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Abstract Background To elucidate the mechanism of dysfunction of tolerogenic dendritic cells (DCs) is of significance. Telomerase involves the regulation of the cell fate and activities. The objective of this study is to investigate the role of telomerase reverse transcriptase (TERT) in regulating the tolerogenic feature of DCs. Methods The telomerase was assessed in DCs, which were collected from patients with allergic rhinitis (AR), healthy control (HC) subjects, and mice. RNAs were extracted from DCs, and analyzed by RNA sequencing (RNAseq), real-time quantitative RT-PCR, and Western blotting. Results The results showed that expression of TERT was higher in peripheral DCs of AR patients. The expression of IL10 in DCs was negatively correlated with the levels of TERT expression. Importantly, the levels of TERT mRNA in DCs were associated with the AR response in patients with AR. Endoplasmic reticulum (ER) stress promoted the expression of Tert in DCs. Sensitization with the ovalbumin-aluminum hydroxide protocol increased the expression of Tert in DCs by exacerbating ER stress. TERT interacting with c-Maf (the transcription factor of IL-10) inducing protein (CMIP) in DCs resulted in CMIP ubiquitination and degradation, and thus, suppressed the production of IL-10. Inhibition of Tert in DCs mitigated experimental AR. Conclusions Elevated amounts of TERT were detected in DCs of patients with AR. The tolerogenic feature of DCs was impacted by TERT. Inhibited TERT attenuated experimental AR.

Abstract Regulatory T cells (Tregs) are a key determinant for the immunosuppressive and premetastatic niche for cancer progression after surgery resection. However, the precise mechanisms regulating Tregs function during surgical stress-facilitated cancer metastasis remain unknown. This study aims to unravel the mechanisms and explore potential strategies for preventing surgical stress-induced metastasis by targeting NEDD8. Using a surgical stress mouse model, we found that surgical stress results in the increased expression of NEDD8 in Tregs. NEDD8 depletion abrogates postoperative lung metastasis of colon cancer cells by inhibiting Treg immunosuppression and thereby partially recovering CD8+T cell and NK cell-mediated anti-tumor immunity. Furthermore, Treg mitophagy and mitochondrial respiration exacerbated in surgically stressed mice were attenuated by NEDD8 depletion. Our observations suggest that cancer progression may result from surgery-induced enhancement of NEDD8 expression and the subsequent immunosuppressive function of Tregs. More importantly, depleting or inhibiting NEDD8 can be an efficient strategy to reduce cancer metastasis after surgery resection by regulating the function of Tregs.

IntroductionThe potential role of the endometrial microbiota in the pathogenesis of endometrial polyps (EPs) warrants further investigation, given the current landscape of limited and inconclusive research findings. We aimed to explore the microecological characteristics of the uterine cavity in patients with EPs and investigate the potential of endometrial microbiota species as novel biomarkers for identifying EPs.MethodsEndometrial samples were collected from 225 patients who underwent hysteroscopies, of whom 167 had EPs, whereas 58 had non- hyperproliferative endometrium status. The endometrial microbiota was assessed using 16S rRNA gene sequencing. We characterized the endometrial microbiota and identified microbial biomarkers for predicting EPs.ResultsThe endometrial microbial diversity and composition were significantly different between the EP and control groups. Predictive functional analyses of the endometrial microbiota demonstrated significant alterations in pathways involved in sphingolipid metabolism, steroid hormone biosynthesis, and apoptosis between the two groups. Moreover, a classification model based on endometrial microbial ASV-based biomarkers along with the presence of abnormal uterine bleeding symptoms achieved powerful classification potential in identifying EPs in both the discovery and validation cohorts.ConclusionOur study indicates a potential association between altered endometrial microbiota and EPs. Endometrial microbiota-based biomarkers may prove valuable for the diagnosis of EPs.Clinical trial registrationChinese Clinical Trial Registry (ChiCTR2100052746).

The Middle Permain Maokou Formation (P2m) is a new region of natural gas exploration in the Sichuan Basin, is characterized by bioclastic limestone with localized dolomitization, and karst fractured-vuggy reservoirs. Currently, on the gas source, hydrocarbon accumulation process and control factors in the Sichuan Basin during the Permian are lacking. To bridge this gap, herein, we identified the filling sequence minerals inside the pores/vugs, along with the oil charge of the Maokou Formation using drill cores, thin sections, oil inclusion analysis, and U-Pb dating of calcite cements. The results showed that the reservoir space of the Maokou Formation was predominated by the residual dissolved pores/vugs, fractures, and dissolved fractures. The pores/vugs underwent four stages of mineral filling by very fine-fine (-crystalline, CC1) calcite → fine-medium calcite (CC2: from 256.4 ± 1.7 to 244.1 ± 6.3 Ma) → fibrous calcite (FC; ∼183.9 ± 8.2 Ma) → coarse-macro calcite (CC3; ∼171.5 ± 5.3 Ma). Combined with the homogenization temperature and salty of fluid inclusion, we considered that three stages of oil charge were present in the Maokou Formation reservoirs. The first stage involved the formation of paleo-oil reservoirs during the Late Permian to Early Triassic, corresponding to the high-maturity aqueous inclusions in CC2, with a homogenization temperature of 106.7°C–137.8°C. At that time, the oil generation from the Lower Cambrian Qiongzhusi Formation rocks peaked, and the generated hydrocarbons migrated upward into the Maokou Formation through the strike-slip faults in the basin center. The second stage involved the formation of paleo-oil reservoirs during the Early Jurassic. The Permian source rocks reached the oil generation window with hydrocarbon expulsion, which was consistent with the oil inclusions in FC. The third stage involved the formation of paleo-gas reservoirs during the Middle Jurassic to Early Cretaceous, corresponding to the high-density methane inclusions and bitumen inclusions occurring in CC3, with the homogenization temperature peaking at 151.9°C–178°C. The natural gas in the Middle Permian of the Central Sichuan Basin is predominantly sourced from the Lower Cambrian Qiongzhusi Formation mudstone and partially from the source rocks of the Middle Permian, indicating a significant source-reservoir conduit of the strike-slip faults in the basin center. The findings provide considerable baseline data to advance further research in the Sichuan Basin.

Abstract Background Aedes aegypti and Ae. albopictus are important human arbovirus vectors that can spread arboviral diseases such as yellow fever, dengue, chikungunya and Zika. These two mosquito species coexist on Hainan Island and the Leizhou Peninsula in China. Over the past 40 years, the distribution of Ae. albopictus in these areas has gradually expanded, while Ae. aegypti has declined sharply. Monitoring their genetic diversity and diffusion could help to explain the genetic influence behind this phenomenon and became key to controlling the epidemic of arboviruses. Methods To better understand the genetic diversity and differentiation of these two mosquitoes, the possible cohabiting areas on Hainan Island and the Leizhou Peninsula were searched between July and October 2021, and five populations were collected. Respectively nine and 11 microsatellite loci were used for population genetic analysis of Ae. aegypti and Ae. albopictus. In addition, the mitochondrial coxI gene was also selected for analysis of both mosquito species. Results The results showed that the mean diversity index (PIC and SI values) of Ae. albopictus (mean PIC = 0.754 and SI = 1.698) was higher than that of Ae. aegypti (mean PIC = 0.624 and SI = 1.264). The same results were also observed for the coxI gene: the genetic diversity of all populations of Ae. albopictus was higher than that of Ae. aegypti (total H = 45 and Hd = 0.89958 vs. total H = 23 and Hd = 0.76495, respectively). UPGMA dendrogram, DAPC and STRUCTURE analyses showed that Ae. aegypti populations were divided into three clusters and Ae. albopictus populations into two. The Mantel test indicated a significant positive correlation between genetic distance and geographic distance for the Ae. aegypti populations (R 2 = 0.0611, P = 0.001), but the correlation was not significant for Ae. albopictus populations (R 2 = 0.0011, P = 0.250). Conclusions The population genetic diversity of Ae. albopictus in Hainan Island and the Leizhou Peninsula was higher than that of Ae. aegypti. In terms of future vector control, the most important and effective measure was to control the spread of Ae. albopictus and monitor the population genetic dynamics of Ae. aegypti on Hainan Island and the Leizhou Peninsula, which could theoretically support the further elimination of Ae. aegypti in China. Graphical Abstract

Abstract By utilizing Optum Life Sciences Claims Data, we constructed Real World Data (RWD) cohorts comprising over 3 million patients and simulated a clinical trial observational study design to evaluate over 200 FDA-approved drugs with COVID-19 repurposing potential, and identified a dozen candidates exhibiting significant reduction in the odds of severe COVID-19 outcomes such as death, intensive care unit (ICU) admission, hospitalization and pneumonia. Notably, certain drug combinations demonstrated effects comparable to those of COVID-19 vaccines. Furthermore, our study revealed a novel finding: a quantitative linear relationship between COVID-19 outcomes and overall patient health risks. This discovery enabled a more precise estimation of drug efficacy using the risk adjustment. The top performing drugs identified include emtricitabine, tenofovir, folic acid, progesterone, estradiol, epinephrine, disulfiram, nitazoxanide and some drug combinations including aspirin-celecoxib.

Summary: Telomeres are an important biomarker in the cell destiny. The relationship between telomeres and regulatory T cells (Tregs) has not yet been investigated. The objective of this study is to evaluate the link between Tregs' telomere length and allergic rhinitis (AR)’s pathogenesis. Here, we report that low telomerase activity and high endoplasmic reticulum stress status were observed in Tregs from AR patients, as shown in the results. Immune regulatory molecules levels were correlated with the length of Tregs' telomeres. The immune-suppressive functions of Tregs were associated with the telomere length/Telomerase reverse transcriptase/Telomerase protein component 1 status in Tregs. The levels of telomere length/telomerase in airway Tregs were reduced by sensitization. Endoplasmic reticulum stress signaling pathway of proline-rich receptor-like protein kinase-eukaryotic translation initiation factor 2A (eIF2a) was associated with the regulation of telomerase. Inhibiting eIF2a had an effect on upregulating telomerase activity in Tregs and mitigating experimental AR.

Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.

The circulating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variant presents an ongoing challenge for surveillance and detection. It is important to establish an assay for SARS-CoV-2 antibodies in vaccinated individuals. Numerous studies have demonstrated that binding antibodies (such as S-IgG and N-IgG) and neutralizing antibodies (Nabs) can be detected in vaccinated individuals. However, it is still unclear how to evaluate the consistency and correlation between binding antibodies and Nabs induced by inactivated SARS-CoV-2 vaccines. In this study, serum samples from humans, rhesus macaques, and hamsters immunized with inactivated SARS-CoV-2 vaccines were analyzed for S-IgG, N-IgG, and Nabs. The results showed that the titer and seroconversion rate of S-IgG were significantly higher than those of N-IgG. The correlation between S-IgG and Nabs was higher compared to that of N-IgG. Based on this analysis, we further investigated the titer thresholds of S-IgG and N-IgG in predicting the seroconversion of Nabs. According to the threshold, we can quickly determine the positive and negative effects of the SARS-CoV-2 variant neutralizing antibody in individuals. These findings suggest that the S-IgG antibody is a better supplement to and confirmation of SARS-CoV-2 vaccine immunization.

It is important to eliminate lipopolysaccharide (LPS) along with killing bacteria in periprosthetic joint infection (PJI) therapy for promoting bone repair due to its effect to regulate macrophages response. Although natural antimicrobial peptides (AMPs) offer a good solution, the unknown toxicity, high cost and exogenetic immune response hamper their applications in clinic. In this work, we fabricated a nanowire-like composite material, named P@C, by combining chitosan and puerarin via solid-phase reaction, which can finely mimic the bio-functions of AMPs. Chitosan, serving as the bacteria membrane puncture agent, and puerarin, serving as the LPS target agent, synergistically destroy the bacterial membrane structure and inhibit its recovery, thus endowing P@C with good antibacterial property. In addition, P@C possesses good osteoimmunomodulation due to its ability of LPS elimination and macrophage differentiation modulation. The in vivo results show that P@C can inhibit the LPS induced bone destruction in the Escherichia coli infected rat. P@C exhibits superior bone regeneration in Escherichia coli infected rat due to the comprehensive functions of its superior antibacterial property, and its ability of LPS elimination and immunomodulation. P@C can well mimic the functions of AMPs, which provides a novel and effective method for treating the PJI in clinic.

BackgroundAedes aegypti and Aedes albopictus are important vectors of human arboviruses, transmitting arboviral diseases such as yellow fever, dengue, chikungunya and Zika. These two mosquitoes coexist on Hainan Island and the Leizhou Peninsula in China. Over the past 40 years, the distribution of Ae. albopictus has gradually expanded in these areas, while the distribution of Ae. aegypti has declined dramatically mainly due to the ecological changes and some other factors such as heavy use of insecticide indoor based on endophagic bloodfeeding of the species.MethodsThis study focused on the knockdown resistance (kdr) genes of both mosquitoes, investigated their mutations, and analyzed their haplotype and evolutionary diversity combined with population genetic features based on the ND4/ND5 genes to further elucidate the molecular mechanisms underlying the development of insecticide resistance in both mosquitoes.ResultsThree mutations, S989P, V1016G and F1534C, were found to be present in Ae. aegypti populations, and the three mutations occurred synergistically. Multiple mutation types (F1534C/S/L/W) of the F1534 locus are found in Ae. albopictus populations, with the three common mutations F1534C, F1534S and F1534L all having multiple independent origins. The F1534W (TTC/TGG) mutation is thought to have evolved from the F1534L (TTC/TTG) mutation. The F1534S (TTC/TCG) mutation has evolved from the F1534S (TTC/TCC) mutation. The most common form of mutation at the F1534 locus found in this study was S1534C, accounting for 20.97%, which may have evolved from the F1534C mutation. In addition, a new non-synonymous mutation M1524I and 28 synonymous mutations were identified in Ae. albopictus populations. Correlation analysis showed that the genetic diversity of Ae. aegypti and Ae. albopictus populations did not correlate with their kdr haplotype diversity (P>0.05), but strong gene flow between populations may have contributed to the evolution of the kdr gene.ConclusionThe study of kdr gene evolution in the two mosquito species may help to identify the evolutionary trend of insecticide resistance at an early stage and provide a theoretical basis for improving the efficiency of biological vector control and subsequent research into new insecticides.

Rice is the staple food for approximately half of the world’s population. Seed vigour has a crucial impact on the yield, which can be evaluated by germination rate, vigor index and etc. Existing seed vigour testing methods heavily rely on manual inspections that are destructive, time-consuming, and labor-intensive. To address the drawbacks of existing rice seed vigour testing, we proposed a multispectral image-based non-destructive seed germination testing approach. Specifically, we collected multispectral data in 19 wavebands for six rice varieties. Furthermore, we designed an end-to-end pipeline, denoted as MsiFormer (MisFormer cod3e will be available at https://github.com/LiaoYun0x0/MisFormer) by integrating a Yolo-based object detector (trained Yolo v5) and a vision transformer-based vigour testing model, which effectively improved the automation and efficiency of existing techniques. In order to objectively evaluate the performance of the proposed method in this paper, we conduct a comparison between MisFormer and other 3 deep learning methods. The results showed that, MisFormer performed much better with the accuracy of 94.17%, which was 2.5%-18.34% higher than the other 3 deep learning methods. Besides MsiFormer, possibilities of CIELab mediated image analysis of TTC (tetrazolium chloride) staining in rice seed viability and nCDA (normalized canonical discriminant analysis) in rice seed vigour were also discussed, where CIELab L* of TTC staining were negatively correlated with vigor index and germination rate, with Pearson’s correlation coefficient of -0.9874, -0.9802 respectively, and CIELab A* of TTC staining were and positively correlated with vigor index and germination rate, with Pearson’s correlation coefficient of 0.9624, 0.9544 respectively, and CIELab A* of nCDA had Pearson’s correlation coefficient of -0.8866 and -0.9340 with vigor index and germination rate, respectively. Besides testing methods, vigour results within and among variety(ies) showed that, there were great variations among the 6 rice varieties, and mean coefficient of variation (CV) of vigor index of individual seed within a variety reached 64.87%, revealing the high risk of conventional methods in random sampling. Vigour variations had close relationship with wavelengths of 780 nm-970 nm, indicating their value in future research.

Wound healing is one of the major global health concerns in patients with diabetes. Overactivation of pro-inflammatory M1 macrophages is associated with delayed wound healing in diabetes. miR-29ab1 plays a critical role in diabetes-related macrophage inflammation. Hence, inhibition of inflammation and regulation of miR-29 expression have been implicated as new points for skin wound healing. In this study, the traditional Chinese medicine, puerarin, was introduced to construct an injectable and self-healing chitosan@puerarin (C@P) hydrogel. The C@P hydrogel promoted diabetic wound healing and accelerated angiogenesis, which were related to the inhibition of the miR-29 mediated inflammation response. Compared to healthy subjects, miR-29a and miR-29b1 were ectopically increased in the skin wound of the diabetic model, accompanied by upregulated M1-polarization, and elevated levels of IL-1β and TNF-α. Further evaluations by miR-29ab1 knockout mice exhibited superior wound healing and attenuated inflammation. The present results suggested that miR-29ab1 is essential for diabetic wound healing by regulating the inflammatory response. Suppression of miR-29ab1 by the C@P hydrogel has the potential for improving medical approaches for wound repair.

The recent emergence of COVID-19 variants has necessitated the development of new vaccines that stimulate the formation of high levels of neutralizing antibodies against S antigen variants. A new strategy involves the intradermal administration of heterologous vaccines composed of one or two doses of inactivated vaccine and a booster dose with the mutated S1 protein (K-S). Such vaccines improve the immune efficacy by increasing the neutralizing antibody titers and promoting specific T cell responses against five variants of the RBD protein. A viral challenge test with the B.1.617.2 (Delta) variant confirmed that both administration schedules (i.e. “1 + 1” and “2 + 1”) ensured protection against this strain. These results suggest that the aforementioned strategy is effective for protecting against new variants and enhances the anamnestic immune response in the immunized population.

Recent studies have indicated that sequentially administering SARS-CoV-2 vaccines can result in increased antibody and cellular immune responses. In this study, we compared homologous and heterologous immunization strategies following two doses of inactivated vaccines in a mouse model. Our research demonstrates that heterologous sequential immunization resulted in more immune responses displayed in the lymph node germinal center, which induced a greater number of antibody-secreting cells (ASCs), resulting in enhanced humoral and cellular immune responses and increased cross-protection against five variant strains. In further single B-cell analysis, the above findings were supported by the presence of unique B-cell receptor (BCR) repertoires and diversity in CDR3 sequence profiles elicited by a heterologous booster immunization strategy.

Abstract Copy–move forgery poses a significant threat to social life and has aroused much attention in recent years. Although many copy‐move forgery detection (CMFD) methods have been proposed, the most existing CMFD methods are short of adaptability in detecting images, which leads to the limitation on detection effects. To solve this problem, the paper proposes a novel keypoint‐based CMFD method: second‐keypoint matching and double adaptive filtering (SMDAF). Motivated by image matching based on keypoint, the second‐keypoint matching method is designed to match keypoints extracted from copy–move forgery images, which can be used for both the single‐CMFD and the multiple‐CMFD. Then, a double adaptive filter (DAF) based on the AdaLAM algorithm and the KANN‐DBSCAN clustering algorithm to filter wrong keypoint matches adaptively are proposed, according to the distinct distribution of keypoints in each image. Finally, the forgery regions are presented by finding their convex hulls and padding them. Compared with existing methods, extensive experiments show that the SMDAF method significantly provides more efficiency in detecting images under simulated real‐world conditions, has better robustness when facing images with different post‐treatment attacks, and is more effective in distinguishing images that look copy–move forged but are real.

Abstract Allergen-specific immunotherapy (AIT) is the main treatment for allergic diseases. The therapeutic efficacy of AIT has to be improved. Neuropeptides, such as TAFA4, have immune-regulating features. The objective of this study is to promote the efficacy of AIT in experimental allergic rhinitis (AR) by the concurrent use of TAFA chemokine as a family member 4 (TAFA4). In this study, an AR mouse model was developed using ovalbumin (OVA) as the specific antigen. The AR response was assessed in mice after treatment with AIT or/and TAFA4. We found that exposure to TAFA4 activated dendritic cells (DCs) in the airway tissues. Activation of DC by TAFA4 resulted in the expression of IL-10. TAFA4 also promoted the activities of c-Maf inducing protein. The FPR1-MyD88-AKT signal pathway was associated with the TAFA4-induced Il10 expression in the DCs. Co-administration of AIT/TAFA4 attenuated the AR response in mice by inducing antigen-specific Tr1 cells. In conclusion, TAFA4 induces the expression of IL-10 in DCs. Acting as an adjuvant, TAFA4 significantly improves AIT’s therapeutic efficacy against AR by inducing antigen-specific Tr1 cells.

The enzyme N-acetyltransferase NAT10 is a negative regulator of neutrophil pyroptosis and its downregulation contributes to the progress of sepsis by exacerbating pyroptosis via the ULK1-STING-NLRP3 pathway.

Hand, foot and mouth disease is a common acute viral infectious disease that poses a serious threat to the life and health of young children. With the development of an effective inactivated EV71 vaccine, CA16 has become the main pathogen causing HFMD. Effective and safe vaccines against this disease are urgently needed. In our previous study, a bivalent inactivated vaccine was shown to have good immunogenicity and to induce neutralizing antibodies in mice and monkeys. Repeated administration toxicity is a critical safety test in the preclinical evaluation of vaccines. In this study, BALB/c mice were used to evaluate the toxicity of the bivalent vaccine after multiple intradermal administrations. Clinical observation was performed daily, and body weight, food intake, hematological characteristics, serum biochemical parameters, antinuclear antibodies, CD4+/CD8a+ T-cell proportions, bone marrow smear results and pathology results were recorded. The results showed that there was no significant change at the injection site and no adverse reactions related to the vaccine. The bivalent inactivated EV71-CA16 vaccine exhibits good safety in mice, and these results provide a sufficient basis for further clinical trials.

Image matching between the optical and synthetic aperture radar (SAR) is one of the most fundamental problems for earth observation. In recent years, many researchers have used hand-made descriptors with their expertise to find matches between optical and SAR images. However, due to the large nonlinear radiation difference between optical images and SAR images, the image matching becomes very difficult. To deal with the problems, the article proposes an efficient feature matching and position matching algorithm (MatchosNet) based on local deep feature descriptor. First, A new dataset is presented by collecting a large number of corresponding SAR images and optical images. Then a deep convolutional network with dense blocks and cross stage partial networks is designed to generate deep feature descriptors. Next, the hard L2 loss function and ARCpatch loss function are designed to improve matching effect. In addition, on the basis of feature matching, the two-dimensional (2-D) Gaussian function voting algorithm is designed to further match the position of optical images and SAR images of different sizes. Finally, a large number of quantitative experiments show that MatchosNet has a excellent matching effect in feature matching and position matching. The code will be released at: https://github.com/LiaoYun0x0/Feature-Matching-and-Position-Matching-between-Optical-and-SAR.

Because of the relatively limited understanding of coronavirus disease 2019 (COVID-19) pathogenesis, immunological analysis for vaccine development is needed. Mice and macaques were immunized with an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine prepared by two inactivators. Various immunological indexes were tested, and viral challenges were performed on day 7 or 150 after booster immunization in monkeys. This inactivated SARS-CoV-2 vaccine was produced by sequential inactivation with formaldehyde followed by propiolactone. The various antibody responses and specific T cell responses to different viral antigens elicited in immunized animals were maintained for longer than 150 days. This comprehensive immune response could effectively protect vaccinated macaques by inhibiting viral replication in macaques and substantially alleviating immunopathological damage, and no clinical manifestation of immunopathogenicity was observed in immunized individuals during viral challenge. This candidate inactivated vaccine was identified as being effective against SARS-CoV-2 challenge in rhesus macaques.

Due to viral envelope glycoprotein D binding to cellular membrane HVEM receptor, HSV-1 can infect certain dendritic cells, which becomes an event in the viral strategy to interfere with the host’s immune system. We previously generated the HSV-1 mutant strain M6, which produced an attenuated phenotype in mice and rhesus monkeys. The attenuated M6 strain was used to investigate how HSV-1 infection of dendritic cells interferes with both innate and adaptive immunity. Our study showed that dendritic cells membrane HVEM receptors could mediate infection of the wild-type strain and attenuated M6 strain and that dendritic cells infected by both viruses in local tissues of animals exhibited changes in transcriptional profiles associated with innate immune and inflammatory responses. The infection of pDCs and cDCs by the two strains promoted cell differentiation to the CD103+ phenotype, but varied transcriptional profiles were observed, implying a strategy that the HSV-1 wild-type strain interferes with antiviral immunity, probably due to viral modification of the immunological phenotype of dendritic cells during processing and presentation of antigen to T cells, leading to a series of deviations in immune responses, ultimately generating the deficient immune phenotype observed in infected individuals in the clinical.

(1) Background: As the COVID-19 pandemic enters its fourth year, it continues to cause significant morbidity and mortality worldwide. Although various vaccines have been approved and the use of homologous or heterologous boost doses is widely promoted, the impact of vaccine antigen basis, forms, dosages, and administration routes on the duration and spectrum of vaccine-induced immunity against variants remains incompletely understood. (2) Methods: In this study, we investigated the effects of combining a full-length spike mRNA vaccine with a recombinant S1 protein vaccine, using intradermal/intramuscular, homologous/heterologous, and high/low dosage immunization strategies. (3) Results: Over a period of seven months, vaccination with a mutant recombinant S1 protein vaccine based on the full-length spike mRNA vaccine maintained a broadly stable humoral immunity against the wild-type strain, a partially attenuated but broader-spectrum immunity against variant strains, and a comparable level of cellular immunity across all tested strains. Furthermore, intradermal vaccination enhanced the heterologous boosting of the protein vaccine based on the mRNA vaccine. (4) Conclusions: This study provides valuable insights into optimizing vaccination strategies to address the ongoing challenges posed by emerging SARS-CoV-2 variants.

Abstract Background Multiple sclerosis (MS) is a debilitating neurological disease caused by autoimmune destruction of the myelin sheath. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the pathogenesis of MS. We and others have previously demonstrated that IL-17 is critical for the pathogenesis of EAE. The concentration of IL-17 is significantly higher in the sera of MS patients than in healthy controls and correlates with disease activity. Moreover, anti-IL-17 neutralizing antibody demonstrated promising efficacy in a phase II trial in MS patients, further substantiating a key pathogenic role for IL-17 in MS. While Th17 and IL-17 are emerging as a bona fide drivers for neuroinflammation, it remains unclear what effector molecule executes the inflammatory tissue destruction in Th17-driven EAE. Methods By microarray analysis, we found STEAP4 is a downstream molecule of IL-17 signaling in EAE. We then used STEAP4 global knockout mice and STEAP4 conditional knockout mice to test its role in the pathogenesis of EAE. Results Here, we report that the metalloreductase, STEAP4, is a key effector molecule that participates and contributes to the pathogenesis of Th17-mediated neuroinflammation in experimental autoimmune encephalomyelitis. STEAP4 knockout mice displayed delayed onset and reduced severity of EAE induced by active immunization. The reduced disease phenotype was not due to any impact of STEAP4 deficiency on myelin reactive T cells. In contrast, STEAP4 knockout mice were resistant to passively induced EAE, pointing to a role for STEAP4 in the effector stage of EAE. Notably, STEAP4 was only induced the spinal cord of EAE mice that received Th17 cells but not Th1 cells. Consistently, STEAP4 deficiency protected from only Th17 but not Th1-induced EAE. Finally, using Nestin-Cre STEAP4fl/fl mice, we showed that ablation of STEAP4 expression in the resident cells in the central nervous system attenuated disease severity in both active immunization and passive Th17 transfer-induced EAE. Conclusion In this study, we identified STEAP4 as a Th17-specific effector molecule that participates and contributes to the pathogenesis of neuroinflammation, thus potentially provide a novel target for MS therapy.

To clarify the implication of alkane carbon and hydrogen isotopes for the genesis and accumulation of over-mature shale gas, we carried out a comparative study on Longmaxi shale gases from eight blocks in the Upper Yangtze area. The results show that the δ13CCH4, δ13CC2H6, and δ13CC3H8 of Longmaxi shale gas are all positively correlated with Ro. According to the distribution model of δ13C with thermal maturity, the Longmaxi shale gas lies in the reversal stage. Shale gas is a mixture of the kerogen cracking gas and secondary cracking gas, and the mixing ratio of the two cracking gas can be estimated by isotopic fractionation experiments of thermogenic gas. The proportion of secondary cracking gas in the shale gas of the Longmaxi Formation ranges from 33 to 72%. The increase of secondary cracking gas with lower δ13C would reduce the carbon isotope of the shale gas. The δ13CC2H6 and δ13CC3H8 have acute sensitivity to the occurrence of secondary cracking gas, hence they can be used as potential indicators of shale gas content. The decline of gas generation capacity, the reduction of micropores, and the destruction of tectonic movement are the considerable factors leading to the decrease of gas content in high-maturity shale.

The aim of this study was to describe radiography, computed tomography (CT), and magnetic resonance imaging (MRI) findings of enzootic nasal tumors in goats infected with enzootic nasal tumor viruses. Five of six goats with a mean age of 2 years, showed clinical signs of respiratory disease. Head radiographs showed increased density of the unilateral or bilateral nasal cavity in four goats, and a CT scan showed that the space-occupying lesion of the nasal cavity originated from the ethmoid bone and was enhanced homogeneously postcontrast in all goats. The nasal concha was destroyed and the paranasal sinus mucosa was thickened and filled with fluid in some goats. On MRI, the mass exhibited equal or slightly higher signal intensity on T2 weighted images, equal signal intensity on T1 weighted images, a high signal on fluid-attenuated inversion recovery images and heterogeneous enhancement postcontrast. After dissection, histopathological examination of the mass and virus genome detection of the nasal secretions confirmed that the intranasal mass was a low-grade adenocarcinoma and that the goats were infected with enzootic nasal tumor virus type 2. In conclusion, CT and MRI have high diagnostic values for enzootic nasal tumors because they match the postmortem findings and are more accurate than radiography.

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.

Neutralizing antibodies in the subjects of an inactivated SARS-CoV-2 vaccine clinical trial showed a decreasing trend over months. An investigation studying the third immunization suggested that the waning of neutralizing antibodies in individuals administered two doses of inactivated vaccine does not mean the disappearance of immunity.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike (S) protein is a critical viral antigenic protein that enables the production of neutralizing antibodies, while other structural proteins, including the membrane (M), nucleocapsid (N) and envelope (E) proteins, have unclear roles in antiviral immunity. In this study, S1, S2, M, N and E proteins were expressed in 16HBE cells to explore the characteristics of the resultant innate immune response. Furthermore, peripheral blood mononuclear cells (PBMCs) from mice immunized with two doses of inactivated SARS-CoV-2 vaccine or two doses of mRNA vaccine were isolated and stimulated by these five proteins to evaluate the corresponding specific T-cell immune response. In addition, the levels of humoral immunity induced by two-dose inactivated vaccine priming followed by mRNA vaccine boosting, two homologous inactivated vaccine doses and two homologous mRNA vaccine doses in immunized mice were compared. Our results suggested that viral structural proteins can activate the innate immune response and elicit a specific T-cell response in mice immunized with the inactivated vaccine. However, the existence of the specific T-cell response against M, N and E is seemingly insufficient to improve the level of humoral immunity.

Circulating cytokines and chemokines play critical roles in hepatitis B virus (HBV) infection. Here, we explored the effects of proinflammatory and anti-inflammatory effector molecules on HBV progression, e antigen seroconversion, and liver function. Our results showed that circulating interleukin (IL)-17 may be helpful in HBV spontaneous clearance [odds ratio OR=1.468, 95%confidence interval CI=1.080–1.995, P=0.014] and protective against HBV-related hepatoma development (OR=0.933, 95%CI=0.910–0.957, P

Summary: Coordination between osteogenesis and angiogenesis is required for bone homeostasis. Here, we show that miR-29cb2 is a bone-specific miRNA and plays critical roles on angiogenesis-osteogenesis coupling during bone remodeling. Mice with deletion of miR-29cb2 exhibit osteopenic phenotypes and osteoblast impairment, accompanied by pronounced decreases in specific H vessels. The decrease in bone miR-29cb2 was associated with pathological ovariectomy stimuli. Mechanistically, hypoxia-inducible factor (HIF)-3α, as a target for miR-29cb2, inhibits HIF-1α activity by competitively bonding with HIF-1β. Notably, miR-29cb2 in peripheral blood (PB) nearly is undetectable in sham and significantly increases in ovariectomy mice. Further evaluation from osteoporosis patients demonstrates similar signatures. ROC analysis shows miR-29cb2 in PB has higher sensitivity and specificity for diagnosing osteoporosis when compared with four clinical biomarkers. Collectively, these findings reveal that miR-29cb2 is essential for bone remodeling by inhibiting HIF-3α and elevated bone-specific miR-29cb2 in PB, which may be a promising biomarker for bone loss

Palygorskite (Pal), a clay nanoparticle, has been demonstrated to be a vehicle for drug delivery. Copper has antibacterial properties, and zinc is an essential micronutrient for intestinal health in animals and humans. However, whether copper/zinc-modified Pal (Cu/Zn-Pal) can protect chickens from Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) infection remains unclear. In this study, three complexes (Cu/Zn-Pal-1, Cu/Zn-Pal-2, and Cu/Zn-Pal-3) were prepared, and Cu/Zn-Pal-1 was shown to be the most effective at inhibiting the growth of S. Typhimurium in vitro, whereas natural Pal alone had no inhibitory effect. In vivo, Cu/Zn-Pal-1 reduced S. Typhimurium colonization in the intestine of infected chickens and relieved S. Typhimurium-induced organ and intestinal mucosal barrier damage. Moreover, this reduction in Salmonella load attenuated intestinal inflammation and the oxidative stress response in challenged chickens. Additionally, Cu/Zn-Pal-1 modulated the intestinal microbiota in infected chickens, which was characterized by the reduced abundance of Firmicutes and the increased abundance of Proteobacteria and Bacteroidetes. Our results indicated that the Cu/Zn-Pal-1 complex may be an effective feed supplement for reducing S. Typhimurium colonization of the gut.

STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.

With the rapid development of nanotechnology, the bio-barcode assay (BCA), as a new diagnostic tool, has been gradually applied to the detection of protein and nucleic acid targets and small-molecule compounds. BCA has the advantages of high sensitivity, short detection time, simple operation, low cost, good repeatability and good linear relationship between detection results. However, bio-barcode technology is not yet fully formed as a complete detection system, and the detection process in all aspects and stages is unstable. Therefore, studying the optimal reaction conditions, optimizing the experimental steps, exploring the multi-residue detection of small-molecule substances, and preparing immuno-bio-barcode kits are important research directions for the standardization and commercialization of BCA. The main theme of this review was to describe the principle of BCA, provide a comparison of its application, and introduce the single-residue and multi-residue detection of macromolecules and single-residue detection of small molecules. We also compared it with other detection methods, summarized its feasibility and limitations, expecting that with further improvement and development, the technique can be more widely used in the field of stable small-molecule and multi-residue detection. Keywords: Bio-barcode assay, Protein, Application, Multi-residue detection of macromolecules, Single-molecule single-residue detection

The novel coronavirus (SARS-CoV-2) epidemic continues to be a global public crisis affecting human health. Many research groups are developing different types of vaccines to suppress the spread of SARS-CoV-2, and some vaccines have entered phase III clinical trials and have been rapidly implemented. Whether multiple antigen matches are necessary to induce a better immune response remains unclear. To address this question, this study tested the immunogenicity and protective effects of a SARS-CoV-2 recombinant S and N peptide vaccine in the Syrian golden hamster model. This experiment was based on two immunization methods: intradermal and intramuscular administration. Immunized hamsters were challenged with live SARS-CoV-2 14 days after booster immunization. Clinical symptoms were observed daily, and the antibody titer and viral load in each tissue were detected. The results showed that immunization of golden hamsters with the SARS-CoV-2 structural protein S alone or in combination with the N protein through different routes induced antibody responses, whereas immunization with the N protein alone did not. However, although the immunized hamsters exhibited partial alleviation of clinical symptoms when challenged with the virus, neither vaccine effectively inhibited the proliferation and replication of the challenging virus. In addition, the pathological damage in the immunized hamsters was similar to that in the control hamsters. Interestingly, the neutralizing antibody levels of all groups including immunized and nonimmunized animals increased significantly after viral challenge. In conclusion, the immune response induced by the experimental S and N polypeptide vaccines had no significant ability to prevent viral infection and pathogenicity in golden hamsters.

The dolomitization of carbonate rocks has always been a hot topic in the study of the dolomite reservoir. In this study, the genesis of Cambrian dolomite in the Bachu area, Tarim Basin, was assessed through petrographic examinations, isotope compositions (C, O, and Sr), trace and rare earth elements, and fluid inclusion microthermometry. Microscopic analysis revealed three types of dolomites: very fine-crystalline, nonplanar dolomite (D1); fine-crystalline, nonplanar to planar-s dolomite (D2); and medium- to coarse-crystalline, planar-e to planar-s dolomite (D3). D1 dolomite exhibits well-preserved original sedimentary features, such as algal laminae, stromatolite, and evaporite streak, and is characterized by the 87Sr/86Sr value and δ18O value in equilibrium with the coeval seawater, its high Sr and Na content, and its low Mn content. This indicates that D1 dolomite is primarily a penecontemporaneous dolomite in tidal flat or lagoon environments, and its dolomitizing fluid is mainly evaporated mesosaline to penesaline seawater. D2 dolomite shows ghosts of precursor particles; features δ13C values in equilibrium with the coeval seawater, high 87Sr/86Sr values, low Sr content, and positive Eu anomaly; and is widely distributed close to stylolite. This illustrates that D2 dolomite was principally formed by seepage–reflux dolomitization, and is closely related to hydrothermal activity and pressure dissolution. D3 dolomite displays a crystal texture with a cloudy core and compositional zoning, and the original sedimentary fabrics cannot be identified. It has similar δ13C values and REE patterns to the calcite precipitated from coeval seawater, high 87Sr/86Sr values, low Sr contents and high Mn/Sr ratios, which suggests that D3 dolomite is chiefly related to the recrystallization of the precursor dolomite during the deep burial stage, and the deep circular brine provides Mg ions through the fluid–rock reaction. This study shows that the Cambrian dolomite in the Bachu area is mainly formed in the coeval seawater environment during the penecontemporaneous and shallow burial stages, and has extensively suffered from recrystallization and burial diagenesis due to long-term deep burial, which was further strengthened in the fracture-enriched area.

Objective: We constructed two DNA vaccines containing the receptor-binding domain (RBD) genes of multiple SARS-CoV-2 variants and used them in combination with inactivated vaccines in a variety of different protocols to explore potential novel immunization strategies against SARS-CoV-2 variants. Methods: Two DNA vaccine candidates with different signal peptides (namely, secreted and membrane signal peptides) and RBD protein genes of different SARS-CoV-2 strains (Wuhan-Hu-1, B.1.351, B.1.617.2, C.37) were used. Four different combinations of DNA and inactivated vaccines were tested, namely, Group A: three doses of DNA vaccine; B: three doses of DNA vaccine and one dose of inactivated vaccine; C: two doses of inactivated vaccine and one dose of DNA vaccine; and D: coadministration of DNA and inactivated vaccines in two doses. Subgroups were grouped according to the signal peptide used (subgroup 1 contained secreted signal peptides, and subgroup 2 contained membrane signal peptides). The in vitro expression of the DNA vaccines, the humoral and cellular immunity responses of the immunized mice, the immune cell population changes in local lymph nodes, and proinflammatory cytokine levels in serum samples were evaluated. Results: The antibody responses and cellular immunity in Group A were weak for all SARS-CoV-2 strains; for Group B, there was a great enhancement of neutralizing antibody (Nab) titers against the B.1.617.2 variant strain. Group C showed a significant increase in antibody responses (NAb titers against the Wuhan-Hu-1 strain were 768 and 1154 for Group C1 and Group C2, respectively, versus 576) and cellular immune responses, especially for variant B.1.617.2 (3240 (p < 0.001) and 2430 (p < 0.05) for Group C1 and Group C2, versus 450); Group D showed an improvement in immunogenicity. Group C induced higher levels of multiple cytokines. Conclusion: The DNA vaccine candidates we constructed, administered as boosters, could enhance the humoral and cellular immune responses of inactivated vaccines against COVID-19, especially for B.1.617.2.

Herpes simplex virus type 2 (HSV2), a pathogen that causes genital herpes lesions, interferes with the host immune system via various known and unknown mechanisms. This virus has been used to study viral antigenic composition. Convalescent serum from HSV2-infected patients was used to identify viral antigens via 2-D protein electrophoresis and immunoblotting. The serum predominantly recognized several capsid scaffold proteins encoded by gene UL26.5, mainly ICP35. This protein has been primarily reported to function temporarily in viral assembly but is not expressed in mature virus particles. Further immunological studies suggested that this protein elicits specific antibody and cytotoxic T lymphocyte (CTL) responses in mice, but these responses do not result in a clinical protective effect in response to HSV2 challenge. The data suggested that immunodominance of ICP35 might be used to design an integrated antigen with other viral glycoproteins.

A rapid, ultra-sensitive and simple fluorescence immunoassay (FLISA) on CdSe/ZnS Quantum dots (QDs) for recognition pesticide triazophos have been established. In this assay, the immunoassay uses (CdSe/ZnS) Quantum dots (QDs) as a probe that carries monoclonal antibody (mAb). The free triazophos and OVA-haptens were competed for binding the mAb on the surface of the QDs. Therefore, the concentration of TRIAZ can get by calculation of the detection of fluorescence value. The assay has a linear response in the 10 ng L−1–25 μg L−1 TRIAZ concentration range, and limit of detection (IC10) was 0.508 ng L−1. The recovery rate in the case of spiked samples ranges from 82.6% to 96.6%, and the RSD is

Herpes simplex virus type 1 (HSV-1), an α subgroup member of the human herpesvirus family, infects cells via the binding of its various envelope glycoproteins to cellular membrane receptors, one of which is herpes virus entry mediator (HVEM), expressed on dendritic cells. Here, HVEM gene-deficient mice were used to investigate the immunologic effect elicited by the HSV-1 infection of dendritic cells. Dendritic cells expressing the surface marker CD11c showed an abnormal biological phenotype, including the altered transcription of various immune signaling molecules and inflammatory factors associated with innate immunity after viral replication. Furthermore, the viral infection of dendritic cells interfered with dendritic cell function in the lymph nodes, where these cells normally play roles in activating the T-cell response. Additionally, the mild clinicopathological manifestations observed during the acute phase of HSV-1 infection were associated with viral replication in dendritic cells.

The COVID-19 has emerged as an epidemic, causing severe pneumonia with a high infection rate globally. To better understand the pathogenesis caused by SARS-CoV-2, we developed a rhesus macaque model to mimic natural infection via the nasal route, resulting in the SARS-CoV-2 virus shedding in the nose and stool up to 27 days. Importantly, we observed the pathological progression of marked interstitial pneumonia in the infected animals on 5-7 dpi, with virus dissemination widely occurring in the lower respiratory tract and lymph nodes, and viral RNA was consistently detected from 5 to 21 dpi. During the infection period, the kinetics response of T cells was revealed to contribute to COVID-19 progression. Our findings implied that the antiviral response of T cells was suppressed after 3 days post infection, which might be related to increases in the Treg cell population in PBMCs. Moreover, two waves of the enhanced production of cytokines (TGF-α, IL-4, IL-6, GM-CSF, IL-10, IL-15, IL-1β), chemokines (MCP-1/CCL2, IL-8/CXCL8, and MIP-1β/CCL4) were detected in lung tissue. Our data collected from this model suggested that T cell response and cytokine/chemokine changes in lung should be considered as evaluation parameters for COVID-19 treatment and vaccine development, besides of observation of virus shedding and pathological analysis.

Herpes simplex virus type 1 (HSV1) is a complicated structural agent with a sophisticated transcription process and a high infection rate. A vaccine against HSV1 is urgently needed. As multiple viral-encoded proteins, including structural and nonstructural proteins, contribute to immune response stimulation, an attenuated or deficient HSV1 vaccine may be relatively reliable. Advances in genomic modification technologies provide reliable means of constructing various HSV vaccine candidates. Based on our previous work, an M6 mutant with mutations in the UL7, UL41, LAT, Us3, Us11 and Us12 genes was established. The mutant exhibited low proliferation in cells and an attenuated phenotype in an animal model. Furthermore, in mice and rhesus monkeys, the mutant can induce remarkable serum neutralizing antibody titers and T cell activation and protect against HSV1 challenge by impeding viral replication, dissemination and pathogenesis.

Objective: This study aimed to investigate the associations between previous TORCH infection (cytomegalovirus, toxoplasmosis, herpes simplex virus, and rubella) with pregnancy and neonatal outcomes in couples undergoing IVF/ICSI-ET.Materials and Methods: A total of 18,074 couples underwent fresh IVF/ICSI-ET (in vitro fertilization/intracytoplasmic sperm injection–embryo transfer) cycles were included in our analyses. TORCH infection status was determined by serological confirmation of cytomegalovirus, toxoplasmosis, herpes simplex virus, and rubella IgG in the absence of IgM antibodies. Clinical pregnancy, ectopic pregnancy, miscarriage, live birth, preterm birth, congenital malformation, and perinatal death were evaluated in both infection and non-infection group. Multivariate logistic regression was applied to calculate odds ratio.Results: Previous toxoplasmosis infection is associated with a significantly decreased preterm birth rate [P = 0.045, OR = 0.755 (95% CI, 0.571–0.997), Adjusted OR = 0.749 (95%CI, 0.566–0.991)]. No differences in clinical pregnancy, ectopic pregnancy, miscarriage, and perinatal death were observed between the corresponding TORCH infection group [IgM (–) IgG(+)] and the non-infection group [IgM (–) IgG (–)].Conclusions: Previous TORCH infections were not associated with adverse pregnancy and neonatal outcomes in IVF/ICSI-ET overall, and toxoplasmosis infection might be associated with a lower preterm birth rate in patients underwent IVF/ICSI-ET. The necessity of TORCH IgG screening in IVF procedure might need re-evaluation, and further cost-effective analysis might be helpful for the clinical management strategy.

Background Colorectal cancer (CRC) is the third most common cancer in the world. The present study is aimed at identifying hub genes associated with the progression of CRC. Method The data of the patients with CRC were obtained from the Gene Expression Omnibus (GEO) database and assessed by weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses performed in R by WGCNA, several hub genes that regulate the mechanism of tumorigenesis in CRC were identified. Differentially expressed genes in the data sets GSE28000 and GSE42284 were used to construct a co-expression network for WGCNA. The yellow, black and blue modules associated with CRC level were filtered. Combining the co-expression network and the PPI network, 15 candidate hub genes were screened. Results After validation using the TCGA-COAD dataset, a total of 10 hub genes (MT1X, MT1G, MT2A, CXCL8, IL1B, CXCL5, CXCL11, IL10RA, GZMB, KIT) closely related to the progression of CRC were identified. The expressions of MT1G, CXCL8, IL1B, CXCL5, CXCL11 and GZMB in CRC tissues were higher than normal tissues (p-value < 0.05). The expressions of MT1X, MT2A, IL10RA and KIT in CRC tissues were lower than normal tissues (p-value < 0.05). Conclusions By combinating with a series of methods including GO enrichment analysis, KEGG pathway analysis, PPI network analysis and gene co-expression network analysis, we identified 10 hub genes that were associated with the progression of CRC.

Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review: flucloxacillin, piperacillin/tazobactam, ceftriaxone, ceftazidime/avibactam, cefepime, ceftolozane/tazobactam, sulbactam, meropenem, imipenem, panipenem, biapenem, ertapenem, doripenem, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, azithromycin, tigecycline, polymyxin B, colistin, vancomycin, teicoplanin, linezolid, daptomycin, sulfamethoxazole/trimethoprim, fluconazole, voriconazole, posaconzole, caspofungin, micafungin, amphotericin B, acyclovir, ganciclovir, oseltamivir, and peramivir.

In a social network, influence maximization is the problem of identifying a set of users that own the maximum influence ability across the network. In this paper, a novel credit distribution (CD)-based model, termed as the multiaction CD (mCD) model, is introduced to quantify the influence ability of each user, which works with practical datasets where one type of action could be recorded for multiple times. Based on this model, influence maximization is formulated as a submodular maximization problem under a general knapsack constraint, which is NP hard. An efficient streaming algorithm with one-round scan over the user set is developed to find a suboptimal solution. Specifically, we first solve a special case of knapsack constraints, i.e., a cardinality constraint, and show that the developed streaming algorithm can achieve ((1/2) - ϵ) approximation of the optimality. Furthermore, for the general knapsack case, we show that the modified streaming algorithm can achieve ((1/3) - ϵ) approximation of the optimality. Finally, experiments are conducted over real Twitter dataset and demonstrate that the mCD model enjoys high accuracy compared to the conventional CD model in estimating the total number of people who get influenced in a social network. Moreover, through the comparison to the conventional CD, non-CD models, and the mCD model with the greedy algorithm on the performance of the influence maximization problem, we show the effectiveness and efficiency of the proposed mCD model with the streaming algorithm.

Abstract Background The Haemophilus influenzae type b (Hib) conjugate vaccine has been widely used in children to prevent invasive Hib disease because of its strong immunogenicity and antibody response induction relative to the capsular polysaccharide (CPS) antigen. The data from vaccine studies suggest that the conjugate vaccine contains carrier proteins that enhance and/or regulate the antigen’s immunogenicity, but the mechanism of this enhancement remains unclear. Methods To explore the immunological role of the conjugate vaccine, we compared the immune responses and gene profiles of rhesus macaques after immunization with CPS, carrier protein tetanus toxoid (TT) or conjugate vaccine. Results A distinct immune response was induced by the Hib conjugate vaccine but not by CPS or carrier protein TT. The genes that were dynamically regulated in conjunction with the macaque immune responses to the conjugate vaccine were investigated. Conclusions We propose that these genes are involved in the induction of specific immunity that is characterized by the appearance and maintenance of antibodies against Hib.

Abstract Background ANFH is a major health problem, to which long lasting and definitive treatments are lacking. The aim of this study is to study RNA alterations attributed to cortisol-induced ANFH. Methods Rat models were stratified into three groups: in vitro group (n = 20) for molecular biological assays, control group (n = 3), and ANFH group induced using lipopolysaccharide and dexamethasone (n = 3). Bone marrow-derived endothelial progenitor cells (BM-EPCs) were extracted from the rats. An RNA expression array was performed on BM-EPCs, and enriched genes were subject to pathway analysis. In vitro studies following findings of array results were also performed using the isolated BM-EPCs. Results Significant alterations in mammalian target of rapamycin (mTOR) and HIF signaling pathways were identified in BM-EPCs of ANFH. By applying cortisol and dexamethasone to BM-EPCs, significant changes in mTOR and HIF elements were identified. The alteration of HIF pathways appeared to be downstream of mTOR signaling. Glucocorticoid receptor (GR) expression was related to glucocorticoid-dependent mRNA expression of mTOR/HIF genes. mTOR-dependent angiogenesis but not anabolism was the target of GR in ANFH. Inhibition of mTOR signaling also induced apoptosis of BM-EPCs via CHOP-dependent DR5 induction in response to GR stimulation. Conclusion Decreased mTOR signaling in response to GR stimulation leading to downregulated HIF pathway as well as increased apoptosis could be the pathophysiology.