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Abstract Lung adenocarcinoma (LUAD), a prevalent type of non-small cell lung cancer (NSCLC), was known for its diversity and intricate tumor microenvironment (TME). Comprehending the interaction among human immune-related genes (IRGs) and the TME is vital in the creation of accurate predictive models and specific treatments. We created a risk score based on IRGs and designed a nomogram to predict the prognosis of LUAD accurately. This involved a thorough examination of TME and the infiltration of immune cells in both high-risk and low-risk LUAD groups. Furthermore, the examination of the association between characteristic genes (BIRC5 and BMP5) and immune cells, along with immune checkpoints in the TME, was also conducted. The findings of our research unveiled unique immune profiles and interactions among individuals in the high- and low-risk categories, which contribute to variations in prognosis. LUAD demonstrated significant associations between BIRC5, BMP5, immune cells, and checkpoints, suggesting their involvement in disease advancement and resistance to medication. Furthermore, by correlating our findings with a multidrug database, we identified specific LUAD patient subsets that might benefit from tailored treatments. Our study establishes a groundbreaking prognostic model for LUAD, which not only underscores the importance of the immune context in LUAD but also paves the way for advancing precision medicine strategies in this complex malignancy.

Abstract Background The cell development atlas of transition stage from late Carnegie to fetal development (7–9 weeks) remain unclear. It can be seen that the early period of human embryos (7–9 weeks) is a critical research gap. Therefore, we employed single‑cell RNA sequencing to identify cell types and elucidate differentiation relationships. Results The single‑cell RNA sequencing analysis determines eighteen cell clusters in human embryos during the 7–9 weeks period. We uncover two distinct pathways of cellular development and differentiation. Initially, mesenchymal progenitor cells differentiated into osteoblast progenitor cells and neural stem cells, respectively. Neural stem cells further differentiated into neurons. Alternatively, multipotential stem cells differentiated into adipocyte, hematopoietic stem cells and neutrophil, respectively. Additionally, COL1A2-(ITGA1 + ITGB1) mediated the cell communication between mesenchymal progenitor cells and osteoblast progenitor cells. NCAM1-FGFR1 facilitated the cell communication between mesenchymal progenitor cells and neural stem cells. Notably, NCAM1-NCAM1 as a major contributor mediated the cell communication between neural stem cells and neurons. Moreover, CGA-FSHR simultaneously mediated the communication between multipotential stem cells, adipocyte, hematopoietic stem cells and neutrophil. Distinct cell clusters activated specific transcription factors such as HIC1, LMX1B, TWIST1, and et al., which were responsible for their specific functions. These coregulators, such as HOXB13, VSX2, PAX5, and et al., may mediate cell development and differentiation in human embryos. Conclusions We provide the cell development atlas for human embryos (7–9 weeks). Two distinct cell development and differentiation pathways are revealed.

Abstract Introduction Alveolar echinococcosis (AE), caused by the larval forms of Echinococcus multilocularis, is a zoonotic disease affecting the liver, lungs, lymph nodes, kidneys, brain, bones, thyroid, and other organs. Diagnosing AE in a non-endemic area is usually challenging. With the rapid development and increasing application of sequencing techniques in recent years, metagenomic next-generation sequencing (mNGS) has become a powerful tool for diagnosing rare infectious diseases. Case Presentation A 45-year-old woman was admitted to the hospital for the presence of pulmonary shadows for more than 3 months. The lung computed tomography (CT) at a local hospital revealed scattered solid and quasi-circular nodules in the left upper lobe, left lower lobe, right middle lobe, and right lower lobe. The largest nodule was located in the dorsal part of the right lung, measuring 2.0 × 1.7 × 1.5 cm. Moreover, abdominal CT revealed one space-occupying lesion each in the left and right lobes. The pathological analysis of the lung biopsy specimen revealed infiltration of lymphocytes, plasma cells, and eosinophils in the alveolar wall and interstitial area. No pathogenic bacteria were observed in the sputum smear and culture tests. There were no parasite eggs in the stool. The mNGS of the lung puncture tissue revealed 6156 sequence reads matching E. multilocularis; thus, the condition was diagnosed as AE. Albendazole 400 mg was administered twice daily, and the patient was stable during follow-up. Conclusion This case emphasizes the role of mNGS in diagnosing AE. As a novel, sensitive, and accurate diagnostic method, mNGS could be an attractive approach for facilitating early diagnosis and prompt treatment of infectious diseases, especially when the infection was caused by rare pathogens.

BackgroundNocardiosis poses a diagnostic challenge due to its rarity in clinical practice, non-specific clinical symptoms and imaging features, and the limitations of traditional detection methods. Nocardia aobensis (N. aobensis) is rarely detected in clinical samples. Metagenomic next-generation sequencing (mNGS) offers significant advantages over traditional methods for rapid and accurate diagnosis of infectious diseases, especially for rare pathogens.Case presentationA 52-year-old woman with a history of immune thrombocytopenia for over 2 years was hospitalized for recurrent fever and cough lasting for 10 days. Her initial diagnosis on admission was community-acquired pneumonia, based on chest computed tomography findings of lung inflammation lesion. Empirical treatment with moxifloxacin and trimethoprim-sulfamethoxazole (TMP-SMZ) was initiated. However, her condition failed to improve significantly even after 1 week of treatment. Bronchoalveolar lavage fluid (BALF) subjected to mNGS revealed the presence of N. aobensis, resulting in a diagnosis of pulmonary nocardiosis caused by N. aobensis. This diagnosis was also supported by Sanger sequencing of the BALF. After adjusting the antibiotic regimen to include TMP-SMZ in combination with imipenem, the patient’s condition significantly improved. She was finally discharged with instructions to continue oral treatment with TMP-SMZ and linezolid for 6 months. The patient’s first follow-up 1 month after discharge showed good treatment outcomes but with obvious side effects of the drugs. Consequently, the antibiotic regimen was changed to doxycycline, and the patient continued to improve.ConclusionWe report the first detailed case of pulmonary nocardiosis caused by N. aobensis diagnosed by mNGS. mNGS could be an effective method that facilitates early diagnosis and timely decision-making for the treatment of nocardiosis, especially in cases that involve rare pathogens.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease accompanied by energy depletion and accumulation of reactive oxygen species (ROS). Inorganic nanoparticles (NPs) offer great promise for the treatment of RA because they mostly have functions beyond being drug carriers. However, conventional nanomaterials become coated with a protein corona (PC) or lose their cargo prematurely in vivo, reducing their therapeutic efficacy. To avoid these problems, we loaded methotrexate (MTX) into hollow structured manganese dioxide nanoparticles (H-MnO2 NPs), then coated them with a ‘pseudo-corona’ of human serum albumin (HSA) at physiological concentrations to obtain HSA-MnO2@MTX NPs. Efficacy of MTX, MnO2@MTX, and HSA-MnO2@MTX NPs was compared in vitro and in vivo. Compared to MnO2@MTX, HSA-coated NPs were taken up better by lipopolysaccharide-activated RAW264.7 and were more effective at lowering levels of pro-inflammatory cytokines and preventing ROS accumulation. HSA-MnO2@MTX NPs were also more efficient at blocking the proliferation and migration of fibroblast-like synoviocytes from rats with collagen-induced arthritis. In this rat model, HSA-MnO2@MTX NPs showed better biodistribution than other treatments, specifically targeting the ankle joint. Furthermore, HSA-MnO2@MTX NPs reduced swelling in the paw, regulated pro-inflammatory cytokine production, and limited cartilage degradation and signs of inflammation. These results establish the therapeutic potential of HSA-MnO2@MTX NPs against RA.

Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products.

Abstract Breast cancer treatment has been a global puzzle, and apoptosis strategies based on mitochondrial Ca2+ overload have attracted extensive attention. However, various limitations of current Ca2+ nanogenerators make it difficult to maintain effective Ca2+ overload concentrations. Here, we constructed a multimodal Ca2+ nano-modulator that, for the first time, combined photothermal therapy (PTT) and mitochondrial Ca2+ overload strategies to inhibit tumor development. By crosslinking sodium alginate (SA) on the surface of calcium carbonate (CaCO3) nanoparticles encapsulating with Cur and ICG, we prepared a synergistic Ca2+ nano-regulator SA/Cur@CaCO3-ICG (SCCI). In vitro studies have shown that SCCI further enhanced photostability while preserving the optical properties of ICG. After uptake by tumor cells, SCCI can reduce mitochondrial membrane potential and down-regulate ATP production by producing large amounts of Ca2+ at low pH. Near-infrared light radiation (NIR) laser irradiation made the tumor cells heat up sharply, which not only accelerated the decomposition of CaCO3, but also produced large amounts of reactive oxygen species (ROS) followed by cell apoptosis. In vivo studies have revealed that the Ca2+ nano-regulators had excellent targeting, biocompatibility, and anti-tumor effects, which can significantly inhibit the proliferation of tumor cells and play a direct killing effect. These findings indicated that therapeutic strategies based on ionic interference and PTT had great therapeutic potential, providing new insights into antitumor therapy. Graphical Abstract

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

Study region: The Laohahe basin, north of China Study focus: In a changing environment, some river’s hydrological regimes have significantly changed and may threatened river ecosystem. Therefore, it is urgent to improve our understanding for the driving mechanism of the evolution of the hydrological regimes. In this study, a comprehensive comparison was carried out to assess the application of the Long Short-Term Memory (LSTM) and the Variable Infiltration Capacity (VIC) model in river ecohydrological regimes alteration attribution. Firstly, the ecohydrological indicators changes were evaluated, including streamflow, ecosurplus, ecodeficit, and hydrological health. Then, the VIC and LSTM models were applied to quantify the climatic and anthropic effects on river ecohydrological indicators, respectively. Finally, the attribution results were compared. New hydrological insights: The research results revealed that (1) the streamflow decreased since 1980 and dramatically decreased after 2000. The ecohydrological indicators also changed significantly (α < 0.05). (2) The alterations were mainly driven by human activities, contributed to more than 80 %. (3) The LSTM and VIC showed little performance difference in quantitative attribution at the monthly and yearly scale, while the LSTM performed a little bad in streamflow simulation at the daily scale. The convenient feature and better simulation capabilities of LSTM provides a new choice for the attribution of ecohydrological regimes evolution, providing a better service in managing local water resources and safeguarding river ecosystems.

To balance the nutrition and improve quality of sausages. This research investigated quality improvements of Sichuan sausages by 41.5% poultry, rabbit meat and fish addition. The moisture, crude fat, crude protein contents, pH, Aw, colour, texture, TBARS, protein carbonyl, free thiol groups, fatty acids composition and sensory attributes of pork, poultry, rabbit meat and fish mixture group sausages were evaluated. The results showed that the hardness of pork and rabbit meat mixture group sausages (76.37, 68.01 kg) was significant (P

Abstract Background Colorectal cancer is a malignant tumor that poses a serious threat to human health. The main objective of this study is to investigate the mechanism by which Jatrorrhizine (JAT), a root extract from Stephania Epigaea Lo, exerts its anticancer effects in colorectal cancer. Methods We initially assessed the inhibitory properties of JAT on SW480 cells using MTT and cell scratch assays. Flow cytometry was employed to detect cell apoptosis. Differentially expressed genes were identified through high-throughput sequencing, and they were subjected to functional enrichment and signaling pathway analysis and PPI network construction. RT-qPCR was used to evaluate gene expression and identify critical differentially expressed genes. Finally, the function and role of differentially expressed genes produced by JAT-treated SW480 cells in colorectal cancer will be further analyzed using the TCGA database. Results Our study demonstrated that JAT exhibits inhibitory effects on SW480 cells at concentrations of 12.5µM, 25µM, 50µM, and 75µM without inducing cell apoptosis. Through high-throughput sequencing, we identified 244 differentially expressed genes. KEGG and GO analysis of high-throughput sequencing results showed that differentially expressed genes were significantly enriched in MAPK, Wnt, and P53 signaling pathways. Notably, JAT significantly altered the expression of genes associated with ferroptosis. Subsequent RT-qPCR showed that the expression of ferroptosis genes SLC2A3 and ASNS was significantly lower in JAT-treated SW480 cells than in the control group. Analysis by TCGA data also showed that ferroptosis genes SLC2A3 and ASNS were significantly highly expressed in COAD. The prognosis of SLC2A3 was significantly worse in COAD compared to the normal group. SLC2A3 may be a core target of JAT for the treatment of COAD. Conclusions JAT can inhibit COAD growth by ferroptosis-related genes. And it is a potential natural substance for the treatment of COAD.

Abstract Mounting evidence has found that tumor microenvironment (TME) plays an important role in the tumor progression of lung adenocarcinoma (LUAD). However, the roles of tumor microenvironment-related genes in immunotherapy and clinical outcomes remain unclear. In this study, 6 TME-related genes (PLK1, LDHA, FURIN, FSCN1, RAB27B, and MS4A1) were identified to construct the prognostic model. The established risk scores were able to predict outcomes at 1, 3, and 5 years with greater accuracy than previously known models. Moreover, the risk score was closely associated with immune cell infiltration and the immunoregulatory genes including T cell exhaustion markers. In conclusion, the TME risk score can function as an independent prognostic biomarker and a predictor for evaluating immunotherapy response in LUAD patients, which provides recommendations for improving patients’ response to immunotherapy and promoting personalized tumor immunotherapy in the future.

Abstract Background Currently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation. Methods We searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI). Results This meta-analysis included 10 studies involving a total of 243 patients. The pooled complete response and complete response with incomplete blood count recovery rate of Venetoclax combined with HMAs for post-transplantation relapse in AML/MDS was 32% (95% CI, 26-39%, I2 = 0%), with an overall response rate of 48% (95% CI, 39-56%, I2 = 37%). The 6-month survival rate was 42% (95% CI, 29-55%, I2 = 62%) and the 1-year survival rate was 23% (95% CI, 11-38%, I2 = 78%). Conclusion This study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.

Abstract Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury. Graphical Abstract Video Abstract

Abstract The development of atherosclerosis (AS) is closely linked to changes in the plaque microenvironment, which consists primarily of the cells that form plaque and the associated factors they secrete. The onset of inflammation, lipid deposition, and various pathological changes in cellular metabolism that accompany the plaque microenvironment will promote the development of AS. Numerous studies have shown that oxidative stress is an important condition that promotes AS. The accumulation of reactive oxygen species (ROS) is oxidative stress’s most important pathological change. In turn, the effects of ROS on the plaque microenvironment are complex and varied, and these effects are ultimately reflected in the promotion or inhibition of AS. This article reviews the effects of ROS on the microenvironment of atherosclerotic plaques and their impact on disease progression over the past five years and focuses on the progress of treatment strategies based on scavenging ROS of nanoparticles for AS. Finally, we also discuss the prospects and challenges of AS treatment.

Abstract Background Due to oral nano-delivery systems for the treatment of inflammatory bowel disease (IBD) are often failed to accumulated to the colonic site and could not achieve controlled drug release, it’s urgent to develop a microenvironment responsive drug delivery to improve therapy efficacy. Inflammation at the IBD site is mainly mediated by macrophages, which are the key effector cells. Excessive inflammation leads to oxidative stress and intestinal mucosal damage. The use of curcumin (CUR) and emodin (EMO) together for the treatment of IBD is promising due to their respective anti-inflammatory and intestinal mucosal repair effects. In view of the pH gradient environment of gastrointestinal tract, here we prepared pH-responsive sodium alginate (SA) hydrogel-coated nanoemulsions to co-deliver CUR and EMO (CUR/EMO NE@SA) to achieve controlled drug release and specifically target macrophages of the colon. Results In this study, a pH-responsive CUR/EMO NE@SA was successfully developed, in which the CUR/EMO NE was loaded by chitosan and further crosslinked with sodium alginate. CUR/EMO NE@SA had a pH-responsive property and could achieve controlled drug release in the colon. The preparation could significantly alleviate and improve the colon inflammatory microenvironment by decreasing TNF-α and IL-6 expression, increasing IL-10 expression, scavenging reactive oxygen species in macrophages, and by ameliorating the restoration of intestinal mucosal tight junction protein expression. Furthermore, we revealed the molecular mechanism of the preparation for IBD treatment, which might due to the CUR and EMO synergic inhibition of NF-κB to improve the pro-inflammatory microenvironment. Our study provides a new IBD therapy strategy via synergically inhibiting inflammatory, repairing mucosal and clearing ROS by pH-sensitive hydrogel-encapsulated nanoemulsion drug delivery system, which might be developed for other chronic inflammatory disease treatment. Conclusions It’s suggested that pH-sensitive hydrogel-coated nanoemulsion-based codelivery systems are a promising combinatorial platform in IBD. Graphical Abstract

BackgroundTargeted next-generation sequencing (tNGS) has emerged as a rapid diagnostic technology for identifying a wide spectrum of pathogens responsible for pulmonary infections.MethodsSputum samples were collected from patients unable or unwilling to undergo bronchoalveolar lavage. These samples underwent tNGS analysis to diagnose pulmonary infections. Retrospective analysis was performed on clinical data, and the clinical efficacy of tNGS was compared to conventional microbiological tests (CMTs).ResultsThis study included 209 pediatric and adult patients with confirmed pulmonary infections. tNGS detected 45 potential pathogens, whereas CMTs identified 23 pathogens. The overall microbial detection rate significantly differed between tNGS and CMTs (96.7% vs. 36.8%, p

ABSTRACTObjectives: The meta-analysis sought to evaluate the efficacy and safety of a combination of venetoclax (Ven) and azacitidine (AZA) in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Methods We searched PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, and Web of Science for eligible studies from inception to June 2022. We used the Cochrane Risk of Bias 2.0 (RoB 2.0) and Methodological Index for Non-Randomized Studies (MINORS) to evaluate the quality of the included literature. The inverse variance method was used to calculate the pooled proportion and 95% confidence interval (CI).Results The meta-analysis included nineteen studies with a total of 1615 patients. The pooled overall CR/CRi (complete response (CR)/complete response with incomplete blood count recovery (CRi)) rate for AML and MDS was 57.9% (95% CI 49.5-65.9%, I2 = 83%). Subgroup analyses showed that the rate of pooled CR/CRi was 67.5% (95% CI 61.1-73.3%, I2 = 54%) for the new-diagnosed (ND) AML group, 30% (95% CI 20-44.1%, I2 = 66%) for relapsed/refractory (R/R) AML, and 67.6% (95% CI 52.6-79.8%, I2 = 65%) for MDS, respectively. One randomized controlled trial (RCT) showed that CR/CRi was 64.7% in ND-AML patients. A total of 9 studies reported adverse events, with neutropenia being the most common of grade 3–4 adverse events, with a rate of 53.7% (95% CI 61.1-73.3%, I2 = 54%).Conclusion The present meta-analysis demonstrated that the Ven + AZA regimen is efficacious for the treatment of AML and MDS, with it being more effective for ND-AML than R/R AML. The most common adverse effects of this regimen are grade 3–4 neutropenia and neutropenia with fever.

AbstractResveratrol is a polyphenol with diverse pharmacological activities, but its clinical efficacy is limited due to low solubility/permeability, light-induced isomerization, auto-oxidation, and rapid metabolism. Nanodelivery systems, such as liposomes, polymeric nanoparticles, lipid nanocarriers, micelles, nanocrystals, inorganic nanoparticles, nanoemulsions, protein-based nanoparticles, exosomes, macrophages, and red blood cells (RBCs) have shown great potential for improving the solubility, biocompatibility, and therapeutic efficacy of resveratrol. This review comprehensively summarizes the recent advances in resveratrol nanoencapsulation and describes potential strategies to improve the pharmacokinetics of existing nanoformulations, enhance targeting, reduce toxicity, and increase drug release and encapsulation efficiency. The article also suggests that in order to avoid potential safety issues, resveratrol nanoformulations must be tested in vivo in a wide range of diseases.

Abstract Background Treatment options for pretreated triple-negative breast cancer (TNBC) are limited. This study aimed to evaluate the efficacy and safety of apatinib, an antiangiogenic agent, in combination of etoposide for pretreated patients with advanced TNBC. Methods In this single-arm phase II trial, patients with advanced TNBC who failed to at least one line of chemotherapy were enrolled. Eligible patients received oral apatinib 500 mg on day 1 to 21, plus oral etoposide 50 mg on day 1 to 14 of a 3-week cycle until disease progression or intolerable toxicities. Etoposide was administered up to six cycles. The primary endpoint was progression-free survival (PFS). Results From September 2018 to September 2021, 40 patients with advanced TNBC were enrolled. All patients received previous chemotherapy in the advanced setting, with the median previous lines of 2 (1–5). At the cut-off date on January 10, 2022, the median follow-up was 26.8 (1.6–52.0) months. The median PFS was 6.0 (95% confidence interval [CI]: 3.8–8.2) months, and the median overall survival was 24.5 (95%CI: 10.2–38.8) months. The objective response rate and disease control rate was 10.0% and 62.5%, respectively. The most common adverse events (AEs) were hypertension (65.0%), nausea (47.5%) and vomiting (42.5%). Four patients developed grade 3 AE, including two with hypertension and two with proteinuria. Conclusions Apatinib combined with oral etoposide was feasible in pretreated advanced TNBC, and was easy to administer. Clinical trial registration Chictr.org.cn, (registration number: ChiCTR1800018497, registration date: 20/09/2018)

Abstract Background H9N2 virus is mainly transmitted through the respiratory mucosal pathway, so mucosal immunity is considered to play a good role in controlling avian influenza infection. It is commonly accepted that no adequate mucosal immunity is achieved by inactivated vaccines, which was widely used to prevent and control avian influenza virus infection. Thus, an improved vaccine to induce both mucosal immunity and systemic immunity is urgently required to control H9N2 avian influenza outbreaks in poultry farms. Methods In this study, we constructed a novel Lactococcus lactis (L. lactis) strain expressing a recombinant fusion protein consisting of the HA1 proteins derived from an endemic H9N2 virus strain and chicken IgY Fc fragment. We evaluated the immunogenicity and protective efficacy of this recombinant L. lactis HA1-Fc strain. Results Our data demonstrated that chickens immunized with L. lactis HA1-Fc strain showed significantly increased levels of serum antibodies, mucosal secretory IgA, T cell-mediated immune responses, and lymphocyte proliferation. Furthermore, following challenge with H9N2 avian influenza virus, chickens immunized with L. lactis HA1-Fc strain showed reduced the weight loss, relieved clinical symptoms, and decreased the viral titers and the pathological damage in the lung. Moreover, oropharyngeal and cloacal shedding of the H9N2 influenza virus was detected in chicken immunized with L. lactis HA1-Fc after infection, the results showed the titer was low and reduced quickly to reach undetectable levels at 7 days after infection. Conclusion Our data showed that the recombinant L. lactis HA1-Fc strain could induce protective mucosal and systemic immunity, and this study provides a theoretical basis for improving immune responses to prevent and control H9N2 virus infection.

Abstract Background The incidence of colorectal cancer (CRC) has increased in recent years. Identification of accurate tumor markers has become the focus of CRC research. Early and frequent DNA methylation tends to occur in cancer. Thus, identifying accurate methylation biomarkers would improve the efficacy of CRC treatment. Neuroglobin (NGB) is involved in neurological and oncological diseases. However, there are currently no reports on epigenetic regulation involvement of NGB in CRC. Results NGB was downregulated or silenced in majority CRC tissues and cell lines. The hypermethylation of NGB was detected in tumor tissue, but no or a very low methylation frequency in normal tissues. Overexpression of NGB induced G2/M phase arrest and apoptosis, suppressed proliferation, migration, invasion in vitro, and inhibited CRC tumor growth and angiogenesis in vivo. Isobaric tag for relative and absolute quantitation (Itraq)-based proteomics identified approximately 40% proteins related to cell–cell adhesion, invasion, and tumor vessel formation in the tumor microenvironment, among which GPR35 was proved critical for NGB-regulated tumor angiogenesis suppression in CRC. Conclusions NGB, an epigenetically silenced factor, inhibits metastasis through the GPR35 in CRC. It is expected to grow into a potential cancer risk assessment factor and a valuable biomarker for early diagnosis and prognosis assessment of CRC.

Abstract Mango flowering is highly sensitive to temperature changes. In this research, the maximum values of pollen germination rate (PGR), pollen tube length (PTL) and their cardinal temperatures (Tmin, Topt and Tmax) were estimated by using quadratic equation and modified bilinear model under the conditions of 14–36 °C. The pollen germination rate in four mango varieties ranged from 29.1% (‘Apple mango’) to 35.5% (‘Renong No. 1’); the length of pollen tube ranged from 51.2 μm (‘Deshehari’) to 56.6 μm (‘Jinhuang’). The cardinal temperatures ranges (Tmin, Topt and Tmax) of pollen germination were 20.3–22.8 °C, 26.7–30.6 °C and 30.4–34.3 °C, respectively; similarly, cardinal temperatures (Tmin, Topt and Tmax) of pollen tube growth were 20.3–21.2 °C, 27.9–32.1 °C and 30.2–34.4 °C respectively. Of those, ‘Renong No. 1’ could maintain relatively high pollen germination rate even at 30 °C, however, ‘Deshehari’ had the narrowest adaptive temperature range. These results were further confirmed by changes of superoxide dismutase, catalase activity and malondialdehyde content. These results showed that mango flowering was highly sensitive to temperature changes and there were significant differences in pollen germination rate and pollen tube length among different varieties. Current research results were of great significance for the introduction of new mango varieties in different ecological regions, the cultivation and management of mango at the flowering stage and the breeding of new mango varieties.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is characterized by synovial inflammation and autoimmunity. The main cause of the disease is the imbalance of the proportion of pro-inflammatory macrophages (M1-type) and anti-inflammatory macrophages (M2-type) in the synovial tissues of the joint. To restore this balance, in our study, the interleukin-10 encoding anti-inflammatory cytokines (IL-10 pDNA) and chemotherapeutic drug dexamethasone sodium phosphate (DSP) were co-loaded into human serum albumin (HSA) preparing pDNA/DSP-NPs to actively target macrophages in synovium tissue to promote M1-M2 polarization. Confocal laser scanning microscope and western blot were used to demonstrate the targeting ability of co-delivery nanoparticles. In vivo, the real-time fluorescence imaging system and HPLC were used to study the tissue distribution and pharmacokinetics of nanoparticles, and the results showed that the accumulation of nanoparticles in the inflammatory joint site was higher. Its pharmacodynamics were evaluated in collagen-induced arthritis (CIA) rat model, and it demonstrated that the pDNA/DSP-NPs significantly reduced the expression of serum inflammatory factors and alleviated joint swelling and bone erosion, suggesting the favorable therapeutic effect. The synergistic treatment effect of IL-10 pDNA and DSP in this system was achieved by reducing the secretion of pro-inflammatory factors (TNF-α, IL-1β) and increasing the expression of anti-inflammatory factors (IL-10) to promote the M1-M2 polarization of macrophages. Our strategy is promising for co-delivery of gene drugs and chemical drugs by biomimetic natural materials to promote macrophages polarization so that to achieve synergically treatment of inflammatory disease.

The construction of marine ranching could restore the marine ecological environment, recover marine fishery resources, and promote the sustainable development of marine fisheries. The construction of marine ranching in China began in the 1970s and has made great achievements. Many domestic scholars had also made plenty of achievements in the researches of marine ranching. Sanya Wuzhizhou Island marine ranching is a tropical island leisure tourism type marine ranching. Through the study of marine ranching in Wuzhizhou Island, it was found that the construction of marine ranching had brought significant ecological, economical, and social benefits to the tourist area. Besides, it had played a great role in the development of ecotourism as well.

Abstract Background C-C chemokine receptor 5 (CCR5) has recently been recognized as an underlying therapeutic target for various malignancies. However, the association of CCR5 with prognosis in the head and neck squamous cell carcinoma (HNSC) patients and tumor-infiltrating lymphocytes (TILs) is unclear. Methods In the current experiment, methods such as the Tumor Immune Estimation Resource Analysis (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier plotter Analysis were used to comprehensively evaluate the expression of CCR5 in human various malignancies and the clinical prognosis in HNSC patients. Subsequently, we used the TIMER database and the TISIDB platform to investigate the correlation between CCR5 expression levels and immune cell infiltration in the HNSC tumor microenvironment. Furthermore, immunomodulatory and chemokine profiling were performed using the TISIDB platform to analyse the correlation between CCR5 expression levels and immunomodulation in HNSC patients. Results We found that CCR5 expression in HNSC tumor tissues was significantly upregulated than in normal tissues. In HNSC, patients with high CCR5 expression levels had worse overall survival (OS, HR = 0.59, p = 0.00015) and worse recurrence-free survival (RFS, HR = 3.27, p = 0.00098). Upregulation of CCR5 expression is closely associated with immunomodulators, chemokines, and infiltrating levels of CD4+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Furthermore, upregulated CCR5 was significantly associated with different immune markers in the immune cell subsets of HNSC. Conclusions High expression of CCR5 plays an important prognostic role in HNSC patients and may serve as a prognostic biomarker correlated with immune infiltration, and further studies are still needed to investigate therapeutic targeting HNSC patients in the future.

This study aimed to research the effectiveness and mode of the disease resistance induced by melatonin (MT) treatment in postharvest plum fruit. Plum fruit Cv ‘Fenghuang’ were treated with 10 mmol/L MT and/or inoculated with R. stolonifer, then stored for 5 days (20 ℃). Disease development, the contents of H2O2, total phenol and lignin and the activities of resistance-related enzyme were determined during the storage. The results showed that 10 mmol/L treatment effectively lowered the disease incidence and delayed the increase of lesion diameter of Rhizopus rot caused by R. stolonifer in plums. Single MT treatment could induce the activities of phenylpropanoid metabolic enzymes and the contents of total phenol and lignin in plums. MT treatment combined with R. tolonifer inoculation showed most significantly effects on the induction of H2O2 burst, and the activities of disease-resistance related enzymes such as chitinase, β-1,3-glucanase, phenylalanine ammonialyase (PAL), cinnamate-4-hydroxylase (C4H), 4-coumaric acid coenzyme A ligase (4-CL), peroxidase (POD) and polyphenol oxidase (PPO) as well as contents of total phenol and lignin in the samples during the storage. These results suggested that the MT treatment could activate the strong and rapid disease resistance upon the pathogenic infection by an induction of priming defence, by which the treatment resultantly maintained the overall quality in plums during the postharvest storage.

Cilia project from cells to serve sensory functions, and ciliary disruption can result in multiple disorders known as ciliopathies. Here the authors show that the ciliopathy gene TCTN1 functions to regulate the ciliary transition zone and ectosome formation.

Abstract Background Methotrexate (MTX) has been highlighted for Rheumatoid arthritis (RA) treatment, however, MTX does not accumulate well at inflamed sites, and long-term administration in high doses leads to severe side effects. In this study, a novel anti-RA nanoparticle complex was designed and constructed, which could improve the targeted accumulation in inflamed joints and reduce side effects. Results Here, we prepared a pH-sensitive biomimetic drug delivery system based on macrophage-derived microvesicle (MV)-coated zeolitic imidazolate framework-8 nanoparticles that encapsulated the drug methotrexate (hereafter MV/MTX@ZIF-8). The MV/MTX@ZIF-8 nanoparticles were further modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate (polyethylene glycol)-2000] (hereafter FPD/MV/MTX@ZIF-8) to exploit the high affinity of folate receptor β for folic acid on the surface of activated macrophages in RA. MTX@ZIF-8 nanoparticles showed high DLE (~ 70%) and EE (~ 82%). In vitro study showed that effective drug release in an acidic environment could be achieved. Further, we confirmed the activated macrophage could uptake much more FPD/MV/MTX@ZIF-8 than inactivated cells. In vivo biodistribution experiment displayed FPD/MV/MTX@ZIF-8 nanoparticles showed the longest circulation time and best joint targeting. Furthermore, pharmacodynamic experiments confirmed that FPD/MV/MTX@ZIF-8 showed sufficient therapeutic efficacy and safety to explore clinical applications. Conclusions This study provides a novel approach for the development of biocompatible drug-encapsulating nanomaterials based on MV-coated metal-organic frameworks for effective RA treatment. Graphical Abstract

Abstract Background LncRNA PRNCR1 has been reported to be involved in LPS-induced inflammation, which contributes to osteoarthritis (OA). We predicted that miR-377-3p could bind to PRNCR1.MiR-377-3p can suppress OA development. We therefore analyzed the potential interaction between them in OA. Methods Expression of miR-377-3p and PRNCR1 in both OA (n = 40) and control (n = 40) samples were analyzed by RT-qPCR. MiR-377-3p or PRNCR1 were overexpressed in synoviocytes to explore their potential interaction. The subcellular location of PRNCR1 was analyzed by nuclear fractionation assay. The direct interaction between miR-377-3p and PRNCR1 was analyzed by RNA-pull down assay. The proliferation and apoptosis of synoviocytes were analyzed by BrdU and apoptosis assay, respectively. Results PRNCR1 was overexpressed in OA, while miR-377-3p was downexpressed in OA. PRNCR1 was detected in the cytoplasm and directly interacted with miR-377-3p. Interestingly, overexpression of PRNCR1 and miR-377-3p showed no regulatory role in each other’s expression. LPS treatment increased PRNCR1 expression and decreased miR-377-3p expression. PRNCR1 overexpression decreased LPS-induced synoviocyte proliferation and increased LPS-induced synoviocyte apoptosis. MiR-377-3p played opposite roles in cell proliferation and apoptosis. Moreover, PRNCR1 suppressed the role of miR-377-3p. Conclusions Therefore, PRNCR1 is was detected in cytoplasm and regulates synoviocyte proliferation and apoptosis in OA by sponging miR-377-3p.

Introduction:. Mature plasmacytoid dendritic cells (pDCs) proliferation associated with myeloid neoplasms (MPDMN) are recognized as a neoplasm related to fully differentiated pDCs. Although it has been reported for many years, the genomic landscape of MPDMN is poorly understood. Methods:. We reported two patients who developed acute myeloid leukemia (French-American-British M5 subtype) coexisted with immunophenotypically mature pDCs proliferation, which fit the diagnosis of MPDMN. We sorted pDCs from myeloid blasts by flow cytometry and performed whole-exome sequencing and RNA sequencing of the two cell populations, respectively. Results:. The immunophenotypes of pDCs in both patients were positive for CD123bri, HLA-DR, CD4, CD303, CD304, and negative for CD56, CD34, CD117, and TdT. The variant allele frequency of gene mutations in myeloid blasts and pDCs were similar. The expression data showed myeloid blasts clustered tightly with hematopoietic stem cells, and pDCs from patients clustered tightly with granulocyte-monocyte progenitors/common myeloid progenitor, rather than with pDCs from the GEO platform. Conclusion:. Our study suggested that pDCs derived from the leukemic clone, evidenced by a shared mutation profile and similar transcriptional signatures between pDCs and concurrent myeloid blasts.

Systemic lupus erythematous (SLE) is a complex chronic autoimmune disease with difficult early treatment and accurate diagnosis. Circulating exosomes containing proteins, lipids and nucleic acids can be ideal diagnostic biomarkers and disease management strategies for SLE. Our aim was to examine the unique expression profiles of circulating exosomal miRNAs and proteins in patients with SLE patients.Using RNA-sequencing and proteomic approaches, we compared the expression patterns of exosomal miRNAs and proteins in the plasma of SLE patients and healthy subjects, and discussed the underlying signaling network of circulating exosomes. We also summarize common molecules (miRNAs and proteins) and pathways shared by our plasma exosomes, as well as previously reported data (PBMC, T cells, B cells and plasma).We identified groups of differentially expressed exosomal miRNAs and proteins in the plasma of SLE patients and healthy controls. We obtained consensus molecules (39 miRNAs, 14 proteins) and 21 signaling pathways that are common in our current study and previous reports.Common molecules (miRNAs and proteins) and pathways shared by our plasma exosomes data and other circulating components data reported previously indicate their potential application in the clinical treatment and diagnosis of SLE disease.

Anti-myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) associated disorder (MOGAD) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disorder that has been widely recognized in recent years. It is distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which are separate disease spectrums. Here we report the case of a 5-year-old boy who was admitted for 3 days with fever, headache, and vomiting. Magnetic resonance imaging revealed abnormal hyperintensity in the left thalamus and positive serum IgM for M. pneumoniae. After treatment with azithromycin, the headache gradually disappeared, but paralysis and urinary retention occurred on the 6th day after admission. MRI re-examination showed that the original abnormal signal in the left thalamus was significantly weakened, but new abnormal signals appeared in the brain and cerebrospinal cord, and the serum MOG-IgG was positive. After treatment, the child has fully recovered and is still receiving follow-up care. We believe that this is a case of MOGAD in a child with a biphasic ADEM phenotype secondary to M. pneumoniae infection, which has potential value in elucidating the pathophysiology of MOGAD.

In the inflammatory microenvironment, there are numerous exosomes secreted by immune cells (Macrophages, neutrophils, dendritic cells), mesenchymal stem cells (MSCs) and platelets as intercellular communicators, which participate in the regulation of inflammation by modulating gene expression and releasing anti-inflammatory factors. Due to their good biocompatibility, accurate targeting, low toxicity and immunogenicity, these exosomes are able to selectively deliver therapeutic drugs to the site of inflammation through interactions between their surface-antibody or modified ligand with cell surface receptors. Therefore, the role of exosome-based biomimetic delivery strategies in inflammatory diseases has attracted increasing attention. Here we review current knowledge and techniques for exosome identification, isolation, modification and drug loading. More importantly, we highlight progress in using exosomes to treat chronic inflammatory diseases such as rheumatoid arthritis (RA), osteoarthritis (OA), atherosclerosis (AS), and inflammatory bowel disease (IBD). Finally, we also discuss their potential and challenges as anti-inflammatory drug carriers.

Abstract Background Family with sequence similarity 65 member A (FAM65A), also known as RIPOR1, is differentially expressed between human tumor and non-tumor tissues in kinds of cancers. In addition, it was reported that the product of FAM65A may be a biomarker for cholangiocarcinoma patients. However, there is still no evidence on the relationship between the FAM65A and different types of tumors. Our study is mainly for exploring the prognostic values of FAM65A in pan-cancer and for further discovering a potential therapeutics target. Methods We analyzed FAM65A expression, prognostic values, genetic alteration, protein phosphorylation, immune infiltration and enrichment analysis across different types of human malignant tumors based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Additionally, Real-Time PCR (RT-qPCR) was performed to further confirm the roles of FAM65A in the pathogenesis of colorectal cancer. Results We found that FAM65A expression was associated with the prognosis of multiple human tumors, especially colorectal cancer. Moreover, we also observed that FAM65A was highly expressed in colorectal cancer through RT-qPCR. We observed that decreasing phosphorylation level of the S351 locus in colon adenocarcinoma, uterine corpus endometrial carcinoma and lung adenocarcinoma. And the expression of FAM65A was positively related to cancer-associated fibroblasts (CAFs) infiltration in many tumors, such as colon adenocarcinoma. Therefore, FAM65A may be a potential prognostic biomarker of human tumors.

Defense elicitors can induce fruit disease resistance to control postharvest decay but may incur quality impairment. Our present work aimed to investigate the resistance against Botrytis cinerea induced by the elicitor β-aminobutyric acid (BABA) and to elucidate the specific transcriptional mechanism implicated in defense-related metabolic regulations. The functional dissection results demonstrated that, after inoculation with the fungal necrotroph B. cinerea, a suite of critical genes encoding enzymes related to the sucrose metabolism and phenylpropanoid pathway in priming defense in grapes were transcriptionally induced by treatment with 10 mM BABA. In contrast, more UDP-glucose, a shared precursor of phenylpropanoid and sucrose metabolism, may be redirected to the phenylpropanoid pathway for the synthesis of phytoalexins, including trans-resveratrol and ɛ-viniferin, in 100 mM BABA–treated grapes, resulting in direct resistance but compromised soluble sugar contents. An R2R3-type MYB protein from Vitis vinifera, VvMYB44, was isolated and characterized. VvMYB44 expression was significantly induced upon the grapes expressed defensive reaction. Subcellular localization, yeast two-hybrid, and coimmunoprecipitation assays revealed that the nuclear-localized VvMYB44 physically interacted with the salicylic acid–responsive transcription coactivator NPR1 in vivo for defense expression. In addition, VvMYB44 directly bound to the promoter regions of sucrose and phenylpropanoid metabolism-related genes and transactivated their expression, thus tipping the balance of antifungal compound accumulation and soluble sugar maintenance. Hence, these results suggest that 2R-type VvMYB44 might be a potential positive participant in BABA-induced priming defense in grape berries that contributes to avoiding the excessive consumption of soluble sugars during the postharvest storage.[Graphic: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Pancreatic cancer is one of the most lethal malignant tumors with a low survival rate, partly because the tumor microenvironment (TME), which consists of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), immune cells, and vascular systems, prevents effective drug delivery and chemoradiotherapy. Thus, modulating the microenvironment of pancreatic cancer is considered a promising therapeutic approach. Since nanoparticles are one of the most effective cancer treatment strategies, several nano-delivery platforms have been developed to regulate the TME and enhance treatment. Here, we summarize the latest advances in nano-delivery systems that alter the TME in pancreatic cancer by depleting ECM, inhibiting CAFs, reversing immunosuppression, promoting angiogenesis, or improving the hypoxic environment. We also discuss promising new targets for such systems. This review is expected to improve our understanding of how to modulate the pancreatic cancer microenvironment and guide the development of new therapies. Graphical Abstract

Abstract Background Autosomal dominant osteopetrosis type II (ADO2) is a genetically and phenotypically metabolic bone disease, caused by osteoclast abnormalities. The pathways dysregulated in ADO2 could lead to the defects in osteoclast formation and function. However, the mechanism remains elusive. Materials and methods To systematically explore the molecular characterization of ADO2, we performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs) and healthy normal control iPSCs (NC-iPSCs) using whole genome re-sequencing, DNA methylation and N6-methyladenosine (m6A) analysis in this study. Results Totally, we detected 7,095,817 single nucleotide polymorphisms (SNPs) and 1,179,573 insertion and deletions (InDels), 1,001,943 differentially methylated regions (DMRs) and 2984 differential m6A peaks, and the comprehensive multi-omics profile was generated from the two cells. Interestingly, the ISG15 m6A level in ADO2-iPSCs is higher than NC-iPSCs by IGV software, and the differentially expressed m6A-modified genes (DEMGs) were highly enriched in the osteoclast differentiation and p53 signaling pathway, which associated with the development of osteopetrosis. In addition, combining our previously published transcriptome and proteome datasets, we found that the change in DNA methylation levels correlates inversely with some gene expression levels. Conclusion Our results indicate that the global multi-omics landscape not only provides a high-quality data resource but also reveals a dynamic pattern of gene expression, and found that the pathogenesis of ADO2 may begin early in life.

Aberrant protocadherins (PCDHs) expression trigger tumor invasion and metastasis. PCDH20 anti-tumor functions in various tumor have been identified. Tumor suppression is due to Wnt/β-catenin pathway antagonism and may be suppressed caused by PCDH20 downregulation through promotor methylation, whereas PCDH20 effects and regulation mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. We analyzed PCDH20 effects on ESCC and underlying action mechanisms for PCDH20. We test PCDH20 expression in ESCC tissues and cells by semi-quantitative PCR (RT-PCR) and q-PCR (real-time quantitative polymerase chain reaction). MSP (methylation-specific PCR) was carried out to assess the methylation of PCDH20 in ESCC cells and tissues. Anti-tumor effects of PCDH20 in vitro were assessed by clone formation assay, CCK8 assay, Transwell assay, and flow cytometry. Nude mice tumorigenicity was used to assess PCDH20 anti-tumor effect in vivo. Online database, qPCR, and Western blotting were used to identify the downregulation of MAP3K9 by PCDH20, associated with AKT/β-catenin signaling inactivation. We found that PCDH20 expression was dramatically attenuated in esophageal cancer tissues and cells, maybe due to promotor methylation, and ectopic PCDH20 expression suppressed ESCC malignant biological phenotypes. PCDH20 exerted anti-tumor effects by MAP3K9 downregulation, which suppressed AKT/β-catenin signaling in ESCC cells.ConclusionPCDH20 was a tumor suppressor gene, which antagonized AKT/β-catenin signaling pathway in ESCC by decreasing MAP3K9.

Summary: The spine has essential roles in supporting body weight, and passaging the neural elements between the body and the brain. In this study, we used integrated single-cell RNA sequencing and single-cell transposase-accessible chromatin sequencing analyses to reveal the cellular heterogeneity, lineage, and transcriptional regulatory network of the developing human spine. We found that EPYC + HAPLN1+ fibroblasts with stem cell characteristics could differentiate into chondrocytes by highly expressing the chondrogenic markers SOX9 and MATN4. Neurons could originate from neuroendocrine cells, and MEIS2 may be an essential transcription factor that promotes spinal neural progenitor cells to selectively differentiate into neurons during early gestation. Furthermore, the interaction of NRP2_SEMA3C and CD74_APP between macrophages and neurons may be essential for spinal cord development. Our integrated map provides a blueprint for understanding human spine development in the early and midgestational stages at single-cell resolution and offers a tool for investigating related diseases.

Sorghum bicolor (L.) is one of the oldest crops cultivated by human beings which has been used in food and wine making. To understand the genetic diversity of sorghum breeding resources and further guide molecular-marker-assisted breeding, six yield-related traits were analyzed for 214 sorghum germplasm from all over the world, and 2,811,016 single-nucleotide polymorphisms (SNPs) markers were produced by resequencing these germplasms. After controlling Q and K, QTLs were found to be related to the traits using three algorisms. Interestingly, an important QTL was found which may affect multiple traits in this study. It was the most likely candidate gene for the gene SORBI_3008G116500, which was a homolog of Arabidopsis thaliana gene-VIP5 found by analyzing the annotation of the gene in the LD block. The haplotype analysis showed that the SORBI_3008G116500hap3 was the elite haplotype, and it only existed in Chinese germplasms. The traits were proven to be more associated with the SNPs of the SORBI_3008G116500 promoter through gene association studies. Overall, the QTLs and the genes identified in this study would benefit molecular-assisted yield breeding in sorghum.

Abstract MnBi alloys were prepared using arc melting with different atomic proportions between Mn and Bi and then heated at 573 K for 30 h. MnBi /Fe hybrid magnets were also prepared by modulating MnBi content. The microstructure evolution, the content of ferromagnetic low temperature phase MnBi, and the magnetic properties of MnBi alloys and MnBi /Fe hybrid magnets were studied systematically. Results showed that the composition and heat treatment had obvious influences on the saturation magnetization of MnBi alloy, where the saturation magnetization increased quickly following the heat treatment. The saturation magnetization initially increased and then decreased with increasing the content of Mn, which was consistent with the change of mass percentage of the LTP MnBi. The MnBi alloy with 50 at% Mn exhibited maximum magnetization as 62.0 emu/g with 30 KOe applied field at 300 K. The ratio of the content between Fe and MnBi had a remarkable effect on the magnetic performance. The saturation magnetization of MnBi/Fe hybrid magnets increased obviously with increasing the content of Fe. Meanwhile, the coercivity of the composite magnet increased dramatically with increasing the content of MnBi.

The "Oil and Gas Water Well Production Data Management System Database" provides great assistance for oilfield production, monitoring, and management. However, due to the harsh conditions of oil field wells and the lack of some test data, traditional management methods are no longer suitable for present condition. At the same time, optimization analysis for a single oil well has a high cost and low efficiency, and it is difficult to achieve the modern management goal of large-scale pumping well groups. In this paper, the grey correlation method is used to analyze the direct correlation between the influencing factors and the system efficiency, surface equipment driving efficiency, and wellbore lifting efficiency, and the improvement method against factors with strong correlation is prioritized. A multi-node evaluation index system for pumping well systems and corresponding improvement methods were constructed, and evaluation software was compiled. This technology considers the running condition of the pumping unit in one oil field block, and selects the oil wells to be improved according to the evaluation index, and puts forward the targeted improvement methods according to the common problems of the oil well. This paper provides a set of reliable technical methods for the efficient management of the oil well in the oil field block.

During inflammation, inflammatory cells are rapidly recruited to sites of infection or injury, where they cross physiological barriers around the infected site and further infiltrate into the tissues. Other cells, such as erythrocytes, endothelial cells and stem cells, also play prominent roles in host defense and tissue repair. In recent years, nanotechnology has been exploited to deliver drugs to sites of inflammation. For example, nanoparticles camouflaged with a cell membrane are a novel drug-delivery platform that can interact with the immune system and that show great potential for treating inflammation. Encapsulating drugs inside plasma membranes derived from various cells involved in inflammatory processes can be effective against inflammation. This review describes the preparation, characterization, and properties of various types of cell membrane-camouflaged biomimetic nanoparticles. It also summarizes preclinical research into their efficacy against inflammation.

Abstract Background Nano-drug delivery systems show considerable promise for effective cancer therapy. Polymeric micelles have attracted extensive attention as practical nanocarriers for target drug delivery and controlled drug delivery system, however, the distribution of micelles and the release of the drug are difficult to trace in cancer cells. Therefore, the construction of a redox-sensitive multifunctional drug delivery system for intelligent release of anticancer drugs and simultaneous diagnostic imaging and therapy remains an attractive research subject. Results To construct a smart drug delivery system for simultaneous imaging and cancer chemotherapy, mPEG-ss-Tripp was prepared and self-assembled into redox-sensitive polymeric micelles with a diameter of 105 nm that were easily detected within cells using confocal laser scanning microscopy based on aggregation-induced emission. Doxorubicin-loaded micelles rapidly released the drug intracellularly when GSH reduced the disulfide bond. The drug-loaded micelles inhibited tumor xenografts in mice, while this efficacy was lower without the GSH-responsive disulfide bridge. These results establish an innovative multi-functional polymeric micelle for intracellular imaging and redox-triggered drug deliver to cancer cells. Conclusions A novel redox-sensitive drug delivery system with AIE property was constructed for simultaneous cellular imaging and intelligent drug delivery and release. This smart drug delivery system opens up new possibilities for multifunctional drug delivery systems.

Abstract Background Spinal Cord injury (SCI) is a kind of severe traumatic disease. The inflammatory response is a significant feature after SCI. Tetramethylpyrazine (TMP), a perennial herb of umbelliferae, is an alkaloid extracted from ligustici. TMP can inhibit the production of nitric oxide and reduce the inflammatory response in peripheral tissues. It can be seen that the therapeutic effect of TMP on SCI is worthy of affirmation. TMP has defects such as short half-life and poor water-solubility. In addition, the commonly used dosage forms of TMP include tablets, dropping pills, injections, etc., and its tissue and organ targeting is still a difficult problem to solve. To improve the solubility and targeting of TMP, here, we developed a nanotechnology-based drug delivery system, TMP-loaded nanoparticles modified with HIV trans-activator of transcription (TAT-TMP-NPs). Results The nanoparticles prepared in this study has integrated structure. The hemolysis rate of each group is less than 5%, indicating that the target drug delivery system has good safety. The results of in vivo pharmacokinetic studies show that TAT-TMP-NPs improves the bioavailability of TMP. The quantitative results of drug distribution in vivo show that TAT-TMP-NPs is more distributed in spinal cord tissue and had higher tissue targeting ability compared with other treatment groups. Conclusions The target drug delivery system can overcome the defect of low solubility of TMP, achieve the targeting ability, and show the further clinical application prospect.

Abstract Background Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. Results The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was − 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. Conclusion The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

In this paper, we establish 5 kinds of integral Opial-type inequalities in (p, q)-calculus by means of Hölder’s inequality, Cauchy inequality, an elementary inequality and some analysis technique. First, we investigated the Opial inequalities in (p, q)-calculus involving one function and its (p, q) derivative. Furthermore, Opial inequalities in (p, q)-calculus involving two functions and two functions with their (p, q) derivatives are given. Our results are (p, q)-generalizations of some known inequalities, such as Opial-type integral inequalities and (p, q)-Wirtinger inequality.

Abstract Background Mounting evidences displayed that miRNAs play crucial roles in tumor initiation and development. However, the regulation and relevant mechanism of miR-1825 in glioblastoma (GBM) remain unclear. Methods qRT-PCR was used to detect miR-1825 and CDK14 mRNA expression. Western blot was applied for testing protein levels (VEGF, E-cadherin, N-cadherin, vimentin, β-catenin, c-myc, p-c-Jun). MTT and transwell assays were used for detecting GBM cell progression, including cell viability, migration, and invasion. Results The results showed that miR-1825 was decreased in GBM tissue specimens by qRT-PCR and it was confirmed as a prognostic marker of GBM by Kaplan-Meier survival analysis. Moreover, we also found that miR-1825 upregulation suppressed GBM cell viability, tumor growth, invasion, and migration. Furthermore, CDK14 was first identified as the direct target of miR-1825 by Luciferase reporter assay. CDK14 acted as an oncogene in GBM development by immunohistochemistry. In addition, Western blot analysis demonstrated that miR-1825 regulated Wnt/β-catenin signaling pathway in GBM development. Conclusion In conclusion, miR-1825 upregulation suppressed GBM progression by targeting CDK14 through Wnt/β-catenin pathway.