and the bacteriostatic ratio method were adopted to determine the in vitro bacteriostatic efficacy of water extracts and 60% alcohol extracts from S. baicalensis. The quantitative analysis of multi-components by single-marker (QAMS) was used to determined the contents of four active components, baicalin, wogonoside, baicalein and wogonin. In addition, with the bacteriostatic ratio and the overall desirability of the contents of four active components as indexes, the orthogonal experiment was adopted to detect the effect of water addition, extraction frequency and extraction time. The optimal extraction process was to add 12 times of water for the first time, 10 times of water for the second time, extract for 2 time, 2 h for each time. This optimization process is stable and feasible, with a higher bacteriostatic ratio in extracts.

Semantic-visual shared knowledge graph for zero-shot learning.

Almost all existing zero-shot learning methods work only on benchmark datasets (e.g., CUB, SUN, AwA, FLO and aPY) which have already provided pre-defined attributes for all the classes. These methods thus are hard to apply on real-world datasets (like ImageNet) since there are no such pre-defined attributes in the data environment. The latest works have explored to use semantic-rich knowledge graphs (such as WordNet) to substitute pre-defined attributes. However, these methods encounter a serious "role="presentation">domain shift" problem because such a knowledge graph cannot provide detailed enough semantics to describe fine-grained information. To this end, we propose a semantic-visual shared knowledge graph (SVKG) to enhance the detailed information for zero-shot learning. SVKG represents high-level information by using semantic embedding but describes fine-grained information by using visual features. These visual features can be directly extracted from real-world images to substitute pre-defined attributes. A multi-modals graph convolution network is also proposed to transfer SVKG into graph representations that can be used for downstream zero-shot learning tasks. Experimental results on the real-world datasets without pre-defined attributes demonstrate the effectiveness of our method and show the benefits of the proposed. Our method obtains a +2.8%, +0.5%, and +0.2% increase compared with the state-of-the-art in 2-hops, 3-hops, and all divisions relatively.

Multi-view graph representation with similarity diffusion for general zero-shot learning.

Zero-shot learning (ZSL) aims to predict unseen classes without using samples of these classes in model training. The ZSL has been widely used in many knowledge-based models and applications to predict various parameters, including categories, subjects, and anomalies, in different domains. Nonetheless, most existing ZSL methods require the pre-defined semantics or attributes of particular data environments. Therefore, these methods are difficult to be applied to general data environments, such as ImageNet and other real-world datasets and applications. Recent research has tried to use open knowledge to enhance the ZSL methods to adapt it to an open data environment. However, the performance of these methods is relatively low, namely the accuracy is normally below 10%, which is due to the inadequate semantics that can be used from open knowledge. Moreover, the latest methods suffer from a significant "semantic gap" problem between the generated features of unseen classes and the real features of seen classes. To this end, this paper proposes a multi-view graph representation with a similarity diffusion model, applying the ZSL tasks to general data environments. This model applies a multi-view graph to enhance the semantics fully and proposes an innovative diffusion method to augment the graph representation. In addition, a feature diffusion method is proposed to augment the multi-view graph representation and bridge the semantic gap to realize zero-shot predicting. The results of numerous experiments in general data environments and on benchmark datasets show that the proposed method can achieve new state-of-the-art results in the field of general zero-shot learning. Furthermore, seven ablation studies analyze the effects of the settings and different modules of the proposed method on its performance in detail and prove the effectiveness of each module.

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets.

Ovarian function influences diverse aspects of fertility and reproductive lifespan by regulating oocyte supply and hormone secretion. Lysine crotonylation (Kcr) and lysine 2-hydroxyisobutyryllysine (Khib) are newly identified post-translational modifications and function as regulators of transactivation in mammals. In this study, we investigated protein post-translational Kcr and 2-hydroxyisobutyrylation in the ovarian tissues of piglets. A total of 653 overlapping proteins among differentially modified proteins were identified for both crotonylation and 2-hydroxyisobutyrylation. Gene Ontology enrichment analysis indicated that 653 DMPs were significantly enriched in nucleosome organization, chromatin assembly, DNA packaging, peptide biosynthetic process and peptide metabolic process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed enrichment in proteasome, ribosome, fatty acid elongation, pyruvate metabolism and pentose phosphate pathway. Fifteen DMPs were identified in the proteasome pathway, of which PSMC6 and PSMB7 were the core proteins. In addition, the significant changes in Kcr and Khib in the complex subunits of the proteasome may be involved in cell cycle processes during oocyte development. Forty-four DMPs with both Kcr and Khib modifications were related to the ribosome pathway. The regulated ribosome pathway may indicate that Kcr and Khib comodified proteins participate in protein synthesis during oocyte development. Western blot and immunofluorescence staining results supported the reliability of the sequencing results. Our results may provide a valuable resource to help illuminate the roles of Kcr and Khib in ovarian development and may serve as new tools to better control diseases.